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Sutanto H, Adytia GJ, Fetarayani D. Hyper IgE Syndrome: Bridging the Gap Between Immunodeficiency, Atopy, and Allergic Diseases. Curr Allergy Asthma Rep 2025; 25:17. [PMID: 40082265 DOI: 10.1007/s11882-025-01196-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/19/2025] [Indexed: 03/16/2025]
Abstract
PURPOSE OF REVIEW It seeks to answer key questions about the molecular and cellular mechanisms underlying Hyper IgE Syndrome (HIES), the genetic mutations responsible, and their contributions to both immunodeficiency and allergic manifestations. Additionally, it aims to explore diagnostic strategies and therapeutic approaches that address these overlapping domains, thereby improving disease management. RECENT FINDINGS Recent research has identified several pivotal genetic mutations, including those in STAT3, DOCK8, and PGM3, which play critical roles in disrupting immune pathways such as Th17 differentiation and IgE regulation. These molecular defects have been linked to the hallmark features of HIES, including recurrent infections and elevated serum IgE levels, as well as its overlap with atopic conditions like eczema, asthma, and food allergies. Advances in diagnostic tools, such as biomarker identification and genetic testing, have improved the differentiation of HIES from more common atopic disorders. Therapeutic advancements, including the use of targeted biologics and interventions addressing both immunodeficiency and allergic symptoms, have shown promise in enhancing patient outcomes. This review highlights the role of specific genetic mutations in shaping the clinical and immunological phenotype of HIES. Key takeaways include the necessity of integrating molecular insights with clinical observations for accurate diagnosis and the potential of emerging targeted therapies to address both immunological and allergic aspects of the syndrome.
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Affiliation(s)
- Henry Sutanto
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Galih Januar Adytia
- Internal Medicine Study Program, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Deasy Fetarayani
- Department of Internal Medicine, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia.
- Division of Allergy and Clinical Immunology, Department of Internal Medicine, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.
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2
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Li SY, Cao W, Ge Y, Lvy W, Liu YP, Qin L. Whole-exome sequencing assists in the diagnosis of hyperimmunoglobulin E syndrome: Insights into dual genetic abnormalities. Heliyon 2025; 11:e42408. [PMID: 40028518 PMCID: PMC11870154 DOI: 10.1016/j.heliyon.2025.e42408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 01/06/2025] [Accepted: 01/30/2025] [Indexed: 03/05/2025] Open
Abstract
Hyperimmunoglobulin E syndrome (HIES) is a rare primary immunodeficiency disorder characterized by recurrent infections, severe eczema, and elevated serum immunoglobulin E (IgE) levels. Genetic testing traditionally focuses on known genes such as STAT3 and DOCK8, responsible for the majority of autosomal-dominant (AD-HIES) and autosomal-recessive (AR-HIES) cases, respectively. However, a significant subset of patients with HIES-like symptoms remain genetically unexplained. Whole-exome sequencing (WES) has emerged as a transformative diagnostic tool, enabling the identification of both novel and incidental genetic mutations. This report highlights the role of WES in diagnosis of AD-HIES, showcasing its utility in detecting a STAT3 mutation while revealing a concurrent BRCA2 pathogenic variant. While the STAT3 mutation confirmed the diagnosis of AD-HIES, the incidental BRCA2 finding underscores the importance of genetic counseling and long-term surveillance.
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Affiliation(s)
- Si-yuan Li
- Department of Hematology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Cao
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ying Ge
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Wei Lvy
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ya-ping Liu
- Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ling Qin
- Department of Infectious Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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3
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AlYafie R, Velayutham D, van Panhuys N, Jithesh PV. The genetics of hyper IgE syndromes. Front Immunol 2025; 16:1516068. [PMID: 40040707 PMCID: PMC11876172 DOI: 10.3389/fimmu.2025.1516068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 01/29/2025] [Indexed: 03/06/2025] Open
Abstract
Hyper IgE syndromes (HIES) form a rare group of primary immunodeficiency disorders (PIDs) distinguished by persistent skin abscesses, dermatitis, allergies, and infections, in addition to their characteristic high serum IgE levels. Autosomal dominant (AD) and autosomal recessive (AR) genetic defects have been reported in HIES. From a clinical perspective, AD-HIES cases generally exhibit several non-immunologic features, including connective tissue, dental and skeletal abnormalities, whilst AR-HIES conditions have a higher incidence of neurologic complications and cutaneous viral infections. Genetic defects associated with HIES lead to impaired immune signaling, affecting pathways crucial for immune cell development, function, and immune response to pathogens/allergens. As a result, HIES patients are predisposed to recurrent bacterial and/or fungal infections, as well as atopic allergic responses. In many cases, the exact biological mechanisms responsible for the variations observed in the clinical phenotypes between the two inherited forms of HIES are still unclear. In this review, we describe the genetic basis of HIES with a distinction between the AR-HIES and AD-HIES forms, to better comprehend the different underlying molecular mechanisms, a distinction which is imperative for the accurate diagnosis, management, and development of targeted therapies for HIES patients.
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Affiliation(s)
- Randa AlYafie
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
- Laboratory of Immunoregulation, Research Department, Sidra Medicine, Doha, Qatar
| | - Dinesh Velayutham
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
| | - Nicholas van Panhuys
- College of Health and Life Sciences, Hamad bin Khalifa University, Doha, Qatar
- Laboratory of Immunoregulation, Research Department, Sidra Medicine, Doha, Qatar
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Trombello S, Jarisch A, Willasch A, Rettinger E, Fekadu-Siebald J, Holzinger D, Adelmann R, Bader P, Bakhtiar S. Case report: Advanced age at transplantation and pre-emptive treatment with dupilumab in DOCK8 deficiency. Front Immunol 2025; 15:1507494. [PMID: 39936153 PMCID: PMC11810938 DOI: 10.3389/fimmu.2024.1507494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2024] [Accepted: 12/02/2024] [Indexed: 02/13/2025] Open
Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency (CID) due to biallelic mutations in the gene encoding DOCK8. Major clinical phenomena are recurrent severe infections of the lungs and skin, atopic eczema, and predisposition to malignancy leading to a poor prognosis. Typical findings include highly elevated IgE and eosinophilia. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is indicated as the only curative treatment option. We present a patient with advanced disease undergoing alloHSCT at the age of 11 years after individualized pre-treatment using dupilumab and rituximab resulting in a decrease in IgE levels and clinical improvement of the skin condition. Additionally, in a review of the literature, we summarize morbidity and outcome in DOCK8-deficient patients older than 8 years of age receiving alloHSCT. Life-threatening infections, malignancy, and disease-related complications with organ damage pre-transplant are challenging in older DOCK8-deficient patients. The therapeutic role of dupilumab in DOCK8 deficiency should be evaluated in larger studies.
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Affiliation(s)
- Sophia Trombello
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
- Children’s Hospital, Heidelberg University Hospital, Heidelberg, Germany
| | - Andrea Jarisch
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Andre Willasch
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Eva Rettinger
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Julia Fekadu-Siebald
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
- Department of Applied Health Sciences, University of Applied Sciences Bochum, Bochum, Germany
| | - Roland Adelmann
- Department for Children and Adolescents Medicine, Hospital Oberberg, Gummersbach, Germany
| | - Peter Bader
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Shahrzad Bakhtiar
- Division for Stem Cell Transplantation and Immunology, Department for Pediatrics, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
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5
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Freeman AF, Gonzalez CE, Yates B, Cole K, Little L, Flannelly E, Steinberg SM, Mo G, Piette N, Hughes TE, Cuellar-Rodriguez J, Gea-Banacloche J, Heller T, Hammoud DA, Holland SM, Kong HH, Young FD, Jing H, Kayaoglu B, Su HC, Pai SY, Hickstein DD, Shah NN. Hematopoietic cell transplantation for DOCK8 deficiency: Results from a prospective clinical trial. J Allergy Clin Immunol 2025; 155:176-187. [PMID: 39233015 DOI: 10.1016/j.jaci.2024.08.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2024] [Revised: 08/02/2024] [Accepted: 08/07/2024] [Indexed: 09/06/2024]
Abstract
BACKGROUND DOCK8 deficiency is a primary immunodeficiency in which allogeneic hematopoietic cell transplantation (HCT) represents the only known cure. We tested the ability of a busulfan-based regimen to achieve reliable engraftment and high levels of donor chimerism with acceptable toxicity in a prospective clinical trial in DOCK8 deficiency. OBJECTIVES To both evaluate the ability of HCT to reverse the clinical phenotype and to correct the immunologic abnormalities by 1 year post HCT. METHODS We conducted a prospective HCT trial for recipients with DOCK8 deficiency. Subjects were recruited from October 5, 2010, to December 30, 2022. Donor sources included fully matched related and unrelated donors and haploidentical donors. The reduced toxicity, myeloablative conditioning regimen contained no serotherapy. Graft-versus-host disease (GVHD) prophylaxis included either a calcineurin inhibitor with methotrexate or post-HCT cyclophosphamide (PT/Cy) followed by tacrolimus and mycophenolate mofetil. The trial was later amended to study PT/Cy in all patients. (Pilot Study of Reduced-Intensity Hematopoietic Stem Cell Transplant of DOCK8 [NCT01176006].) RESULTS: Thirty-six subjects, both children and adults (median age 16.4 years), underwent HCT for DOCK8 deficiency. Most patients, 33 of 36 (92%), achieved full (≥98%) donor chimerism in whole blood as early as day +30. With a median potential follow-up of 7.4 years, 29 (80.6%) were alive with no evidence of new DOCK8 deficiency-related complications. PT/Cy was effective in reducing the risk of acute GVHD in patients who had received matched unrelated donor and haploidentical transplants, but it was associated with transient delays in immune-reconstitution and hemorrhagic cystitis. CONCLUSIONS A busulfan-based HCT regimen using PT/Cy for GVHD prophylaxis and a broad range of donor types and hematopoietic cell sources were well tolerated, leading to the reversal of the clinical immunophenotype.
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Affiliation(s)
- Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Corina E Gonzalez
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md.
| | - Bonnie Yates
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | - Kristen Cole
- Transplant and Cell Therapy Program, Clinical Center, Bethesda, Md
| | - Lauren Little
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | - Erin Flannelly
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Seth M Steinberg
- Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Md
| | - George Mo
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
| | | | | | - Jennifer Cuellar-Rodriguez
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Juan Gea-Banacloche
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Theo Heller
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Md
| | - Dima A Hammoud
- Center for Infectious Disease Imaging, Radiology and Imaging Sciences, Clinical Center, Bethesda, Md
| | - Steve M Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Heidi H Kong
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md
| | - Fernanda D Young
- Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Huie Jing
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Basak Kayaoglu
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Md
| | - Sung-Yun Pai
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Dennis D Hickstein
- Immune-Deficiency Cellular Therapy Program, National Cancer Institute, Bethesda, Md
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Md
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Singh N, Ranganath P, Jayaram A, Jhawar P, Kotecha U, Janardhanan J, Kumar H, Sudheer KA, Ali SMN, Arigela K, Ginigeri C, Bhattad S. Clinical and molecular profile of 20 patients with DOCK8 deficiency-a single-center experience from Southern India. Immunol Res 2024; 73:8. [PMID: 39666233 DOI: 10.1007/s12026-024-09571-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 10/21/2024] [Indexed: 12/13/2024]
Abstract
DOCK8 deficiency is the most common cause of autosomal recessive hyper-IgE syndrome (AR-HIES). The clinical spectrum is wide resulting in combined immunodeficiency, atopy, autoimmunity, and malignancies. To study the clinical and molecular profile of 20 patients with DOCK8 deficiency. Four hundred and eight patients with various inborn errors of immunity (IEIs) were diagnosed in the Pediatric Immunology Unit of our hospital during the study period of February 2017 to August 2023. Based on the clinical and immunological phenotype, DOCK8 deficiency was suspected in 31 patients. Genetic studies confirmed DOCK8 deficiency in 20 patients, and their profile was analyzed in detail. Twenty patients from 17 kindreds were diagnosed with DOCK8 deficiency. The female-to-male ratio was 1.2:1. The mean age at onset of symptoms and diagnosis was 9.8 and 69.8 months, respectively. Thirteen out of 17 families (76%) reported consanguinity. Eczema was the presenting manifestation in 19 patients (95%). Mucocutaneous manifestations included oromucosal hyperpigmentation (n = 8), scalp seborrhoea (n = 2), psoriasis (n = 2), and alopecia (n = 1). The spectrum of infections included pneumonia (n = 14), otitis media (n = 6), gastrointestinal infections (n = 6), cutaneous viral infections (n = 5), oral candidiasis (n = 4), and meningoencephalitis (n = 2). Three patients had developed bronchiectasis. Four patients had autoimmune manifestations including autoimmune hemolytic anemia (n = 2) and vasculitis (n = 2). The whole exome sequencing showed deletions (8 kindreds) as the most common mutation in the DOCK8 gene. Overall, 11 of these mutations were novel. Ten patients were on monthly intravenous immunoglobulin therapy and antibiotic prophylaxis at the time of writing this paper. Three patients underwent hematopoietic stem cell transplants elsewhere, two of whom succumbed to post-transplant complications and one is doing well. Nine patients died during the study period. We present one of the largest single-center experiences on DOCK8 deficiency from India. A significant delay in the diagnosis contributed to poor outcomes in our cohort.
