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Wen L, Zhang X, Yang Q, Zhou F. Chromatin accessibility profiling of Treg cells in acute urticaria. Epigenetics 2025; 20:2503126. [PMID: 40355834 PMCID: PMC12077484 DOI: 10.1080/15592294.2025.2503126] [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: 10/29/2024] [Revised: 04/20/2025] [Accepted: 05/01/2025] [Indexed: 05/15/2025] Open
Abstract
Acute urticaria can be a presenting symptom of anaphylaxis characterized by transient red swellings or fulminant wheals, often accompanied by severe pruritus. Numerous studies have substantiated the important involvement of regulatory T cells (Tregs) in the occurrence of allergic diseases and autoimmune diseases. However, the role of Tregs in the pathogenesis of acute urticaria is unclear. In this study, we found that the frequency of Tregs in peripheral blood mononuclear cells (PBMCs) was decreased in patients with acute urticaria compared with normal controls by flow cytometry. Analysis of Assay for transposase-accessible chromatin with sequencing (ATAC-seq) data identified 28 differentially accessible regions comparing Tregs from healthy individuals and patients with acute urticaria, all showing increased chromatin accessibility in the Tregs from acute urticaria. IL-1b was highly expressed in sera of patients with acute urticaria and the level of IL-1b was moderately positively related to white blood cell count. The elevated expression of IL-1b may be due to the diminished immune-suppressive function following the decline of Tregs in this study. We found that IL1B gene expression was also significantly increased in the skin lesions of both chronic spontaneous urticaria and solar urticaria compared to healthy controls. IL1B might play a key role in the development of acute urticaria and IL1B could be a potential prognostic biomarker and therapeutic target in urticaria.
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Affiliation(s)
- Leilei Wen
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China
| | - Xiaojing Zhang
- Department of Dermatology, Hangzhou First People’s Hospital Xiasha Campus, Hangzhou Rehabilitation Hospital, Hangzhou, China
| | - Qiaoshan Yang
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China
| | - Fusheng Zhou
- Department of Dermatology, The First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
- Institute of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Ministry of Education, Key Laboratory of Dermatology, Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
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2
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Tumentemur G, Aygun EG, Yurtsever B, Cakirsoy D, Ovali E. Effect of amniotic fluid on hair follicle growth. J DERMATOL TREAT 2025; 36:2451389. [PMID: 39827901 DOI: 10.1080/09546634.2025.2451389] [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: 10/17/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025]
Abstract
Purpose: Human amniotic fluid stem cells (hAFSCs) have shown significant regenerative potential in treating hair loss, wound healing, and tissue repair. This study aims to evaluate the effects of human amniotic fluid (hAF) on hair follicle (HF) regeneration and immune system modulation. Materials and Methods: The hAF used was pooled, acellular, and gamma-irradiated to standardize its contents and enhance its stability. Both irradiated (FAFI) and non-irradiated (FAF) hAF were assessed for their efficacy and safety in promoting hair growth and modulating immune responses in a rat model of hair loss. The study examined HF regeneration, transition to the anagen phase, and macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype. Results: Both FAF and FAFI treatments significantly increased HF density, with FAFI exhibiting enhanced effects. Histological analysis demonstrated improved HF regeneration, increased M2 macrophages, and reduced collagen fiber deposition in treated areas. Gamma irradiation likely improved the efficacy of FAFI by stabilizing active components and inhibiting protease activity. Conclusions: Irradiated hAF is a safe and effective therapeutic candidate for alopecia and HF growth disorders. These findings support further evaluation of hAF in clinical trials to validate its potential for hair regeneration therapies.
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Affiliation(s)
- Gamze Tumentemur
- Vocational School of Health Services, Acibadem Mehmet Ali Aydinlar University, Istanbul, Turkey
| | - Elif Ganime Aygun
- Department of Obstetrics and Gynecology, Acibadem Mehmet Ali Aydinlar University Atakent Hospital, Istanbul, Turkey
| | - Bulut Yurtsever
- Acibadem Labcell Cellular Therapy Laboratory, Istanbul, Turkey
| | - Didem Cakirsoy
- Acibadem Labcell Cellular Therapy Laboratory, Istanbul, Turkey
| | - Ercument Ovali
- Acibadem Labcell Cellular Therapy Laboratory, Istanbul, Turkey
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3
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Borna S, Meffre E, Bacchetta R. FOXP3 deficiency, from the mechanisms of the disease to curative strategies. Immunol Rev 2024; 322:244-258. [PMID: 37994657 DOI: 10.1111/imr.13289] [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: 11/24/2023]
Abstract
FOXP3 gene is a key transcription factor driving immune tolerance and its deficiency causes immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome (IPEX), a prototypic primary immune regulatory disorder (PIRD) with defective regulatory T (Treg) cells. Although life-threatening, the increased awareness and early diagnosis have contributed to improved control of the disease. IPEX currently comprises a broad spectrum of clinical autoimmune manifestations from severe early onset organ involvement to moderate, recurrent manifestations. This review focuses on the mechanistic advancements that, since the IPEX discovery in early 2000, have informed the role of the human FOXP3+ Treg cells in controlling peripheral tolerance and shaping the overall immune landscape of IPEX patients and carrier mothers, contributing to defining new treatments.