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Affiliation(s)
- Neha Singh
- Paediatric Immunology and Rheumatology Unit, Aster CMI Hospital, Bengaluru, India
| | - Priya Ranganath
- Clinical Genetics, Neuberg Center for Genomic Medicine, Ahmedabad, Gujarat, India
| | | | - Prerna Jhawar
- Department of Fetal Medicine, Cloud Nine Hospital, Bengaluru, India
| | - Udhaya Kotecha
- Clinical Genetics, Neuberg Center for Genomic Medicine, Ahmedabad, Gujarat, India
| | - Jyothi Janardhanan
- Paediatric Immunology and Rheumatology Unit, Aster CMI Hospital, Bengaluru, India
| | - Harish Kumar
- Pediatric Intensive Care Unit, Department of Paediatrics, Aster CMI Hospital, Bengaluru, India
| | - K A Sudheer
- Department of Paediatrics, Aster CMI Hospital, Bengaluru, India
| | | | - Karthik Arigela
- Pediatric Intensive Care Unit, Department of Paediatrics, Aster CMI Hospital, Bengaluru, India
| | - Chetan Ginigeri
- Pediatric Intensive Care Unit, Department of Paediatrics, Aster CMI Hospital, Bengaluru, India
| | - Sagar Bhattad
- Paediatric Immunology and Rheumatology Unit, Aster CMI Hospital, Bengaluru, India.
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Oktelik FB, Wang M, Keles S, Eke Gungor H, Cansever M, Can S, Karakoc-Aydiner E, Baris S, Schmitz-Abe K, Benamar M, Chatila TA. DOCK8 deficiency due to a deep intronic variant in two kindreds with hyper-IgE syndrome. Clin Immunol 2024; 268:110384. [PMID: 39437980 PMCID: PMC11531991 DOI: 10.1016/j.clim.2024.110384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 10/18/2024] [Indexed: 10/25/2024]
Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency underlies the majority of cases of patients with autosomal recessive form of the hyper-immunoglobulin E syndrome (HIES). Most DOCK8 mutations involve deletions and splice junction mutations that abrogate protein expression. However, a few patients whose presentation is reminiscent of DOCK8 deficiency have no identifiable mutations. Using Whole Exome Sequencing (WES), we identified a deep intronic homozygous DOCK8 variant located in intron 36 (c.4626 + 76 A > G) in two unrelated patients with features of HIES that resulted in an in-frame 75 base pair intronic sequence insertion in DOCK8 cDNA, resulting in a premature stop codon (p.S1542ins6Ter). This variant resulted in variable decrease in DOCK8 expression that was associated with impaired T cell receptor-triggered actin polymerization, decreased IL-6-induced STAT3 phosphorylation, reduced expression of the Th17 cell markers CCR6 and IL-17, and higher frequencies of GATA3+ T cells indicative of Th2 skewing. Our approach extends the reach of WES in identifying disease-related intronic variants. It highlights the role of non-coding mutations in immunodeficiency disorders, including DOCK8 deficiency, and emphasizes the need to explore these mutations in unexplained inborn errors of immunity.
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Affiliation(s)
- Fatma Betul Oktelik
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Immunology, Aziz Sancar Institute of Experimental Medicine (Aziz Sancar DETAE), Istanbul University, Istanbul, Turkiye; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Muyun Wang
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA
| | - Sevgi Keles
- Necmettin Erbakan University, Medical Faculty, Department of Pediatric Allergy and Immunology, Konya, Turkiye
| | - Hatice Eke Gungor
- University of Health Sciences, Kayseri City Hospital, Department of Pediatric Allergy and Immunology, Kayseri, Turkiye
| | - Murat Cansever
- University of Health Sciences, Kayseri City Hospital, Department of Pediatric Allergy and Immunology, Kayseri, Turkiye
| | - Salim Can
- Marmara University, School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkiye; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkiye; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkiye
| | - Elif Karakoc-Aydiner
- Marmara University, School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkiye; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkiye; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkiye
| | - Safa Baris
- Marmara University, School of Medicine, Division of Pediatric Allergy and Immunology, Istanbul, Turkiye; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkiye; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkiye
| | - Klaus Schmitz-Abe
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Division of Neonatology, Department of Pediatrics, University of Miami Miller School of Medicine and Jackson Health System, Miami, FL, USA
| | - Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
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Sun H, Knight JM, Li YD, Ashoori F, Citardi MJ, Yao WC, Corry DB, Luong AU. Allergic fungal rhinosinusitis linked to other hyper-IgE syndromes through defective T H17 responses. J Allergy Clin Immunol 2024; 154:1169-1179. [PMID: 39032670 DOI: 10.1016/j.jaci.2024.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 05/15/2024] [Accepted: 06/07/2024] [Indexed: 07/23/2024]
Abstract
BACKGROUND In a gene expression analysis comparing sinus mucosa samples from allergic fungal rhinosinusitis (AFRS) patients with samples from non-AFRS chronic rhinosinusitis with nasal polyp (CRSwNP) patients, the antimicrobial peptide (AMP) histatin 1 (HTN1) was found to be the most differentially downregulated gene in AFRS. OBJECTIVE We sought to identify the molecular etiology of the downregulated expression of HTN1. METHODS We used RT-PCR to compare the expression of AMPs and a fungistasis assay to evaluate the antifungal activity of sinus secretions. Using flow cytometry, we characterized the presence of TH17/TH22 cells and signal transducer and activator of transcription (STAT) signaling from AFRS patients, non-AFRS CRSwNP patients, and healthy controls. RESULTS We confirmed decreased expression of AMPs in AFRS sinus mucosa with concordant decrease in antifungal activity in sinus secretions. IL-22 and IL-22-producing T cells were deficient within sinus mucosa of AFRS patients. In vitro studies demonstrated a defect in IL-6/STAT3 signaling critical for TH17/TH22 differentiation. Epithelial cells from AFRS patients could express AMPs when stimulated with exogenous IL-22/IL-17 and circulating TH17 cell abundance was normal. CONCLUSIONS Similar to other hyper-IgE syndromes, but distinct from CRSwNP, AFRS patients express a defect in STAT3 activation limited to IL-6-dependent STAT3 phosphorylation that is critical for TH17/TH22 differentiation. This defect leads to a local deficiency of IL-17/IL-22 cytokines and deficient AMP expression within diseased sinus mucosa of AFRS patients. Our findings support evaluation of therapeutic approaches that enhance airway AMP production in AFRS.
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Affiliation(s)
- Hua Sun
- Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School of The University of Texas Health Science Center at Houston, Houston, Tex; Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex
| | - J Morgan Knight
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex
| | - Yi-Dong Li
- Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School of The University of Texas Health Science Center at Houston, Houston, Tex; Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex
| | - Faramarz Ashoori
- Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex
| | - Martin J Citardi
- Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex
| | - William C Yao
- Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex
| | - David B Corry
- Department of Pathology & Immunology, Baylor College of Medicine, Houston, Tex; Department of Medicine, Baylor College of Medicine, Houston, Tex; Biology of Inflammation Center and Center for Translational Research in Inflammatory Diseases, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Tex
| | - Amber U Luong
- Center for Immunology and Autoimmune Diseases, The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, McGovern Medical School of The University of Texas Health Science Center at Houston, Houston, Tex; Department of Otorhinolaryngology-Head and Neck Surgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Tex.
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9
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Du H, Lun MY, Gagarina L, Mehaffey MG, Hwang JP, Jhangiani SN, Bhamidipati SV, Muzny DM, Poli MC, Ochoa S, Chinn IK, Linstrand A, Posey JE, Gibbs RA, Lupski JR, Carvalho CMB. VizCNV: An integrated platform for concurrent phased BAF and CNV analysis with trio genome sequencing data. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.27.620363. [PMID: 39553991 PMCID: PMC11565771 DOI: 10.1101/2024.10.27.620363] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/19/2024]
Abstract
Background Copy number variation (CNV) is a class of genomic Structural Variation (SV) that underlie genomic disorders and can have profound implications for health. Short-read genome sequencing (sr-GS) enables CNV calling for genomic intervals of variable size and across multiple phenotypes. However, unresolved challenges include an overwhelming number of false-positive calls due to systematic biases from non-uniform read coverage and collapsed calls resulting from the abundance of paralogous segments and repetitive elements in the human genome. Methods To address these interpretative challenges, we developed VizCNV. The VizCNV computational tool for inspecting CNV calls uses various data signal sources from sr-GS data, including read depth, phased B-allele frequency, as well as benchmarking signals from other SV calling methods. The interactive features and view modes are adept for analyzing both chromosomal abnormalities [e.g., aneuploidy, segmental aneusomy, and chromosome translocations], gene exonic CNV and non-coding gene regulatory regions. In addition, VizCNV includes a built-in filter schema for trio genomes, prioritizing the detection of impactful germline CNVs, such as de novo CNVs. Upon computational optimization by fine-tuning parameters to maximize sensitivity and specificity, VizCNV demonstrated approximately 83.8% recall and 77.2% precision on the 1000 Genome Project data with an average coverage read depth of 30x. Results We applied VizCNV to 39 families with primary immunodeficiency disease without a molecular diagnosis. With implemented build-in filter, we identified two de novo CNVs and 90 inherited CNVs >10 kb per trio. Genotype-phenotype analyses revealed that a compound heterozygous combination of a paternal 12.8 kb deletion of exon 5 and a maternal missense variant allele of DOCK8 are likely the molecular cause of one proband. Conclusions VizCNV provides a robust platform for genome-wide relevant CNV discovery and visualization of such CNV using sr-GS data.
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Affiliation(s)
- Haowei Du
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Ming Yin Lun
- Pacific Northwest Research Institute, Seattle, WA 98122, USA
| | - Lidiia Gagarina
- Pacific Northwest Research Institute, Seattle, WA 98122, USA
| | | | - James Paul Hwang
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Shalini N Jhangiani
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Sravya V Bhamidipati
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - Donna M Muzny
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - M Cecilia Poli
- Program of Immunogenetics and Translational Immunology, Faculty of Medicine, Clínica Alemana-Universidad del Desarrollo, Santiago, Chile
| | - Sebastian Ochoa
- Department of Pediatrics, Section of Immunology, Allergy, and Retrovirology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
- Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Ivan K Chinn
- Department of Pediatrics, Section of Immunology, Allergy, and Retrovirology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
- Center for Human Immunobiology of Texas Children's Hospital/Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | - Anna Linstrand
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Clinical Genetics and Genomics, Karolinska University Hospital, Stockholm, Sweden
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Richard A Gibbs
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
| | - James R Lupski
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Texas Children's Hospital, Houston, TX 77030, USA
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10
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Fekrvand S, Abolhassani H, Esfahani ZH, Fard NNG, Amiri M, Salehi H, Almasi-Hashiani A, Saeedi-Boroujeni A, Fathi N, Mohtashami M, Razavi A, Heidari A, Azizi G, Khanmohammadi S, Ahangarzadeh M, Saleki K, Hassanpour G, Rezaei N, Yazdani R. Cancer Trends in Inborn Errors of Immunity: A Systematic Review and Meta-Analysis. J Clin Immunol 2024; 45:34. [PMID: 39466473 DOI: 10.1007/s10875-024-01810-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 09/16/2024] [Indexed: 10/30/2024]
Abstract
BACKGROUND Patients with inborn errors of immunity (IEI) are susceptible to developing cancer due to defects in the immune system. The prevalence of cancer is higher in IEI patients compared to the immunocompetent population and cancers are considered as an important and common cause of death in IEI patients. OBJECTIVES To systematically review demographic, genetic and cancer-related data of IEI patients with a history of malignancy. Moreover, we performed a meta-analysis aiming to determine the frequency of cancer in patients with different types of IEI. METHODS We conducted electronic searches on Embase, Web of Science, PubMed, and Scopus (until September 2023) introducing terms related to IEI and cancer. Studies with human subjects with confirmed IEI who had developed at least one malignancy during their lifetime were included. RESULTS A total number of 4607 IEI patients with a cancer history were included in the present study. Common variable immunodeficiency (CVID) had the highest number of reported cases (1284 cases), mainly due to a higher relative proportion of patients with predominantly antibody deficiencies (PAD) and their increased life expectancy contributing to the higher detection and reporting of cancers among these patients. The most common malignancy was hematologic/blood cancers (3026 cases, mainly diffuse large B cell lymphoma). A total number of 1173 cases (55.6%) succumbed to cancer, with the highest rate of bone marrow failure (64.9%). Among the patients with monogenic defects in IEI-associated genes, the majority of cases had ATM deficiency (926 cases), but the highest cancer frequency rate belonged to NBS1 deficiency (50.5%). 1928 cases out of total 4607 eligible cases had detailed data to allow further statistical analysis that revealed BRCA2 deficiency had the earliest cancer development (~ 38 months), lowest cure frequency, and highest fatality rate (85%), while ATM deficiency had the lowest cure frequency and highest fatality rate (72%) among total cases reviewed with exclusion of Fanconi anemia. CONCLUSION The overall reported cancer frequency in the cases reviewed with and without exclusion of Fanconi anemia was 11.1% (95% confidence interval: 9.8-12.5%) and 12.0% (95% confidence interval: 10.6-13.5%), respectively. Our study revealed that the incidence of cancer is significantly dependent on the molecular and pathway defects in IEI patients, and individualized early screening and appropriate treatment, might improve the prognosis of these patients.