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Affiliation(s)
- Simon Borna
- Department of Pediatrics, Division of Hematology, Oncology Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
| | - Eric Meffre
- Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA
| | - Rosa Bacchetta
- Department of Pediatrics, Division of Hematology, Oncology Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA
- Center for Definitive and Curative Medicine (CDCM), Stanford University School of Medicine, Stanford, California, USA
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4
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Cohen JN, Gouirand V, Macon CE, Lowe MM, Boothby IC, Moreau JM, Gratz IK, Stoecklinger A, Weaver CT, Sharpe AH, Ricardo-Gonzalez RR, Rosenblum MD. Regulatory T cells in skin mediate immune privilege of the hair follicle stem cell niche. Sci Immunol 2024; 9:eadh0152. [PMID: 38181095 PMCID: PMC11003870 DOI: 10.1126/sciimmunol.adh0152] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 11/10/2023] [Indexed: 01/07/2024]
Abstract
Immune tolerance is maintained in lymphoid organs (LOs). Despite the presence of complex immune cell networks in non-LOs, it is unknown whether self-tolerance is maintained in these tissues. We developed a technique to restrict genetic recombination to regulatory T cells (Tregs) only in skin. Selective depletion of skin Tregs resulted in T cell-mediated inflammation of hair follicles (HFs). Suppression did not rely on CTLA-4, but instead on high-affinity interleukin-2 (IL-2) receptor expression by skin Tregs, functioning exclusively in a cell-extrinsic manner. In a novel model of HF stem cell (HFSC)-driven autoimmunity, we reveal that skin Tregs immunologically protect the HFSC niche. Finally, we used spatial transcriptomics to identify aberrant IL-2 signaling at stromal-HF interfaces in a rare form of human alopecia characterized by HFSC destruction and alopecia areata. Collectively, these results reveal the fundamental biology of Tregs in skin uncoupled from the systemic pool and elucidate a mechanism of self-tolerance.
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Affiliation(s)
- Jarish N. Cohen
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
- Department of Pathology, University of California, San Francisco, San Francisco, CA, USA
| | - Victoire Gouirand
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Courtney E. Macon
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Margaret M. Lowe
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Ian C. Boothby
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
- Medical Scientist Training Program, University of California, San Francisco, CA, USA
| | - Joshua M. Moreau
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Iris K. Gratz
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
| | - Angelika Stoecklinger
- Department of Molecular Biology, University of Salzburg, Salzburg, Austria
- EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology, University Hospital of the Paracelsus Medical, University of Salzburg, Salzburg, Austria
| | - Casey T. Weaver
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Arlene H. Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, MA, USA
- Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
| | | | - Michael D. Rosenblum
- Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
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5
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Englander H, Paiewonsky B, Castelo-Soccio L. Alopecia Areata: A Review of the Genetic Variants and Immunodeficiency Disorders Associated with Alopecia Areata. Skin Appendage Disord 2023; 9:325-332. [PMID: 37900769 PMCID: PMC10601931 DOI: 10.1159/000530432] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Accepted: 03/23/2023] [Indexed: 10/31/2023] Open
Abstract
Alopecia areata (AA) is an autoimmune form of non-scarring hair loss that occurs on a spectrum from patchy loss of hair on the scalp, to complete hair loss. Histology features can vary, but increased abundance of telogen hair and miniaturized hair follicles are classic hallmarks [Clin Cosmet Investig Dermatol. 2015;8:397-403]. Additionally, lymphocytic infiltration of the hair bulb is a commonly observed histology feature of AA which underscores how the disease is an autoimmune-mediated one that results from immune-mediated attack of the hair follicle. In a healthy individual, the hair follicle is one of the body's immune-privileged sites, but the breakdown of this immune privilege is thought to be an important driver in AA disease development. Diagnosis of AA is usually based on phenotypic manifestations in conjunction with biopsies which can help conclude whether the hair loss is autoimmune based. However, varied manifestation of disease both clinically and histologically makes diagnosis criteria more ambiguous and early identification of disease harder to achieve. A better understanding of genes that are associated with increased AA risk may help elucidate potential gene targets for future therapeutics.