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Affiliation(s)
- Saba Fekrvand
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, Stockholm, Huddinge, Sweden
| | - Zahra Hamidi Esfahani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Najmeh Nameh Goshay Fard
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Mahboube Amiri
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Helia Salehi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Almasi-Hashiani
- Department of Epidemiology, School of Health, Arak University of Medical Sciences, Arak, Iran
| | - Ali Saeedi-Boroujeni
- Department of Basic Medical Sciences, Faculty of Medicine, Abadan University of Medical Sciences, Abadan, Iran
| | - Nazanin Fathi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Mohtashami
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Azadehsadat Razavi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Arash Heidari
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Gholamreza Azizi
- Noncommunicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
- Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Shaghayegh Khanmohammadi
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Milad Ahangarzadeh
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Kiarash Saleki
- Student Research Committee, Babol University of Medical Sciences, Babol, Iran
- Department of E-Learning, Virtual School of Medical Education and Management, Shahid Beheshti University of MedicalSciences (SBMU), Tehran, Iran
- USERN Office, Babol University of Medical Sciences, Babol, Iran
| | - Gholamreza Hassanpour
- Center for Research of Endemic Parasites of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
| | - Reza Yazdani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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11
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Galletta F, Gambadauro A, Foti Randazzese S, Passanisi S, Sinatra V, Caminiti L, Zirilli G, Manti S. Pathophysiology of Congenital High Production of IgE and Its Consequences: A Narrative Review Uncovering a Neglected Setting of Disorders. Life (Basel) 2024; 14:1329. [PMID: 39459629 PMCID: PMC11509725 DOI: 10.3390/life14101329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 10/06/2024] [Accepted: 10/16/2024] [Indexed: 10/28/2024] Open
Abstract
Elevated serum IgE levels serve as a critical marker for uncovering hidden immunological disorders, particularly inborn errors of immunity (IEIs), which are often misdiagnosed as common allergic conditions. IgE, while typically associated with allergic diseases, plays a significant role in immune defense, especially against parasitic infections. However, extremely high levels of IgE can indicate more severe conditions, such as Hyper-IgE syndromes (HIES) and disorders with similar features, including Omenn syndrome, Wiskott-Aldrich syndrome, and IPEX syndrome. Novel insights into the genetic mutations responsible for these conditions highlight their impact on immune regulation and the resulting clinical features, including recurrent infections, eczema, and elevated IgE. This narrative review uniquely integrates recent advances in the genetic understanding of IEIs and discusses how these findings impact both diagnosis and treatment. Additionally, emerging therapeutic strategies, such as hematopoietic stem cell transplantation (HSCT) and gene therapies, are explored, underscoring the potential for personalized treatment approaches. Emphasizing the need for precise diagnosis and tailored interventions aims to enhance patient outcomes and improve the quality of care for those with elevated IgE levels and associated immunological disorders.
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Affiliation(s)
| | | | | | - Stefano Passanisi
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age ‘Gaetano Barresi’, University of Messina, 98124 Messina, Italy; (F.G.); (A.G.); (S.F.R.); (V.S.); (L.C.); (G.Z.)
| | | | | | | | - Sara Manti
- Pediatric Unit, Department of Human Pathology in Adult and Developmental Age ‘Gaetano Barresi’, University of Messina, 98124 Messina, Italy; (F.G.); (A.G.); (S.F.R.); (V.S.); (L.C.); (G.Z.)
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12
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Yazdanpanah N, Rezaei N. The multidisciplinary approach to diagnosing inborn errors of immunity: a comprehensive review of discipline-based manifestations. Expert Rev Clin Immunol 2024; 20:1237-1259. [PMID: 38907993 DOI: 10.1080/1744666x.2024.2372335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/21/2024] [Indexed: 06/24/2024]
Abstract
INTRODUCTION Congenital immunodeficiency is named primary immunodeficiency (PID), and more recently inborn errors of immunity (IEI). There are more than 485 conditions classified as IEI, with a wide spectrum of clinical and laboratory manifestations. AREAS COVERED Regardless of the developing knowledge of IEI, many physicians do not think of IEI when approaching the patient's complaint, which leads to delayed diagnosis, misdiagnosis, serious infectious and noninfectious complications, permanent end-organ damage, and even death. Due to the various manifestations of IEI and the wide spectrum of associated conditions, patients refer to specialists in different disciplines of medicine and undergo - mainly symptomatic - treatments, and because IEI are not included in physicians' differential diagnosis, the main disease remains undiagnosed. EXPERT OPINION A multidisciplinary approach may be a proper solution. Manifestations and the importance of a multidisciplinary approach in the diagnosis of main groups of IEI are discussed in this article.
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Affiliation(s)
- Niloufar Yazdanpanah
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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13
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Jiang P, Zhao S, Li X, Hu S, Chen S, Liang Y, Zhang L, Lu L, Fang G, Yang L, Huang Y, Miller H, Guan F, Lei J, Liu C. Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4 + T cells. MedComm (Beijing) 2024; 5:e747. [PMID: 39329018 PMCID: PMC11424684 DOI: 10.1002/mco2.747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/28/2024] Open
Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the DOCK8 gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a DOCK8 exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that DOCK8 mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, DOCK8 mutation CD4+ T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of DOCK8 mutant CD4+ T cells. We observed that DOCK8 mutation upregulates the glycolysis levels in CD4+ T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4+ T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.
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Affiliation(s)
- Panpan Jiang
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Siyu Zhao
- Department Immunology School of Medicine Yangtze University Jingzhou China
| | - Xiaoyu Li
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Shiyan Hu
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Shuhan Chen
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Yinming Liang
- Center of Disease Model and Immunology Hunan Academy of Chinese Medicine Changsha China
| | - Lichen Zhang
- Laboratory of Genetic Regulators in the Immune System School of Medical Technology Xinxiang Medical University Xinxiang China
| | - Liaoxun Lu
- Laboratory of Genetic Regulators in the Immune System School of Medical Technology Xinxiang Medical University Xinxiang China
| | - Guofeng Fang
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Lu Yang
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Yanmei Huang
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Heather Miller
- Cytek Biosciences R&D Clinical Reagents Fremont California USA
| | - Fei Guan
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Jiahui Lei
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
| | - Chaohong Liu
- Department of Pathogen Biology School of Basic Medicine Tongji Medical College and State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases Huazhong University of Science and Technology Wuhan China
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14
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Fekrvand S, Abolhassani H, Rezaei N. An overview of early genetic predictors of IgA deficiency. Expert Rev Mol Diagn 2024; 24:715-727. [PMID: 39087770 DOI: 10.1080/14737159.2024.2385521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
INTRODUCTION Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown. AREAS COVERED This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells. EXPERT OPINION A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.
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Affiliation(s)
- Saba Fekrvand
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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15
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Christodoulou A, Tsai JY, Suwankitwat N, Anderson A, Iritani BM. Hem1 inborn errors of immunity: waving goodbye to coordinated immunity in mice and humans. Front Immunol 2024; 15:1402139. [PMID: 39026677 PMCID: PMC11254771 DOI: 10.3389/fimmu.2024.1402139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2024] [Accepted: 06/19/2024] [Indexed: 07/20/2024] Open
Abstract
Inborn errors of immunity (IEI) are a group of diseases in humans that typically present as increased susceptibility to infections, autoimmunity, hyperinflammation, allergy, and in some cases malignancy. Among newly identified genes linked to IEIs include 3 independent reports of 9 individuals from 7 independent kindreds with severe primary immunodeficiency disease (PID) and autoimmunity due to loss-of-function mutations in the NCKAP1L gene encoding Hematopoietic protein 1 (HEM1). HEM1 is a hematopoietic cell specific component of the WASp family verprolin homologous (WAVE) regulatory complex (WRC), which acts downstream of multiple immune receptors to stimulate actin nucleation and polymerization of filamentous actin (F-actin). The polymerization and branching of F-actin is critical for creating force-generating cytoskeletal structures which drive most active cellular processes including migration, adhesion, immune synapse formation, and phagocytosis. Branched actin networks at the cell cortex have also been implicated in acting as a barrier to regulate inappropriate vesicle (e.g. cytokine) secretion and spontaneous antigen receptor crosslinking. Given the importance of the actin cytoskeleton in most or all hematopoietic cells, it is not surprising that HEM1 deficient children present with a complex clinical picture that involves overlapping features of immunodeficiency and autoimmunity. In this review, we will provide an overview of what is known about the molecular and cellular functions of HEM1 and the WRC in immune and other cells. We will describe the common clinicopathological features and immunophenotypes of HEM1 deficiency in humans and provide detailed comparative descriptions of what has been learned about Hem1 disruption using constitutive and immune cell-specific mouse knockout models. Finally, we discuss future perspectives and important areas for investigation regarding HEM1 and the WRC.
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Affiliation(s)
- Alexandra Christodoulou
- The Department of Comparative Medicine, University of Washington, Seattle, WA, United States
| | - Julia Y Tsai
- The Department of Comparative Medicine, University of Washington, Seattle, WA, United States
| | - Nutthakarn Suwankitwat
- The Department of Comparative Medicine, University of Washington, Seattle, WA, United States
- Virology Laboratory, National Institute of Animal Health, Bangkok, Thailand
| | - Andreas Anderson
- The Department of Comparative Medicine, University of Washington, Seattle, WA, United States
| | - Brian M Iritani
- The Department of Comparative Medicine, University of Washington, Seattle, WA, United States
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16
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Fusaro M, Dupré L. Mechanisms underlying skin inflammation of DOCK8 deficiency. J Allergy Clin Immunol 2024; 154:88-90. [PMID: 38759801 DOI: 10.1016/j.jaci.2024.04.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/18/2024] [Accepted: 04/24/2024] [Indexed: 05/19/2024]
Affiliation(s)
- Mathieu Fusaro
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Laboratoire d'Immunologie, Institut Fédératif de Biologie, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Loïc Dupré
- Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), INSERM, CNRS, Toulouse III Paul Sabatier University, Toulouse, France; Department of Dermatology, Medical University of Vienna, Vienna, Austria.
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17
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Wilkie H, Das M, Pelovitz T, Bainter W, Woods B, Alasharee M, Sobh A, Baris S, Eltan SB, Al-Herz W, Barbouche MR, Ben-Mustapha I, Ben-Ali M, Sallam MTH, Awad A, Lotfy S, El Marsafy A, Ezzelarab M, Farrar M, Schmidt BAR, NandyMazumdar M, Guttman-Yassky E, Sheets A, Vidic KM, Murphy G, Schlievert PM, Chou J, Leyva-Castillo JM, Janssen E, Timilshina M, Geha RS. Regulatory T-cell dysfunction and cutaneous exposure to Staphylococcus aureus underlie eczema in DOCK8 deficiency. J Allergy Clin Immunol 2024; 154:143-156. [PMID: 38185418 DOI: 10.1016/j.jaci.2023.12.020] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 12/19/2023] [Accepted: 12/27/2023] [Indexed: 01/09/2024]
Abstract
BACKGROUND Dedicator of cytokinesis 8 (DOCK8)-deficient patients have severe eczema, elevated IgE, and eosinophilia, features of atopic dermatitis (AD). OBJECTIVE We sought to understand the mechanisms of eczema in DOCK8 deficiency. METHODS Skin biopsy samples were characterized by histology, immunofluorescence microscopy, and gene expression. Skin barrier function was measured by transepidermal water loss. Allergic skin inflammation was elicited in mice by epicutaneous sensitization with ovalbumin (OVA) or cutaneous application of Staphylococcus aureus. RESULTS Skin lesions of DOCK8-deficient patients exhibited type 2 inflammation, and the patients' skin was colonized by Saureus, as in AD. Unlike in AD, DOCK8-deficient patients had a reduced FOXP3:CD4 ratio in their skin lesions, and their skin barrier function was intrinsically intact. Dock8-/- mice exhibited reduced numbers of cutaneous T regulatory (Treg) cells and a normal skin barrier. Dock8-/- and mice with an inducible Dock8 deletion in Treg cells exhibited increased allergic skin inflammation after epicutaneous sensitization with OVA. DOCK8 was shown to be important for Treg cell stability at sites of allergic inflammation and for the generation, survival, and suppressive activity of inducible Treg cells. Adoptive transfer of wild-type, but not DOCK8-deficient, OVA-specific, inducible Treg cells suppressed allergic inflammation in OVA-sensitized skin of Dock8-/- mice. These mice developed severe allergic skin inflammation and elevated serum IgE levels after topical exposure to Saureus. Both were attenuated after adoptive transfer of WT but not DOCK8-deficient Treg cells. CONCLUSION Treg cell dysfunction increases susceptibility to allergic skin inflammation in DOCK8 deficiency and synergizes with cutaneous exposure to Saureus to drive eczema in DOCK8 deficiency.
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Affiliation(s)
- Hazel Wilkie
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Mrinmoy Das
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Tyler Pelovitz
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Wayne Bainter
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Brian Woods
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Mohammed Alasharee
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Ali Sobh
- Department of Pediatrics, Mansoura University Children's Hospital, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Safa Baris
- Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Sevgi Bilgic Eltan
- Division of Pediatric Allergy and Immunology, Marmara University, Istanbul, Turkey
| | - Waleed Al-Herz
- Department of Pediatrics, Allergy and Clinical Immunology Unit, Al-Sabah Hospital, Kuwait City, Kuwait
| | - Mohamed-Ridha Barbouche
- Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Imen Ben-Mustapha
- Department of Immunology, Institut Pasteur de Tunis and University Tunis El-Manar, Tunis, Tunisia
| | - Meriem Ben-Ali
- Department of Immunology, Institut Pasteur de Tunis and University Tunis El-Manar, Tunis, Tunisia
| | - Mohamed T H Sallam
- Clinical Pathology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Amany Awad
- Dermatology, Andrology, and STDs Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sohilla Lotfy
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Aisha El Marsafy
- Department of Pediatrics, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Moushira Ezzelarab
- Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Michael Farrar
- Center for Immunology, Masonic Cancer Center, Department of Laboratory and Pathology, University of Minnesota, Minneapolis, Minn
| | - Brigitta A R Schmidt
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, Mass
| | - Monali NandyMazumdar
- Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Emma Guttman-Yassky
- Department of Dermatology and the Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Anthony Sheets
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Katie Maria Vidic
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - George Murphy
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass
| | - Patrick M Schlievert
- Department of Microbiology and Immunology, Carver College of Medicine, University of Iowa Health Care, Iowa City, Iowa
| | - Janet Chou
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Juan Manuel Leyva-Castillo
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Erin Janssen
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass
| | - Maheshwor Timilshina
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass.
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital, and the Department of Pediatrics Harvard Medical School, Boston, Mass.
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18
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Zhang B, Chen S, Yin X, McBride CD, Gertie JA, Yurieva M, Bielecka AA, Hoffmann B, Travis Hinson J, Grassmann J, Xu L, Siniscalco ER, Soldatenko A, Hoyt L, Joseph J, Norton EB, Uthaman G, Palm NW, Liu E, Eisenbarth SC, Williams A. Metabolic fitness of IgA + plasma cells in the gut requires DOCK8. Mucosal Immunol 2024; 17:431-449. [PMID: 38159726 PMCID: PMC11571232 DOI: 10.1016/j.mucimm.2023.12.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 11/16/2023] [Accepted: 12/01/2023] [Indexed: 01/03/2024]
Abstract
Dedicator of cytokinesis 8 (DOCK8) mutations lead to a primary immunodeficiency associated with recurrent gastrointestinal infections and poor antibody responses but, paradoxically, heightened IgE to food antigens, suggesting that DOCK8 is central to immune homeostasis in the gut. Using Dock8-deficient mice, we found that DOCK8 was necessary for mucosal IgA production to multiple T cell-dependent antigens, including peanut and cholera toxin. Yet DOCK8 was not necessary in T cells for this phenotype. Instead, B cell-intrinsic DOCK8 was required for maintenance of antigen-specific IgA-secreting plasma cells (PCs) in the gut lamina propria. Unexpectedly, DOCK8 was not required for early B cell activation, migration, or IgA class switching. An unbiased interactome screen revealed novel protein partners involved in metabolism and apoptosis. Dock8-deficient IgA+ B cells had impaired cellular respiration and failed to engage glycolysis appropriately. These results demonstrate that maintenance of the IgA+ PC compartment requires DOCK8 and suggest that gut IgA+ PCs have unique metabolic requirements for long-term survival in the lamina propria.
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Affiliation(s)
- Biyan Zhang
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove, Immunos, Singapore 138648, Singapore
| | - Shuting Chen
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Xiangyun Yin
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Caleb D McBride
- The Department Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - Jake A Gertie
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Marina Yurieva
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA
| | - Agata A Bielecka
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Microbial Immunoregulation, Helmholtz Center for Infection Research, 38124 Braunschweig, Germany
| | - Brian Hoffmann
- Mass Spectrometry and Protein Chemistry, The Jackson Laboratory for Genomic Medicine, Bar Harbor, ME 04609, USA
| | - J Travis Hinson
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA; Cardiology center, Department of Medicine, UConn Health, Farmington, CT, USA
| | - Jessica Grassmann
- The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA
| | - Lan Xu
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Emily R Siniscalco
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Arielle Soldatenko
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Laura Hoyt
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Julie Joseph
- Department of Laboratory Medicine, USA; Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
| | - Elizabeth B Norton
- Department of Microbiology & Immunology, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Gowthaman Uthaman
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655, USA
| | - Noah W Palm
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Elise Liu
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Rheumatology, Allergy & Immunology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Stephanie C Eisenbarth
- Department of Laboratory Medicine, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; The Department Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
| | - Adam Williams
- The Department Medicine, Division of Allergy and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; The Jackson Laboratory for Genomic Medicine, Farmington, CT 06030, USA; Center for Human Immunobiology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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19
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Guo M, Ma Y, Cai K, Liu X, Liu W, Wang F, Qu N, Liu S. A novel hemizygous CD40L mutation of X-linked hyper IgM syndromes and compound heterozygous DOCK8 mutations of hyper IgE syndromes in two Chinese families. Immunogenetics 2024; 76:165-173. [PMID: 38587548 DOI: 10.1007/s00251-024-01340-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 03/31/2024] [Indexed: 04/09/2024]
Abstract
X-linked hyper-immunoglobulin M (X-HIGM) syndrome and autosomal recessive hyper-immunoglobulin E syndrome (HIES) are rare inborn errors of immunity characterized by recurrent infections due to immune system impairment. In this study, we identified a novel hemizygous CD40 ligand (CD40L) mutation and compound heterozygous dedicator of cytokinesis-8 (DOCK8) mutations in two Han Chinese families with X-HIGM and HIES, respectively. We aimed to investigate the association between their genotypes and phenotypes. Genomic DNA was extracted from peripheral blood samples obtained from the families. Whole exome sequencing and Sanger sequencing were performed to identify and verify pathogenic variants in the two families. Clinical analyses of the probands were also performed. A novel hemizygous mutation of CD40L in exon 2 (c.257delA) was identified in the first proband, resulting in the substitution of glycine with glutamic acid at codon 86 of the protein. This leads to premature termination of translation at downstream codon 9 (p.E86Gfs*9). Sanger sequencing confirmed that the variant was inherited from the mother. The second proband carried two novel compound heterozygous mutations in DOCK8: one at exon 14 (c.1546C > G) inherited from the father, and the other at intron 41 (c.5355 + 6C > T; splicing) inherited from the mother. This study enhances our understanding of the pathogenetic mutation spectrum of CD40L and DOCK8 genes, facilitating the prenatal diagnosis of X-HIGM and HIES and enabling timely treatment of patients.
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Affiliation(s)
- Mingzhen Guo
- Department of Laboratory, Women and Children's Hospital, Affiliated to Qingdao University, Qingdao, 266034, Shandong, China
| | - Yuanxuan Ma
- Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China
- Department of Medical Genetics, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Kangxi Cai
- School of Basic Medicine, Qingdao University, Qingdao, 266071, China
| | - Xiuxiang Liu
- Neonatal Intensive Care Unit, Women and Children's Hospital, Affiliated to Qingdao University, Qingdao, 266034, Shandong, China
| | - Wenmiao Liu
- Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China
- Department of Medical Genetics, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Fengqi Wang
- Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China
- Department of Medical Genetics, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, Shandong, China
| | - Niyan Qu
- Pediatric Intensive Care Unit, Women and Children's Hospital, Affiliated to Qingdao University, 6 Tongfu Road, Qingdao, 266034, Shandong, China.
| | - Shiguo Liu
- Prenatal Diagnosis Center, The Affiliated Hospital of Qingdao University, Qingdao, 266003, Shandong, China.
- Department of Medical Genetics, the Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, Shandong, China.
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20
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Kurz H, Lehmberg K, Farmand S. Inborn errors of immunity with susceptibility to S. aureus infections. Front Pediatr 2024; 12:1389650. [PMID: 38720948 PMCID: PMC11078099 DOI: 10.3389/fped.2024.1389650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 03/25/2024] [Indexed: 05/12/2024] Open
Abstract
Staphylococcus aureus (S. aureus) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population.
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Affiliation(s)
- Hannah Kurz
- Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Kai Lehmberg
- Division of Pediatric Stem Cell Transplantation and Immunology, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Susan Farmand
- Division of Pediatric Stem Cell Transplantation and Immunology, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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21
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Netravali IA, Sockler PG, Heimall J, Treat JR. Rapid resolution of diffuse warts following initiation of dupilumab for severe atopic dermatitis. Pediatr Dermatol 2024; 41:275-278. [PMID: 37680146 DOI: 10.1111/pde.15414] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2023] [Accepted: 07/30/2023] [Indexed: 09/09/2023]
Abstract
Cutaneous warts are an exceedingly common cutaneous viral infection for which existing treatment options are often painful, expensive, and only marginally effective. Extensive warts may occur in the setting of primary immunodeficiencies, wherein they can co-occur with other diseases of immune dysfunction, such as atopic dermatitis (AD). Dupilumab, an IL-4 receptor α (IL-4Rα)-blocking monoclonal antibody, is a biologic agent recently approved for the treatment of moderate-to-severe eczema. Here, we report a case of a young girl with both severe AD and diffuse filiform warts, which resolved shortly after initiating treatment for AD with dupilumab.
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Affiliation(s)
- Ilka Arun Netravali
- Section of Dermatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Patrick G Sockler
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Jennifer Heimall
- Division of Allergy & Immunology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
| | - James R Treat
- Section of Dermatology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
- Department of Dermatology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA
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22
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Tangye SG, Mackie J, Pathmanandavel K, Ma CS. The trajectory of human B-cell function, immune deficiency, and allergy revealed by inborn errors of immunity. Immunol Rev 2024; 322:212-232. [PMID: 37983844 DOI: 10.1111/imr.13288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2023]
Abstract
The essential role of B cells is to produce protective immunoglobulins (Ig) that recognize, neutralize, and clear invading pathogens. This results from the integration of signals provided by pathogens or vaccines and the stimulatory microenvironment within sites of immune activation, such as secondary lymphoid tissues, that drive mature B cells to differentiate into memory B cells and antibody (Ab)-secreting plasma cells. In this context, B cells undergo several molecular events including Ig class switching and somatic hypermutation that results in the production of high-affinity Ag-specific Abs of different classes, enabling effective pathogen neutralization and long-lived humoral immunity. However, perturbations to these key signaling pathways underpin immune dyscrasias including immune deficiency and autoimmunity or allergy. Inborn errors of immunity that disrupt critical immune pathways have identified non-redundant requirements for eliciting and maintaining humoral immune memory but concomitantly prevent immune dysregulation. Here, we will discuss our studies on human B cells, and how our investigation of cytokine signaling in B cells have identified fundamental requirements for memory B-cell formation, Ab production as well as regulating Ig class switching in the context of protective versus allergic immune responses.
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Affiliation(s)
- Stuart G Tangye
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Joseph Mackie
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Karrnan Pathmanandavel
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
| | - Cindy S Ma
- Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
- School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia
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23
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Kumar Jindal A, Sil A, Aggarwal R, Tyagi R, Mondal S, Singh A, Barman P, Chawla S, Loganathan SK, Gupta K, Vinay K, Mahajan R, Saikia B, Kaur G, Sharma R, Saka R, Bhatia A, Sankhyan N, Pandiarajan V, Pilania R, Dhaliwal M, Sharma S, Vyas S, Suri D, Rawat A, Singh S. Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India. Clin Exp Dermatol 2024; 49:226-234. [PMID: 37815217 DOI: 10.1093/ced/llad345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/23/2023] [Accepted: 10/03/2023] [Indexed: 10/11/2023]
Abstract
BACKGROUND Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. OBJECTIVES To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. METHODS Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. RESULTS Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. CONCLUSIONS DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Anmol Bhatia
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Naveen Sankhyan
- Paediatric Neurology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | | | | | | | | | - Sameer Vyas
- Department of Radiodiagnosis and Imaging, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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24
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Biglari S, Moghaddam AS, Tabatabaiefar MA, Sherkat R, Youssefian L, Saeidian AH, Vahidnezhad F, Tsoi LC, Gudjonsson JE, Hakonarson H, Casanova JL, Béziat V, Jouanguy E, Vahidnezhad H. Monogenic etiologies of persistent human papillomavirus infections: A comprehensive systematic review. Genet Med 2024; 26:101028. [PMID: 37978863 PMCID: PMC10922824 DOI: 10.1016/j.gim.2023.101028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 11/19/2023] Open
Abstract
PURPOSE Persistent human papillomavirus infection (PHPVI) causes cutaneous, anogenital, and mucosal warts. Cutaneous warts include common warts, Treeman syndrome, and epidermodysplasia verruciformis, among others. Although more reports of monogenic predisposition to PHPVI have been published with the development of genomic technologies, genetic testing is rarely incorporated into clinical assessments. To encourage broader molecular testing, we compiled a list of the various monogenic etiologies of PHPVI. METHODS We conducted a systematic literature review to determine the genetic, immunological, and clinical characteristics of patients with PHPVI. RESULTS The inclusion criteria were met by 261 of 40,687 articles. In 842 patients, 83 PHPVI-associated genes were identified, including 42, 6, and 35 genes with strong, moderate, and weak evidence for causality, respectively. Autosomal recessive inheritance predominated (69%). PHPVI onset age was 10.8 ± 8.6 years, with an interquartile range of 5 to 14 years. GATA2,IL2RG,DOCK8, CXCR4, TMC6, TMC8, and CIB1 are the most frequently reported PHPVI-associated genes with strong causality. Most genes (74 out of 83) belong to a catalog of 485 inborn errors of immunity-related genes, and 40 genes (54%) are represented in the nonsyndromic and syndromic combined immunodeficiency categories. CONCLUSION PHPVI has at least 83 monogenic etiologies and a genetic diagnosis is essential for effective management.