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Affiliation(s)
- Hanna Englander
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA
| | - Briana Paiewonsky
- Charles E Schmidt College of Medicine at Florida Atlantic University, Boca Raton, FL, USA
| | - Leslie Castelo-Soccio
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD, USA
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6
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Lee WQ, Leong KF. Infantile vitiligo and alopecia in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. Pediatr Dermatol 2023; 40:886-889. [PMID: 36727435 DOI: 10.1111/pde.15266] [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: 09/12/2022] [Accepted: 01/17/2023] [Indexed: 02/03/2023]
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is characterized by failure to thrive, severe chronic diarrhea, neonatal type 1 diabetes or thyroiditis, and eczematous dermatitis. We report a patient with infantile onset IPEX syndrome who developed vitiligo, alopecia, and chronic diarrhea. Awaiting stem cell transplant, he had multiple episodes of sepsis and succumbed at the age of 10 months. The constellation of symptoms is important to prompt clinicians to suspect this rare syndrome as early hematopoietic stem cell transplantation is the only cure for IPEX patients.
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Affiliation(s)
- Wai Quen Lee
- Paediatric Dermatology Unit, Department of Paediatrics, Hospital Tunku Azizah, Kuala Lumpur, Malaysia
| | - Kin Fon Leong
- Paediatric Dermatology Unit, Department of Paediatrics, Hospital Tunku Azizah, Kuala Lumpur, Malaysia
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Costa F, Beltrami E, Mellone S, Sacchetti S, Boggio E, Gigliotti CL, Stoppa I, Dianzani U, Rolla R, Giordano M. Genes and Microbiota Interaction in Monogenic Autoimmune Disorders. Biomedicines 2023; 11:1127. [PMID: 37189745 PMCID: PMC10135656 DOI: 10.3390/biomedicines11041127] [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: 03/10/2023] [Revised: 03/30/2023] [Accepted: 04/05/2023] [Indexed: 05/17/2023] Open
Abstract
Monogenic autoimmune disorders represent an important tool to understand the mechanisms behind central and peripheral immune tolerance. Multiple factors, both genetic and environmental, are known to be involved in the alteration of the immune activation/immune tolerance homeostasis typical of these disorders, making it difficult to control the disease. The latest advances in genetic analysis have contributed to a better and more rapid diagnosis, although the management remains confined to the treatment of clinical manifestations, as there are limited studies on rare diseases. Recently, the correlation between microbiota composition and the onset of autoimmune disorders has been investigated, thus opening up new perspectives on the cure of monogenic autoimmune diseases. In this review, we will summarize the main genetic features of both organ-specific and systemic monogenic autoimmune diseases, reporting on the available literature data on microbiota alterations in these patients.
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Affiliation(s)
- Federica Costa
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Eleonora Beltrami
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Simona Mellone
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Sara Sacchetti
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Elena Boggio
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Casimiro Luca Gigliotti
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Ian Stoppa
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
| | - Umberto Dianzani
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Roberta Rolla
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
| | - Mara Giordano
- Department of Health Sciences, Università del Piemonte Orientale, 28100 Novara, Italy; (F.C.); (S.S.); (E.B.); (C.L.G.); (I.S.); (R.R.); (M.G.)
- Maggiore della Carità University Hospital, 28100 Novara, Italy; (E.B.); (S.M.)
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Maher MC, Hall EM, Horii KA. Generalized eczematous dermatitis and pruritus responsive to dupilumab in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Pediatr Dermatol 2021; 38:1370-1371. [PMID: 34272772 DOI: 10.1111/pde.14717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
This case describes a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome with diffuse eczematous dermatitis and severe, intractable pruritus. Despite a bone marrow transplant and immunosuppressive therapy, his skin findings and pruritus persisted. Off-label dupilumab provided significant improvement and almost complete clearance of the dermatitis and pruritus. This is the first known report of dupilumab being used in a patient with IPEX syndrome.