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Affiliation(s)
- Sajjad Biglari
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran; Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA
| | | | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Roya Sherkat
- Immunodeficiency Diseases Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Leila Youssefian
- Department of Pathology and Laboratory Medicine, UCLA Clinical Genomics Center, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Amir Hossein Saeidian
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA
| | | | - Lam C Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI
| | | | - Hakon Hakonarson
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA
| | - Jean-Laurent Casanova
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France; Imagine Institute, Paris Cité University, France; Department of Pediatrics, Necker Hospital for Sick Children, Paris, France, EU; Howard Hughes Medical Institute, Chevy Chase, MD
| | - Vivien Béziat
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France; Imagine Institute, Paris Cité University, France
| | - Emmanuelle Jouanguy
- St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France; Imagine Institute, Paris Cité University, France
| | - Hassan Vahidnezhad
- Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA.
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25
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Liquidano-Perez E, Maza-Ramos G, Perez Arias BA, Lugo Reyes SO, Barragan Arevalo T, Solorzano-Morales SA, Venegas Montoya E, Staines-Boone AT, Guzmán Cotaya R, Okada S, Picard C, Patin E, Ramirez-Uribe N, Bustamante-Ogando JC, Scheffler-Mendoza SC, Yamazaki-Nakashimada MA, Saez-de-Ocariz M, Espinosa Padilla SE, Gonzalez-Serrano ME. Clinical, immunological, and genetic description of a Mexican cohort of patients with DOCK8 deficiency. Pediatr Allergy Immunol 2024; 35:e14073. [PMID: 38351896 DOI: 10.1111/pai.14073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2023] [Revised: 12/16/2023] [Accepted: 01/07/2024] [Indexed: 02/16/2024]
Abstract
PURPOSE We aimed to describe the clinical, immunological, and genetic features of patients with DOCK8 deficiency (DOCK8-Def) in a tertiary care center for children. METHODS Retrospective chart review of patients' clinical, immunological, and genetic characteristics with DOCK8-Def. Genetic analysis was performed with targeted- or whole-exome sequencing; we also assessed DOCK8 protein expression and a lymphoproliferation assay and analyzed survival by the Kaplan-Meier method. RESULTS We described 11 patients from 8 unrelated kindreds. The median age at symptoms' onset was 10 months (range 1-54 months). The median follow-up time was 53.4 months (4.8-118.8). All patients presented eczema and recurrent sinopulmonary and cutaneous infections. Besides those symptoms, the most frequent manifestations were bronchiectases (8/11), food allergies (6/11), and severe infections (6/11). Infrequent characteristics were detection of CMV in bronchial lavage, C. parvum-driven sclerosing cholangitis, Takayasu vasculitis, neurological syndromes, pulmonary tuberculosis, and lymphomatoid granulomatosis. CONCLUSION DOCK8-Def has a broad spectrum of manifestations, including allergy, autoimmunity, inflammation, infection, and cancer. The hallmark of this inborn error of immunity is IEI-associated eczema with eosinophilia and increased IgE. Here, we report six new mutations causing human DOCK8 deficiency and symptoms previously unrecognized to occur in DOCK8-Def. Therefore, an early diagnosis of DOCK8-Def is essential to facilitate an adequate treatment such as HSCT.
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Affiliation(s)
| | | | | | | | - Tania Barragan Arevalo
- Department of Genetics, Institute of Ophthalmology "Conde de Valenciana", Mexico City, Mexico
| | | | - Edna Venegas Montoya
- Highly Specialized Medical Unit 25, Mexican Social Security Institute, Torreón, Mexico
| | | | | | | | | | | | - Nideshda Ramirez-Uribe
- Hematopoietic Stem Cell Transplantation Unit, National Institute of Pediatrics, Mexico City, Mexico
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26
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Mohammadi T, Azizi G, Rafiemanesh H, Farahani P, Nirouei M, Tavakol M. A systematic review regarding the prevalence of malignancy in patients with the hyper-IgE syndrome. Clin Exp Med 2023; 23:4835-4859. [PMID: 37924455 DOI: 10.1007/s10238-023-01228-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 10/18/2023] [Indexed: 11/06/2023]
Abstract
The hyper-immunoglobulin E syndrome (HIES) is a primary immunodeficiency disease originally described as Job syndrome. The fundamental causative variant of the HIES is an autosomal dominant mutation in the signal transducer and activator of transcription 3 (STAT3) gene. It is characterized by recurrent staphylococcal cold skin abscess, sinopulmonary infection, eczema, head and face anomalies, frequent bone fractures, eosinophilia and extremely high serum IgE levels (IgE ≥ 2000 IU/mL). However, multiple other genetic defects are also known as HIES-like disorders. Apart from infectious manifestations, STAT3, DOCK8 and TYK2 gene mutations are associated with various malignancies. The most common malignancies reported in these patients are lymphomas, including Hodgkin's and non-Hodgkin's lymphomas (NHL) of B and T cells. This systematic review aimed to investigate the prevalence of malignancies in HIES and the factors associated with malignancy in these patients. In this survey, all articles published until April 1st, 2023, in Scopus, PubMed and Web of Science databases based on three groups of keywords related to HIES syndrome and malignancy were reviewed by three different researchers. Finally, 26 articles were evaluated from which 24 papers were meta-analyzed. In the current study, the demographic information of 1133 patients with HIES, which was mentioned in 24 articles enrolled in the project, was collected, and the information related to patients who had malignancy was analyzed and meta-analyzed. A total of 96 patients out of 1133 studied patients had at least one type of malignancy, the overall prevalence of malignancies reported in the articles was 6.5% (95% confidence interval 4.1-9%), and the total prevalence of malignancy in patients with NHL type and patients with squamous cell carcinoma (SCC) was 2.9% (95% confidence interval 1.7-4.4%) and 2.2% (95% confidence interval 0.3-4.1%), respectively. The results of this study indicated that in 6.5% of cases, HIES was complicated with malignancy, and considering the higher rate of these malignancies in women as well as in DOCK8 mutation sufferers, it is necessary for physicians to be aware of this association and includes malignancy screening in follow-up and periodic examinations of these patients. Indeed, more studies in this field will help to clarify the precise figures and predisposing factors of the relationship between HIES and malignancy.
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Affiliation(s)
- Tayebeh Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Gholamreza Azizi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Hosein Rafiemanesh
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Pouria Farahani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Marzieh Tavakol
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Pediatrics, Alborz University of Medical Sciences, Karaj, Iran.
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Wobma H, Janssen E. Expanding IPEX: Inborn Errors of Regulatory T Cells. Rheum Dis Clin North Am 2023; 49:825-840. [PMID: 37821198 DOI: 10.1016/j.rdc.2023.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Regulatory T cells (Tregs) are critical for enforcing peripheral tolerance. Monogenic "Tregopathies" affecting Treg development, stability, and/or function commonly present with polyautoimmunity, atopic disease, and infection. While autoimmune manifestations may present in early childhood, as more disorders are characterized, conditions with later onset have been identified. Treg numbers in the blood may be decreased in Tregopathies, but this is not always the case, and genetic testing should be pursued when there is high clinical suspicion. Currently, hematopoietic cell transplantation is the only curative treatment, but gene therapies are in development, and small molecule inhibitors/biologics may also be used.
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Affiliation(s)
- Holly Wobma
- Division of Immunology, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA
| | - Erin Janssen
- Department of Pediatrics, Division of Pediatric Rheumatology, Michigan Medicine, C.S. Mott Children's Hospital, 1500 East Medical Center Drive, SPC 5718, Ann Arbor, MI 48109, USA.
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28
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Kasap N, Kara A, Celik V, Bilgic Eltan S, Akay Haci I, Kose H, Aygun A, Akkelle E, Yakici N, Guner SN, Reisli I, Keles S, Cekic S, Kilic SS, Karaca NE, Gulez N, Genel F, Ozen A, Yucelten AD, Karakoc-Aydiner E, Schmitz-Abe K, Baris S. Atypical Localization of Eczema Discriminates DOCK8 or STAT3 Deficiencies from Atopic Dermatitis. J Clin Immunol 2023; 43:1882-1890. [PMID: 37507632 DOI: 10.1007/s10875-023-01554-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023]
Abstract
PURPOSE Autosomal recessive dedicator of cytokinesis 8 (DOCK8-/-) and autosomal dominant signal transducer and activator of transcription 3 (STAT3-/+) deficiencies are inborn errors of immunity (IEI) disorders present with the classic features of eczema and create a dilemma during differentiation from atopic dermatitis (AD). Therefore, an appropriate approach is required for eczema to diagnose DOCK8-/- and STAT3-/+ early. Here, we described a set of clinical and immunological variables, including atypical AD localizations and lymphocyte subsets, to differentiate DOCK8-/- or STAT3-/+ from AD. METHODS This multicenter study involved 100 patients with DOCK8-/- and STAT3-/+ and moderate/severe AD. We recruited disease manifestations, including detailed localizations of eczema, infections, and allergy. Principle component analysis (PCA) was used to discriminate DOCK8-/- or STAT3-/+ from AD. RESULTS There were 43 patients with DOCK8-/-, 23 with STAT3-/+, and 34 with AD. Pneumonia, severe infections, mucocutaneous candidiasis, and skin abscesses were commonly observed in DOCK8 and STAT3 deficiencies. Atypical skin involvement with neonatal rash, retro auricular, axillary, sacral, and genital eczema discriminate DOCK8-/- and STAT3-/+ from AD with high specificity ranges between 73.5 and 94.1% and positive predictive index ranges between 55 and 93.1%. Together with using absolute numbers of CD3+, CD4+, and CD8+ T cells, the combined clinical and laboratory features showed perfect differentiation between DOCK8-/- or STAT3-/+ and AD via PCA. CONCLUSIONS The described features can be easily implemented by physicians providing early diagnosis of DOCK8 and STAT3 deficiencies.
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Affiliation(s)
- Nurhan Kasap
- Division of Pediatric Allergy/Immunology, Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Altan Kara
- TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey
| | - Velat Celik
- Faculty of Medicine, Pediatric Allergy and Immunology, Trakya University, Edirne, Turkey
| | - Sevgi Bilgic Eltan
- Division of Pediatric Allergy/Immunology, Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Idil Akay Haci
- Department of Pediatric Allergy and Immunology, Dr Behçet Uz Children's Hospital, Izmir, Turkey
| | - Hulya Kose
- Department of Pediatric Immunology and Rheumatology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Ayse Aygun
- Department of Pediatrics, Division of Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Emre Akkelle
- Pediatric Allergy and Immunology Department, Sancaktepe Training and Research Hospital, Istanbul, Turkey
| | - Nalan Yakici
- Pediatric Allergy and Immunology Department, Faculty of Medicine, Karadeniz Teknik University, Trabzon, Turkey
| | - Sukru Nail Guner
- Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
| | - Ismail Reisli
- Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
| | - Sevgi Keles
- Division of Pediatric Allergy and Immunology, Meram Medical Faculty, Necmettin Erbakan University, Konya, Turkey
| | - Sukru Cekic
- Department of Pediatric Immunology and Rheumatology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Sara Sebnem Kilic
- Department of Pediatric Immunology and Rheumatology, Medical Faculty, Uludag University, Bursa, Turkey
| | - Neslihan Edeer Karaca
- Department of Pediatrics, Division of Immunology, Faculty of Medicine, Ege University, Izmir, Turkey
| | - Nesrin Gulez
- Department of Pediatric Allergy and Immunology, Dr Behçet Uz Children's Hospital, Izmir, Turkey
| | - Ferah Genel
- Department of Pediatric Allergy and Immunology, Dr Behçet Uz Children's Hospital, Izmir, Turkey
| | - Ahmet Ozen
- Division of Pediatric Allergy/Immunology, Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ayse Deniz Yucelten
- Department of Dermatology, Faculty of Medicine, Marmara University, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Division of Pediatric Allergy/Immunology, Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Klaus Schmitz-Abe
- Division of Immunology, Boston Children's Hospital, Boston, MA, USA
- Department of Pediatrics, Harvard Medical School, Boston, MA, USA
- The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA
| | - Safa Baris
- Division of Pediatric Allergy/Immunology, Faculty of Medicine, Pediatric Allergy and Immunology, Marmara University, Fevzi Çakmak Mah. No: 41, Pendik, Istanbul, Turkey.
- Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey.
- The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey.
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29
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Mandato E, Yan Q, Ouyang J, Paczkowska J, Qin Y, Hao Y, Bojarczuk K, Hansen J, Chapuy B, Rodig SJ, Khan SJ, Redd RA, Shipp MA. MYD88L265P augments proximal B-cell receptor signaling in large B-cell lymphomas via an interaction with DOCK8. Blood 2023; 142:1219-1232. [PMID: 37467575 DOI: 10.1182/blood.2023019865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 05/31/2023] [Accepted: 06/16/2023] [Indexed: 07/21/2023] Open
Abstract
Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease with at least 5 recognized molecular subtypes. Cluster 5 (C5)/MCD tumors frequently exhibit concurrent alterations in the toll-like receptor (TLR) and B-cell receptor (BCR) pathway members, MYD88L265P and CD79B, and have a less favorable prognosis. In healthy B cells, the synergy between TLR and BCR signaling pathways integrates innate and adaptive immune responses and augments downstream NF-κB activation. In addition, physiologic TLR9 pathway engagement via MYD88, protein tyrosine kinase 2 (PYK2), and dedicator of cytokinesis 8 (DOCK8) increases proximal BCR signaling in healthy murine B cells. Although C5/MCD DLBCLs are selectively sensitive to Bruton tyrosine kinase (BTK) inhibition in in vitro studies and certain clinical trials, the role of mutated MYD88 in proximal BCR signaling remains undefined. Using engineered DLBCL cell line models, we found that concurrent MYD88L265P and CD79B alterations significantly increased the magnitude and duration of proximal BCR signaling, at the level of spleen tyrosine kinase and BTK, and augmented PYK2-dependent DOCK8 phosphorylation. MYD88L265P DLBCLs have significantly increased colocalization of DOCK8 with both MYD88 and the proximal BCR-associated Src kinase, LYN, in comparison with MYD88WT DLBCLs, implicating DOCK8 in MYD88L265P/proximal BCR cross talk. Additionally, DOCK8 depletion selectively decreased proximal BCR signaling, cellular proliferation, and viability of DLBCLs with endogenous MYD88L265P/CD79BY196F alterations and increased the efficacy of BTK blockade in these lymphomas. Therefore, MYD88L265P/DOCK8-enhanced proximal BCR signaling is a likely mechanism for the increased sensitivity of C5/MCD DLBCLs to BTK blockade.
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Affiliation(s)
- Elisa Mandato
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Qingsheng Yan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Jing Ouyang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Bristol Myers Squibb, Cambridge, MA
| | - Julia Paczkowska
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Yan Qin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Parthenon Therapeutics, Boston, MA
| | - Yansheng Hao
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pathology, University of Rochester Medical Center, Rochester, NY
| | - Kamil Bojarczuk
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Julia Hansen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Max Planck Institute for Biology of Ageing, Cologne, Germany
| | - Björn Chapuy
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Hematology, Oncology, and Tumor Immunology, Charité - University Medical Center Berlin, Campus Benjamin Franklin, Berlin, Germany
| | - Scott J Rodig
- Department of Pathology, Brigham and Women's Hospital, Boston, MA
| | - Sumbul Jawed Khan
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Robert A Redd
- Department of Data Science, Dana-Farber Cancer Institute, Boston, MA
| | - Margaret A Shipp
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
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30
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Kono A, Wakamatsu M, Umezawa Y, Muramatsu H, Fujiwara H, Tomomasa D, Inoue K, Hattori K, Mitsui T, Takada H, Minegishi Y, Takahashi Y, Yamamoto M, Mori T, Kanegane H. Successful treatment of DOCK8 deficiency by allogeneic hematopoietic cell transplantation from alternative donors. Int J Hematol 2023; 118:519-525. [PMID: 37131080 DOI: 10.1007/s12185-023-03613-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 05/04/2023]
Abstract
Dedicator of cytokinesis 8 (DOCK8) deficiency is a rare autosomal recessive inborn error of immunity (IEI) characterized by eczematous dermatitis, elevated serum IgE, and recurrent infections, comprising a seemingly hyper-IgE syndrome (HIES). DOCK8 deficiency is only curable with allogeneic hematopoietic cell transplantation (HCT), but the outcome of HCT from alternative donors is not fully understood. Here, we describe the cases of two Japanese patients with DOCK8 deficiency who were successfully treated by allogeneic HCT from alternative donors. Patient 1 underwent cord blood transplantation at the age of 16 years, and Patient 2 underwent haploidentical peripheral blood stem cell transplantation with post-transplant cyclophosphamide at the age of 22 years. Each patient received a fludarabine-based conditioning regimen. Their clinical manifestations, including refractory molluscum contagiosum, promptly improved post-HCT. They achieved successful engraftment and immune reconstitution without serious complications. Alternative donor sources such as cord blood and haploidentical donors can be options for allogeneic HCT for DOCK8 deficiency.
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Affiliation(s)
- Asuka Kono
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Manabu Wakamatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yoshihiro Umezawa
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
| | - Hideki Muramatsu
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroki Fujiwara
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Dan Tomomasa
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kento Inoue
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Keiichiro Hattori
- Department of Hematology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Tetsuo Mitsui
- Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Hidetoshi Takada
- Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yoshiyuki Minegishi
- Division of Molecular Medicine, Institute of Advanced Enzyme Research, Tokushima University, Tokushima, Japan
| | - Yoshiyuki Takahashi
- Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahide Yamamoto
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Takehiko Mori
- Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan.
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31
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Wilkie H, Timilshina M, Rahmayanti S, Das M, Pelovitz T, Geha RS. DOCK8 is essential for neutrophil mediated clearance of cutaneous S. aureus infection. Clin Immunol 2023; 254:109681. [PMID: 37385324 PMCID: PMC10529992 DOI: 10.1016/j.clim.2023.109681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 07/01/2023]
Abstract
DOCK8 deficient patients are susceptible to skin infection with Staphylococcus aureus which is normally cleared by neutrophils. We examined the mechanism of this susceptibility in mice. Dock8-/- mice had delayed clearance of S. aureus from skin mechanically injured by tape stripping. The numbers and viability of neutrophils in infected but not in uninfected, tape stripped skin were significantly reduced in Dock8-/- mice compared to WT controls. This is despite comparable numbers of circulating neutrophils, and normal to elevated cutaneous expression of Il17a and IL-17A inducible neutrophil attracting chemokines Cxcl1, Cxcl2 and Cxcl3. DOCK8 deficient neutrophils were significantly more susceptible to cell death upon in vitro exposure to S. aureus and exhibited reduced phagocytosis of S. aureus bioparticles but had a normal respiratory burst. Impaired neutrophil survival in infected skin and defective neutrophil phagocytosis likely underlie the susceptibility to cutaneous S. aureus infection in DOCK8 deficiency.
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Affiliation(s)
- Hazel Wilkie
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA
| | - Maheshwor Timilshina
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA
| | - Siti Rahmayanti
- Division of Plastic & Reconstructive Surgery, Brigham and Womens Hospital, Harvard Medical School, USA
| | - Mrinmoy Das
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA
| | - Tyler Pelovitz
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA
| | - Raif S Geha
- Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA.
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32
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Satitsuksanoa P, Iwasaki S, Boersma J, Bel Imam M, Schneider SR, Chang I, van de Veen W, Akdis M. B cells: The many facets of B cells in allergic diseases. J Allergy Clin Immunol 2023; 152:567-581. [PMID: 37247640 DOI: 10.1016/j.jaci.2023.05.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 03/30/2023] [Accepted: 05/16/2023] [Indexed: 05/31/2023]
Abstract
B cells play a key role in our immune system through their ability to produce antibodies, suppress a proinflammatory state, and contribute to central immune tolerance. We aim to provide an in-depth knowledge of the molecular biology of B cells, including their origin, developmental process, types and subsets, and functions. In allergic diseases, B cells are well known to induce and maintain immune tolerance through the production of suppressor cytokines such as IL-10. Similarly, B cells protect against viral infections such as severe acute respiratory syndrome coronavirus 2 that caused the recent coronavirus disease 2019 pandemic. Considering the unique and multifaceted functions of B cells, we hereby provide a comprehensive overview of the current knowledge of B-cell biology and its clinical applications in allergic diseases, organ transplantation, and cancer.
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Affiliation(s)
- Pattraporn Satitsuksanoa
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
| | - Sayuri Iwasaki
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Wageningen University & Research, Wageningen, The Netherlands
| | - Jolien Boersma
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Wageningen University & Research, Wageningen, The Netherlands
| | - Manal Bel Imam
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland
| | - Stephan R Schneider
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland
| | - Iris Chang
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland; Sean N. Parker Centre for Allergy and Asthma Research, Department of Medicine, Stanford University, Palo Alto, Calif
| | - Willem van de Veen
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland
| | - Mübeccel Akdis
- Swiss Institute of Allergy and Asthma Research (SIAF), University of Zürich, Davos, Switzerland.
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33
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Johar RA, Hasanain A, Khouqeer Y. Efficacy of Dupilumab in Treating Atopic Dermatitis With Recurrent Eczema Herpeticum in a Patient With DOCK8-Deficiency Hyper-IgE Syndrome: A Case Report. Cureus 2023; 15:e43360. [PMID: 37701007 PMCID: PMC10494277 DOI: 10.7759/cureus.43360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/21/2023] [Indexed: 09/14/2023] Open
Abstract
Dupilumab, a monoclonal antibody targeting interleukin 4 and interleukin 13, was used to successfully induce remission of chronic, disseminated eczema herpeticum in a six-year-old girl who has DOCK8-deficiency hyper-IgE syndrome. The patient was started on 200 mg of dupilumab administered once every four weeks. The patient had achieved complete resolution of all active herpetic lesions by the time her third dose was due. During the course of three months, she had not developed any new lesions, and significant improvement of the patient's skin, scalp, hair restoration, and nails was appreciated.
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Affiliation(s)
- Reshale A Johar
- Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
| | - Afnan Hasanain
- Dermatology, King Faisal Specialist Hospital and Research Centre, Jeddah, SAU
| | - Yousef Khouqeer
- Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, SAU
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34
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Baris S, Benamar M, Chen Q, Catak MC, Martínez-Blanco M, Wang M, Fong J, Massaad MJ, Sefer AP, Kara A, Babayeva R, Eltan SB, Yucelten AD, Bozkurtlar E, Cinel L, Karakoc-Aydiner E, Zheng Y, Wu H, Ozen A, Schmitz-Abe K, Chatila TA. Severe allergic dysregulation due to a gain of function mutation in the transcription factor STAT6. J Allergy Clin Immunol 2023; 152:182-194.e7. [PMID: 36758835 PMCID: PMC10330134 DOI: 10.1016/j.jaci.2023.01.023] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/10/2023]
Abstract
BACKGROUND Inborn errors of immunity have been implicated in causing immune dysregulation, including allergic diseases. STAT6 is a key regulator of allergic responses. OBJECTIVES This study sought to characterize a novel gain-of-function STAT6 mutation identified in a child with severe allergic manifestations. METHODS Whole-exome and targeted gene sequencing, lymphocyte characterization, and molecular and functional analyses of mutated STAT6 were performed. RESULTS This study reports a child with a missense mutation in the DNA binding domain of STAT6 (c.1114G>A, p.E372K) who presented with severe atopic dermatitis, eosinophilia, and elevated IgE. Naive lymphocytes from the affected patient displayed increased TH2- and suppressed TH1- and TH17-cell responses. The mutation augmented both basal and cytokine-induced STAT6 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase 1/2 inhibitor ruxolitinib reversed STAT6 hyperresponsiveness to IL-4, normalized TH1 and TH17 cells, suppressed the eosinophilia, and improved the patient's atopic dermatitis. CONCLUSIONS This study identified a novel inborn error of immunity due to a STAT6 gain-of-function mutation that gave rise to severe allergic dysregulation. Janus kinase inhibitor therapy could represent an effective targeted treatment for this disorder.
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Affiliation(s)
- Safa Baris
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Mehdi Benamar
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Qian Chen
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Mehmet Cihangir Catak
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Mónica Martínez-Blanco
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Muyun Wang
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Jason Fong
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass
| | - Michel J Massaad
- Department of Experimental Pathology, Immunology, and Microbiology, American University of Beirut, Beirut, Lebanon; Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Asena Pinar Sefer
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Altan Kara
- TUBITAK Marmara Research Center, Gene Engineering and Biotechnology Institute, Gebze, Turkey
| | - Royala Babayeva
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Sevgi Bilgic Eltan
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Ayse Deniz Yucelten
- Department of Dermatology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Emine Bozkurtlar
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Leyla Cinel
- Department of Pathology, School of Medicine, Marmara University, Istanbul, Turkey
| | - Elif Karakoc-Aydiner
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Yumei Zheng
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Mass; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Mass
| | - Hao Wu
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Mass; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Mass
| | - Ahmet Ozen
- Division of Pediatric Allergy and Immunology School of Medicine, Marmara University, Istanbul, Turkey; Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies, Istanbul, Turkey; The Isil Berat Barlan Center for Translational Medicine, Istanbul, Turkey
| | - Klaus Schmitz-Abe
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass; The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Mass
| | - Talal A Chatila
- Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass.
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35
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Ma CS, Freeman AF, Fleisher TA. Inborn Errors of Immunity: A Role for Functional Testing and Flow Cytometry in Aiding Clinical Diagnosis. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1579-1591. [PMID: 37054882 PMCID: PMC10330903 DOI: 10.1016/j.jaip.2023.03.049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Revised: 03/13/2023] [Accepted: 03/31/2023] [Indexed: 04/15/2023]
Abstract
With the exponential discovery of new inborn errors of immunity (IEI), it is becoming increasingly difficult to differentiate between a number of the more recently defined disorders. This is compounded by the fact that although IEI primarily present with immunodeficiency, the spectrum of disease is broad and often extends to features typical of autoimmunity, autoinflammation, atopic disease, and/or malignancy. Here we use case studies to discuss the laboratory and genetic tests used that ultimately led to the specific diagnoses.
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Affiliation(s)
- Cindy S Ma
- Immunology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia.
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Thomas A Fleisher
- Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, Md
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36
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Kothari R, Mohamed M, Vivekanandh K, Sandhu S, Sinha P, Bhatnagar A. Hyper-Immunoglobulin E Syndrome: Case Series of 6 Children from India. Indian Dermatol Online J 2023; 14:379-382. [PMID: 37266097 PMCID: PMC10231702 DOI: 10.4103/idoj.idoj_472_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/14/2022] [Accepted: 12/25/2022] [Indexed: 06/03/2023] Open
Abstract
Hyper-immunoglobulin E syndrome is a rare primary immunodeficiency syndrome characterized by severe atopic dermatitis, recurrent pulmonary and staphylococcal skin infections. Its diagnosis requires a high degree of suspicion, typical clinical features, and not mere rise in serum IgE levels. Genetic studies are not always possible in a resource poor setting in developing countries. In this case series, all children had recurrent eczematoid rash, secondary infections, multiple episodes of hospitalization for pulmonary infection and raised serum IgE levels. Diagnostic genetic study was feasible in only one of the cases which revealed pathogenic homozygous deletions of exons 15 to 18 (Transcript: NM_203447) in DOCK8 gene. The main goal of management of hyper-immunoglobulin E syndrome is aggressive treatment of infections and optimum skin care. Our case series highlights various characteristic, presentations, and management of this rare syndrome childhood cases. Awareness of these manifestations may facilitate early identification and contribute to optimal care of patients as representative data on the same is limited in literature.