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Affiliation(s)
- Maeve C Maher
- Division of Dermatology, Children's Mercy-Kansas City, Kansas City, MO, USA
| | - Erin M Hall
- Division of Hematology/Oncology/Bone Marrow Transplant, Children's Mercy-Kansas City, Kansas City, MO, USA
| | - Kimberly A Horii
- Division of Dermatology, Children's Mercy-Kansas City, Kansas City, MO, USA
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9
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Andersen SM, Fage S, Rubak SL, Holm M, Jensen JMB, Mogensen T, Deleuran M. Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked Syndrome Manifesting as Lymphocytic Interstitial Pneumonia and Treatment-Resistant Bullous Pemphigoid. PEDIATRIC ALLERGY IMMUNOLOGY AND PULMONOLOGY 2021; 34:76-79. [PMID: 34143686 DOI: 10.1089/ped.2020.1307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare immune deficiency with a broad clinical presentation. IPEX syndrome causes dysfunctional regulatory T cells, increasing the risk of autoimmune diseases. In this case report, we describe a 7-year-old boy with lymphocytic interstitial pneumonia and bullous pemphigoid who was recently diagnosed with IPEX syndrome.
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Affiliation(s)
| | - Simon Fage
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
| | - Sune Leisgaard Rubak
- Department of Pediatrics and Adolescents Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Mette Holm
- Department of Pediatrics and Adolescents Medicine, Aarhus University Hospital, Aarhus, Denmark
| | | | - Trine Mogensen
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Mette Deleuran
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
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Tan G, Wang X, Zheng G, Du J, Zhou F, Liang Z, Wei W, Yu H. Meta-analysis reveals significant association between FOXP3 polymorphisms and susceptibility to Graves' disease. J Int Med Res 2021; 49:3000605211004199. [PMID: 33858251 PMCID: PMC8054215 DOI: 10.1177/03000605211004199] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE This meta-analysis aimed to determine the associations between the rs3761547, rs3761548, and rs3761549 single-nucleotide polymorphisms (SNPs) of the forkhead box P3 (FOXP3) gene and susceptibility to Graves' disease (GD). METHODS Case-control studies with information on the associations between the rs3761547, rs3761548, and rs3761549 FOXP3 SNPs and GD published before 01 May 2020 were identified in the PubMed, Embase, Web of Science, and China National Knowledge Infrastructure databases. Data from the studies were analyzed using RevMan version 5.3. RESULTS Seven independent case-control studies including 4051 GD patients and 4569 controls were included in the meta-analysis. The overall pooled analysis indicated that FOXP3/rs3761548 and FOXP3/rs3761549 polymorphisms were significantly associated with GD susceptibility (rs3761548: A vs. C, odds ratio [OR] = 1.32, 95% confidence interval [CI] 1.05-1.67; rs3761549: TT vs. CC, OR = 1.98, 95%CI 1.49-2.65; (TT + TC) vs. CC, OR = 1.44, 95%CI 1.11-1.88). In contrast, the FOXP3/rs3761547 polymorphism was not associated with GD susceptibility. Subgroup analysis according to ethnicity showed that rs3761548 was associated with GD in Asians but not in Caucasians, whereas rs3761549 was associated in both Asians and Caucasians. CONCLUSION This meta-analysis demonstrated that FOXP3/rs3761548 and FOXP3/rs3761549 SNPs were significantly associated with susceptibility to GD, at least in Asian populations.
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Affiliation(s)
- Guiqin Tan
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Xin Wang
- Department of Basic Medical Education, Zunyi Medical University, Zunyi, China
| | - Guangbing Zheng
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Juan Du
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Fangyu Zhou
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Zhongzhi Liang
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Wenwen Wei
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
| | - Hongsong Yu
- Department of Immunology, Special Key Laboratory of Gene Detection and Therapy of Guizhou Province, Zunyi Medical University, Zunyi, China
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11
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Ben-Skowronek I. IPEX Syndrome: Genetics and Treatment Options. Genes (Basel) 2021; 12:323. [PMID: 33668198 PMCID: PMC7995986 DOI: 10.3390/genes12030323] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/03/2022] Open
Abstract
(1) Background: IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome characterizes a complex autoimmune reaction beginning in the perinatal period, caused by a dysfunction of the transcription factor forkhead box P3 (FOXP3). (2) Objectives: Studies have shown the clinical, immunological, and molecular heterogeneity of patients with IPEX syndrome. The symptoms, treatment, and survival were closely connected to the genotype of the IPEX syndrome. Recognition of the kind of mutation is important for the diagnostics of IPEX syndrome in newborns and young infants, as well as in prenatal screening. The method of choice for treatment is hematopoietic stem cell transplantation and immunosuppressive therapy. In children, supportive therapy for refractory diarrhea is very important, as well as replacement therapy of diabetes mellitus type 1 (DMT1) and other endocrinopathies. In the future, genetic engineering methods may be of use in the successful treatment of IPEX syndrome. (3) Conclusions: The genetic defects determine a diagnostic approach and prognosis, making the knowledge of the genetics of IPEX syndrome fundamental to introducing novel treatment methods.