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Affiliation(s)
- Rohit Kothari
- Department of Dermatology, Command Hospital Air Force, Bengaluru, Karnataka, India
| | - Muneer Mohamed
- Department of Dermatology, Command Hospital Air Force, Bengaluru, Karnataka, India
| | - K Vivekanandh
- Consultant Dermatologist, Edappal Hospitals Pvt Limited, Kerala, India
| | - Sunmeet Sandhu
- Department of Dermatology, Sree Mookambika Institute of Medical Sciences, Kulasekharam, Kanyakumari, Tamil Nadu, India
| | - Preema Sinha
- Department of Dermatology, 7 Air Force Hospital, Kanpur, India
| | - Anuj Bhatnagar
- Department of Dermatology, Command Hospital Air Force, Bengaluru, Karnataka, India
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37
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Slatter M, Lum SH. Personalized hematopoietic stem cell transplantation for inborn errors of immunity. Front Immunol 2023; 14:1162605. [PMID: 37090739 PMCID: PMC10113466 DOI: 10.3389/fimmu.2023.1162605] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Accepted: 03/20/2023] [Indexed: 04/08/2023] Open
Abstract
Patients with inborn errors of immunity (IEI) have been transplanted for more than 50 years. Many long-term survivors have ongoing medical issues showing the need for further improvements in how hematopoietic stem cell transplantation (HSCT) is performed if patients in the future are to have a normal quality of life. Precise genetic diagnosis enables early treatment before recurrent infection, autoimmunity and organ impairment occur. Newborn screening for severe combined immunodeficiency (SCID) is established in many countries. For newly described disorders the decision to transplant is not straight-forward. Specific biologic therapies are effective for some diseases and can be used as a bridge to HSCT to improve outcome. Developments in reduced toxicity conditioning and methods of T-cell depletion for mismatched donors have made transplant an option for all eligible patients. Further refinements in conditioning plus precise graft composition and additional cellular therapy are emerging as techniques to personalize the approach to HSCT for each patient.
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Affiliation(s)
- Mary Slatter
- Paediatric Immunology and HSCT, Newcastle University, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom
| | - Su Han Lum
- Paediatric Immunology and HSCT, Newcastle University, Newcastle upon Tyne, United Kingdom
- Translational and Clinical Research Institute, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom
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38
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Ma CS. T-helper-2 cells and atopic disease: lessons learnt from inborn errors of immunity. Curr Opin Immunol 2023; 81:102298. [PMID: 36870225 DOI: 10.1016/j.coi.2023.102298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 01/30/2023] [Accepted: 02/02/2023] [Indexed: 03/06/2023]
Abstract
Inborn errors of immunity (IEI) are caused by monogenic variants that affect the host response to bacterial, viral, and fungal pathogens. As such, individuals with IEI often present with severe, recurrent, and life-threatening infections. However, the spectrum of disease due to IEI is very broad and extends to include autoimmunity, malignancy, and atopic diseases such as eczema, atopic dermatitis, and food and environmental allergies. Here, I review IEI that affect cytokine signaling pathways that dysregulate CD4+ T-cell differentiation, resulting in increased T-helper-2 (Th2) cell development, function, and pathogenicity. These are elegant examples of how rare IEI can provide unique insights into more common pathologies such as allergic disease that are impacting the general population at increased frequency.
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Affiliation(s)
- Cindy S Ma
- Garvan Institute of Medical Research, Sydney, NSW, Australia; School of Clinical Medicine, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia; Clinical Immunogenomics Research Consortium of Australasia (CIRCA), Australia.
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Deciphering actin remodelling in immune cells through the prism of actin-related inborn errors of immunity. Eur J Cell Biol 2023; 102:151283. [PMID: 36525824 DOI: 10.1016/j.ejcb.2022.151283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Revised: 11/14/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
Actin cytoskeleton remodelling drives cell motility, cell to cell contacts, as well as membrane and organelle dynamics. Those cellular activities operate at a particularly high pace in immune cells since these cells migrate through various tissues, interact with multiple cellular partners, ingest microorganisms and secrete effector molecules. The central and multifaceted role of actin cytoskeleton remodelling in sustaining immune cell tasks in humans is highlighted by rare inborn errors of immunity due to mutations in genes encoding proximal and distal actin regulators. In line with the specificity of some of the actin-based processes at work in immune cells, the expression of some of the affected genes, such as WAS, ARPC1B and HEM1 is restricted to the hematopoietic compartment. Exploration of these natural deficiencies highlights the fact that the molecular control of actin remodelling is tuned distinctly in the various subsets of myeloid and lymphoid immune cells and sustains different networks associated with a vast array of specialized tasks. Furthermore, defects in individual actin remodelling proteins are usually associated with partial cellular impairments highlighting the plasticity of actin cytoskeleton remodelling. This review covers the roles of disease-associated actin regulators in promoting the actin-based processes of immune cells. It focuses on the specific molecular function of those regulators across various immune cell subsets and in response to different stimuli. Given the fact that numerous immune-related actin defects have only been characterized recently, we further discuss the challenges lying ahead to decipher the underlying patho-mechanisms.
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40
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Moser LM, Fekadu J, Willasch A, Rettinger E, Sörensen J, Jarisch A, Kirwil M, Lieb A, Holzinger D, Calaminus G, Bader P, Bakhtiar S. Treatment of inborn errors of immunity patients with inflammatory bowel disease phenotype by allogeneic stem cell transplantation. Br J Haematol 2023; 200:595-607. [PMID: 36214981 DOI: 10.1111/bjh.18497] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 12/12/2022]
Abstract
Patients with inborn errors of immunity (IEI) can suffer from treatment-refractory inflammatory bowel disease (IBD) causing failure to thrive and consequences of long-term multiple immunosuppressive treatments. Allogeneic haematopoietic stem cell transplantation (alloHSCT) can serve as a curative treatment option. In this single-centre retrospective cohort study we report on 11 paediatric and young adult IEI patients with IBD and failure to thrive, who had exhausted symptomatic treatment options and received alloHSCT. The cohort included chronic granulomatous disease (CGD), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency, STAT3 gain-of-function (GOF), Wiskott-Aldrich syndrome (WAS), dedicator of cytokinesis 8 (DOCK8) deficiency and one patient without genetic diagnosis. All patients achieved stable engraftment and immune reconstitution, and gastrointestinal symptoms were resolved after alloHSCT. The overall survival was 11/11 over a median follow-up of 34.7 months. Graft-versus-host disease (GVHD) was limited to grade I-II acute GVHD (n = 5), one case of grade IV acute GVHD and one case of limited chronic GVHD. Since treatment recommendations are limited, this work provides a centre-specific approach to treatment prior to transplant as well as conditioning in IEI patients with severe IBD.
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Affiliation(s)
- Laura M Moser
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Julia Fekadu
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - André Willasch
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Eva Rettinger
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Jan Sörensen
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Andrea Jarisch
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Marta Kirwil
- Division for Pediatric Gastroenterology, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Adrian Lieb
- Division for Pediatric Gastroenterology, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Dirk Holzinger
- Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany.,Department of Applied Health Sciences, University of Applied Sciences Bochum, Bochum, Germany
| | - Gabriele Calaminus
- Department for Children and Adolescents, University Hospital Bonn, Bonn, Germany
| | - Peter Bader
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
| | - Shahrzad Bakhtiar
- Division for Stem Cell Transplantation, Immunology and Intensive Care Medicine, Department for Children and Adolescents, University Hospital Frankfurt, Frankfurt, Germany
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Infections in Inborn Errors of Immunity with Combined Immune Deficiency: A Review. Pathogens 2023; 12:pathogens12020272. [PMID: 36839544 PMCID: PMC9958715 DOI: 10.3390/pathogens12020272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/13/2023] [Accepted: 02/04/2023] [Indexed: 02/10/2023] Open
Abstract
Enhanced susceptibility to microbes, often resulting in severe, intractable and frequent infections due to usually innocuous organisms at uncommon sites, is the most striking feature in individuals with an inborn error of immunity. In this narrative review, based on the International Union of Immunological Societies' 2022 (IUIS 2022) Update on phenotypic classification of human inborn errors of immunity, the focus is on commonly encountered Combined Immunodeficiency Disorders (CIDs) with susceptibility to infections. Combined immune deficiency disorders are usually commensurate with survival beyond infancy unlike Severe Combined Immune Deficiency (SCID) and are often associated with clinical features of a syndromic nature. Defective humoral and cellular immune responses result in susceptibility to a broad range of microbial infections. Although disease onset is usually in early childhood, mild defects may present in late childhood or even in adulthood. A precise diagnosis is imperative not only for determining management strategies, but also for providing accurate genetic counseling, including prenatal diagnosis, and also in deciding empiric treatment of infections upfront before investigation reports are available.
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Al-Tamemi S, Al-Zadjali S, Bruwer Z, Naseem SUR, Al-Siyabi N, ALRawahi M, Alkharusi K, Al-Thihli K, Al-Murshedi F, AlSayegh A, Al-Maawali A, Dennison D. Genetic Causes, Clinical Features, and Survival of Underlying Inborn Errors of Immunity in Omani Patients: a Single-Center Study. J Clin Immunol 2023; 43:452-465. [PMID: 36324046 DOI: 10.1007/s10875-022-01394-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 10/25/2022] [Indexed: 11/06/2022]
Abstract
PURPOSE Early identification of inborn errors of immunity (IEIs) is crucial due to the significant risk of morbidity and mortality. This study aimed to describe the genetic causes, clinical features, and survival rate of IEIs in Omani patients. METHODS A prospective study of all Omani patients evaluated for immunodeficiency was conducted over a 17-year period. Clinical features and diagnostic immunological findings were recorded. Targeted gene testing was performed in cases of obvious immunodeficiency. For cases with less conclusive phenotypes, a gene panel was performed, followed by whole-exome sequencing if necessary. RESULTS A total of 185 patients were diagnosed with IEIs during the study period; of these, 60.5% were male. Mean ages at symptom onset and diagnosis were 30.0 and 50.5 months, respectively. Consanguinity and a family history of IEIs were present in 86.9% and 50.8%, respectively. Most patients presented with lower respiratory infections (65.9%), followed by growth and development manifestations (43.2%). Phagocytic defects were the most common cause of IEIs (31.9%), followed by combined immunodeficiency (21.1%). Overall, 109 of 132 patients (82.6%) who underwent genetic testing received a genetic diagnosis, while testing was inconclusive for the remaining 23 patients (17.4%). Among patients with established diagnoses, 37 genes and 44 variants were identified. Autosomal recessive inheritance was present in 81.7% of patients with gene defects. Several variants were novel. Intravenous immunoglobulin therapy was administered to 39.4% of patients and 21.6% received hematopoietic stem cell transplantation. The overall survival rate was 75.1%. CONCLUSION This study highlights the genetic causes of IEIs in Omani patients. This information may help in the early identification and management of the disease, thereby improving survival and quality of life.
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Affiliation(s)
- Salem Al-Tamemi
- Clinical Immunology & Allergy Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman.
| | - Shoaib Al-Zadjali
- Molecular Hematology Unit, Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Zandre Bruwer
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
| | - Shafiq-Ur-Rehman Naseem
- Clinical Immunology & Allergy Unit, Department of Child Health, Sultan Qaboos University Hospital, Muscat, Oman
| | - Nabila Al-Siyabi
- Clinical Immunology & Allergy Unit, Directorate of Nursing, Sultan Qaboos University Hospital, Muscat, Oman
| | - Mohammed ALRawahi
- Molecular Hematology Unit, Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman
| | - Khalsa Alkharusi
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
| | - Khalid Al-Thihli
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
| | - Fathiya Al-Murshedi
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
| | - Abeer AlSayegh
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
| | - Almundher Al-Maawali
- Department of Clinical Genetics, Sultan Qaboos University Hospital, Muscat, Oman
- Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman
| | - David Dennison
- Molecular Hematology Unit, Department of Hematology, Sultan Qaboos University Hospital, Muscat, Oman
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Su HC. Insights into the pathogenesis of allergic disease from dedicator of cytokinesis 8 deficiency. Curr Opin Immunol 2023; 80:102277. [PMID: 36508760 PMCID: PMC9972721 DOI: 10.1016/j.coi.2022.102277] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/01/2022] [Accepted: 11/25/2022] [Indexed: 12/13/2022]
Abstract
Clinical observations and mechanistic studies in dedicator of cytokinesis 8 (DOCK8)-deficient patients and mice have revealed multiple mechanisms that could contribute to their unusually prevalent and severe allergic disease manifestations. Physical interactions of DOCK8 with STAT3 in B cells and T cells may contribute to increased IgE isotype switching or defective immune synapse formation that decreases T-cell receptor signal strength. A newly discovered TFH13 cell type promotes the development of life-threatening allergy via production of IL-13 and is increased in DOCK8 deficiency. Cytoskeletal derangements and cytothripsis, which were previously shown to account for the increased susceptibility to viral skin infection in DOCK8 deficiency, can lead to interplay between myeloid cells and T cells to ultimately increase production of IL-4, IL-5, and IL-13. Finally, the effects on type-2 innate lymphoid cells may also contribute to allergic disease.
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Affiliation(s)
- Helen C Su
- Human Immunological Diseases Section, Laboratory of Clinical Immunology and Microbiology, Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, United States.
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44
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Olewicz-Gawlik A, Kowala-Piaskowska A. Self-reactive IgE and anti-IgE therapy in autoimmune diseases. Front Pharmacol 2023; 14:1112917. [PMID: 36755957 PMCID: PMC9899859 DOI: 10.3389/fphar.2023.1112917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/06/2023] [Indexed: 01/24/2023] Open
Abstract
Growing evidence indicates the pathogenic role of autoreactive IgE in autoimmune diseases. Incidence of autoimmune and allergic diseases in the industrialized countries is consistently icreasing, thus leading to concerted efforts to comprehend the regulation of IgE-mediated mechanisms. The first reports of a presence of IgE autoantibodies in patients with autoimmune diseases have been published a long time ago, and it is now recognized that self-reactive IgE can mediate inflammatory response in bullous pemhigoid, systemic lupus erythematosus, chronic urticaria, and atopic dermatitis. The advances in understanding the pathomechanisms of these disorders brought to a successful use of anti-IgE strategies in their management. The present review discusses the current state of knowledge on the IgE-mediated autoimmunity and anti-IgE treatment, and pave the way for further exploration of the subject.
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Affiliation(s)
- Anna Olewicz-Gawlik
- Department of Immunology, Poznan University of Medical Sciences, Poznan, Poland,Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Poznan University of Medical Sciences, Poznan, Poland,*Correspondence: Anna Olewicz-Gawlik,
| | - Arleta Kowala-Piaskowska
- Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, Poznan University of Medical Sciences, Poznan, Poland
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Yaakoubi R, Mekki N, Ben-Mustapha I, Ben-Khemis L, Bouaziz A, Ben Fraj I, Ammar J, Hamzaoui A, Turki H, Boussofara L, Denguezli M, Haddad S, Ouederni M, Bejaoui M, Chan KW, Lau YL, Mellouli F, Barbouche MR, Ben-Ali M. Diagnostic challenge in a series of eleven patients with hyper IgE syndromes. Front Immunol 2023; 13:1057679. [PMID: 36703986 PMCID: PMC9871884 DOI: 10.3389/fimmu.2022.1057679] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/22/2022] [Indexed: 01/12/2023] Open
Abstract
Hyper IgE syndromes (HIES) is a heterogeneous group of Inborn Errors of Immunity characterized by eczema, recurrent skin and lung infections associated with eosinophilia and elevated IgE levels. Autosomal dominant HIES caused by loss of function mutations in Signal transducer and activator of transcription 3 (STAT3) gene is the prototype of these disorders. Over the past two decades, advent in genetic testing allowed the identification of ten other etiologies of HIES. Although Dedicator of Cytokinesis 8 (DOCK8) deficiency is no more classified among HIES etiologies but as a combined immunodeficiency, this disease, characterized by severe viral infections, food allergies, autoimmunity, and increased risk of malignancies, shares some clinical features with STAT3 deficiency. The present study highlights the diagnostic challenge in eleven patients with the clinical phenotype of HIES in a resource-limited region. Candidate gene strategy supported by clinical features, laboratory findings and functional investigations allowed the identification of two heterozygous STAT3 mutations in five patients, and a bi-allelic DOCK8 mutation in one patient. Whole Exome Sequencing allowed to unmask atypical presentations of DOCK8 deficiency in two patients presenting with clinical features reminiscent of STAT3 deficiency. Our study underlies the importance of the differential diagnosis between STAT3 and DOCK8 deficiencies in order to improve diagnostic criteria and to propose appropriate therapeutic approaches. In addition, our findings emphasize the role of NGS in detecting mutations that induce overlapping phenotypes.
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Affiliation(s)
- Roukaya Yaakoubi
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia,Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia
| | - Najla Mekki
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia,Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia
| | - Imen Ben-Mustapha
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia,Faculty of Medicine, Tunis El Manar University, Tunis, Tunisia
| | - Leila Ben-Khemis
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia
| | - Asma Bouaziz
- Department of Pediatrics, Ben Arous Hospital of Tunis, Tunis, Tunisia
| | - Ilhem Ben Fraj
- Department of Pediatrics, National Bone Marrow Transplantation Center, Tunis, Tunisia
| | - Jamel Ammar
- Pulmonology B Department, AbderrahmenMami Hospital, Ariana, Tunisia
| | - Agnès Hamzaoui
- Pulmonology B Department, AbderrahmenMami Hospital, Ariana, Tunisia
| | - Hamida Turki
- Department of Dermatology, HédiChaker Hospital of SFAX, Sfax, Tunisia
| | - Lobna Boussofara
- Department of Dermatology, Farhat Hached Hospital, Sousse, Tunisia
| | | | - Samir Haddad
- Department of Pediatrics, Children Hospital of Tunis, Tunis, Tunisia
| | - Monia Ouederni
- Department of Pediatrics, National Bone Marrow Transplantation Center, Tunis, Tunisia
| | - Mohamed Bejaoui
- Department of Pediatrics, National Bone Marrow Transplantation Center, Tunis, Tunisia
| | - Koon Wing Chan
- Department of Pediatrics and Adolescent Medicine, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yu Lung Lau
- Department of Pediatrics and Adolescent Medicine, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Fethi Mellouli
- Department of Pediatrics, National Bone Marrow Transplantation Center, Tunis, Tunisia
| | - Mohamed-Ridha Barbouche
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia,Department of Microbiology, Immunology and Infectious Diseases, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Bahrain
| | - Meriem Ben-Ali
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, University Tunis El-Manar, Tunis, Tunisia,*Correspondence: Meriem Ben-Ali,
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Cohn IS, Henrickson SE, Striepen B, Hunter CA. Immunity to Cryptosporidium: Lessons from Acquired and Primary Immunodeficiencies. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:2261-2268. [PMID: 36469846 PMCID: PMC9731348 DOI: 10.4049/jimmunol.2200512] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 08/30/2022] [Indexed: 01/04/2023]
Abstract
Cryptosporidium is a ubiquitous protozoan parasite that infects gut epithelial cells and causes self-limited diarrhea in immunocompetent individuals. However, in immunocompromised hosts with global defects in T cell function, this infection can result in chronic, life-threatening disease. In addition, there is a subset of individuals with primary immunodeficiencies associated with increased risk for life-threatening cryptosporidiosis. These patients highlight MHC class II expression, CD40-CD40L interactions, NF-κB signaling, and IL-21 as key host factors required for resistance to this enteric pathogen. Understanding which immune deficiencies do (or do not) lead to increased risk for severe Cryptosporidium may reveal mechanisms of parasite restriction and aid in the identification of novel strategies to manage this common pathogen in immunocompetent and deficient hosts.
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Affiliation(s)
- Ian S. Cohn
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Sarah E. Henrickson
- Institute for Immunology, University of Pennsylvania, Philadelphia, PA, USA
- Division of Allergy Immunology, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | - Boris Striepen
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Christopher A. Hunter
- Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Sharma D, Ben Yakov G, Kapuria D, Viana Rodriguez G, Gewirtz M, Haddad J, Kleiner DE, Koh C, Bergerson JRE, Freeman AF, Heller T. Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity. Hepatology 2022; 76:1845-1861. [PMID: 35466407 DOI: 10.1002/hep.32539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 03/30/2022] [Accepted: 04/17/2022] [Indexed: 12/08/2022]
Abstract
Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.
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Affiliation(s)
- Disha Sharma
- Department of Internal MedicineMedStar Washington Hospital Center & Georgetown UniversityWashingtonDCUSA.,Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Gil Ben Yakov
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA.,26744Center for Liver DiseaseSheba Medical CenterTel HaShomerIsrael
| | - Devika Kapuria
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA.,Department of GastroenterologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Gracia Viana Rodriguez
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Meital Gewirtz
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - James Haddad
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - David E Kleiner
- 3421Laboratory of PathologyNational Cancer InstituteBethesdaMarylandUSA
| | - Christopher Koh
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Jenna R E Bergerson
- Laboratory of Clinical Immunology and MicrobiologyNIAID, NIHBethesdaMarylandUSA
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and MicrobiologyNIAID, NIHBethesdaMarylandUSA
| | - Theo Heller
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
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48
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Silbert S, Cole K, Bedoya SZ, Freeman AF, Whangbo JS, Avila DN, Su HC, Yates B, Epstein M, Wendler DS, Pai SY, Hickstein DD, Wiener L, Shah NN. Tandem hematopoietic stem cell transplant considerations in families with multiple siblings affected by DOCK8 deficiency. Bone Marrow Transplant 2022; 57:1721-1723. [PMID: 35999252 PMCID: PMC10391740 DOI: 10.1038/s41409-022-01778-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 08/02/2022] [Accepted: 08/03/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Sara Silbert
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
- Children's National Hospital, Center for Cancer and Blood Disorders, Washington, DC, USA.
| | - Kristen Cole
- Search, Procurement, and Outcomes Coordinator, Office of the Clinical Director, Center of Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Sima Z Bedoya
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Jennifer S Whangbo
- Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Daniele N Avila
- Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Helen C Su
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Bonnie Yates
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Monica Epstein
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - David S Wendler
- Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Sung-Yun Pai
- Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Dennis D Hickstein
- Immune Deficiency-Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Lori Wiener
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| | - Nirali N Shah
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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49
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Alshengeti A. Eczema herpeticum vs dermatitis herpetiformis as a clue of dedicator of cytokinesis 8 deficiency diagnosis: A case report. World J Clin Cases 2022; 10:10735-10741. [PMID: 36312485 PMCID: PMC9602220 DOI: 10.12998/wjcc.v10.i29.10735] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/10/2022] [Accepted: 09/07/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Dedicator of cytokinesis 8 (DOCK 8) deficiency, also known as autosomal recessive hyper immunoglobulin E (IgE) syndrome, is a combined immunodeficiency disease that was first recognized in 2009. It is caused by genetic alterations (mutations or deletions) in the DOCK 8 gene and is characterized by multiple allergies, elevated IgE levels, and susceptibility to viral and bacterial infections. Early diagnosis is critical to optimize the success of stem cell transplantation.
CASE SUMMARY This study reports the case of a pediatric patient with DOCK 8 deficiency who had negative genetic testing using multiplex primary immunodeficiency (PID) panel and whole-exome sequencing (WES) with a next-generation sequencing method. He presented with chronic diarrhea and was managed as celiac disease based on previous negative workup for immunodeficiency and duodenal biopsy. He developed a generalized vesicular rash which was thought to be dermatitis herpetiformis associated with celiac disease. However, it turned out to be Eczema herpeticum based on positive herpes simplex virus from blood and lesions. The diagnosis was re-evaluated after the child was found to have multiple viral, bacterial, and parasitic co-infections (herpes simplex virus, cytomegalovirus, Epstein-Barr virus, Salmonella, and cryptosporidiosis). Re-evaluation with target gene testing with copy number variation (CNV) analysis and Multiplex Ligation Probe Amplification (MLPA) showed a large homozygous deletion in the DOCK 8 gene, confirming the diagnosis of DOCK 8 deficiency.
CONCLUSION Targeted gene testing with CNV analysis might detect deletions that can be missed by WES for diagnosing patients with PID.
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Affiliation(s)
- Amer Alshengeti
- Department of Pediatrics, College of Medicine, Taibah University; Department of Infection prevention and control, Prince Mohammad Bin Abdulaziz Hospital, National Guard Health Affairs, Al-Madinah 41491, Saudi Arabia
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50
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Pan C, Zhao A, Li M. Atopic Dermatitis-like Genodermatosis: Disease Diagnosis and Management. Diagnostics (Basel) 2022; 12:diagnostics12092177. [PMID: 36140582 PMCID: PMC9498295 DOI: 10.3390/diagnostics12092177] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 07/23/2022] [Accepted: 08/15/2022] [Indexed: 11/29/2022] Open
Abstract
Eczema is a classical characteristic not only in atopic dermatitis but also in various genodermatosis. Patients suffering from primary immunodeficiency diseases such as hyper-immunoglobulin E syndromes, Wiskott-Aldrich syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome, STAT5B deficiency, Omenn syndrome, atypical complete DiGeorge syndrome; metabolic disorders such as acrodermatitis enteropathy, multiple carboxylase deficiency, prolidase deficiency; and other rare syndromes like severe dermatitis, multiple allergies and metabolic wasting syndrome, Netherton syndrome, and peeling skin syndrome frequently perform with eczema-like lesions. These genodermatosis may be misguided in the context of eczematous phenotype. Misdiagnosis of severe disorders unavoidably affects appropriate treatment and leads to irreversible outcomes for patients, which underlines the importance of molecular diagnosis and genetic analysis. Here we conclude clinical manifestations, molecular mechanism, diagnosis and management of several eczema-related genodermatosis and provide accessible advice to physicians.
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Affiliation(s)
- Chaolan Pan
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Anqi Zhao
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
| | - Ming Li
- Department of Dermatology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Institute of Dermatology, Shanghai Jiaotong University School of Medicine, Shanghai 200092, China
- Department of Dermatology, The Children’s Hospital of Fudan University, Shanghai 200092, China
- Correspondence: ; Tel.: +86-2125078571
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