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MESH Headings
- Allografts
- Animals
- Diabetes Mellitus, Type 1/congenital
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/metabolism
- Diabetes Mellitus, Type 1/therapy
- Diarrhea/diagnosis
- Diarrhea/genetics
- Diarrhea/metabolism
- Diarrhea/therapy
- Female
- Forkhead Transcription Factors/genetics
- Forkhead Transcription Factors/metabolism
- Genetic Diseases, X-Linked/diagnosis
- Genetic Diseases, X-Linked/genetics
- Genetic Diseases, X-Linked/metabolism
- Genetic Diseases, X-Linked/therapy
- Hematopoietic Stem Cell Transplantation
- Humans
- Immune System Diseases/congenital
- Immune System Diseases/diagnosis
- Immune System Diseases/genetics
- Immune System Diseases/metabolism
- Immune System Diseases/therapy
- Infant
- Infant, Newborn
- Male
- Mutation
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Affiliation(s)
- Iwona Ben-Skowronek
- Department of Pediatric Endocrinology and Diabetology, Medical University, 20-093 Lublin, Poland
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12
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Consonni F, Ciullini Mannurita S, Gambineri E. Atypical Presentations of IPEX: Expect the Unexpected. Front Pediatr 2021; 9:643094. [PMID: 33614561 PMCID: PMC7892580 DOI: 10.3389/fped.2021.643094] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 01/13/2021] [Indexed: 12/11/2022] Open
Abstract
Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder that has become a model of monogenic autoimmunity. IPEX is caused by mutations in FOXP3 gene, a master regulator of regulatory T cells (Treg). Cases reported in the last 20 years demonstrate that IPEX clinical spectrum encompasses more than the classical triad of early-onset intractable diarrhea, type 1 diabetes (T1D) and eczema. Atypical cases of IPEX include patients with late-onset of symptoms, single-organ involvement, mild disease phenotypes or rare clinical features (e.g., atrophic gastritis, interstitial lung disease, nephropathy etc.). Several atypical presentations have recently been reported, suggesting that IPEX incidence might be underestimated. Immunosuppression (IS) treatment strategies can control the disease, however at the moment allogeneic hematopoietic stem cell transplantation (HSCT) is the only available definitive cure, therefore it is important to achieve a prompt diagnosis. This review aims to describe unusual clinical phenotypes, beyond classical IPEX. Overall, our analysis contributes to increase awareness and finally improve diagnosis and treatment intervention in IPEX in order to ensure a good quality of life.
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Affiliation(s)
- Filippo Consonni
- Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Sara Ciullini Mannurita
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy
| | - Eleonora Gambineri
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research, and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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Barzaghi F, Passerini L. IPEX Syndrome: Improved Knowledge of Immune Pathogenesis Empowers Diagnosis. Front Pediatr 2021; 9:612760. [PMID: 33692972 PMCID: PMC7937806 DOI: 10.3389/fped.2021.612760] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/21/2021] [Indexed: 12/18/2022] Open
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic autoimmune disease with variable clinical manifestations, ranging from early-onset severe autoimmunity, including enteropathy, eczema, and type 1 diabetes, to late-onset or atypical symptoms. Despite the clinical heterogeneity, the unifying feature of IPEX is mutation of the FOXP3 gene, which encodes a transcription factor essential for maintenance of thymus-derived regulatory T cells (Tregs). In IPEX patients, Tregs can be present, although unstable and impaired in function, unable to inhibit proliferation and cytokine production of effector T (Teff) cells. Mutated FOXP3 can also disrupt other compartments: FOXP3-deficient Teff cells proliferate more than the wild-type counterpart, display altered T-cell-receptor signaling response, a reduced T-naïve compartment and a skew toward a Th2 profile. Due to FOXP3 mutations, the frequency of autoreactive B cells is increased and the IgA and IgE production is altered, together with early emergence of tissue-specific autoantibodies. Recently, the awareness of the wide clinical spectrum of IPEX improved the diagnostic tools. In cases presenting with enteropathy, histological evaluation is helpful, although there are no pathognomonic signs of disease. On the other hand, the study of FOXP3 expression and in vitro Treg function, as well as the detection of specific circulating autoantibodies, is recommended to narrow the differential diagnosis. Nowadays, Sanger sequencing should be limited to cases presenting with the classical triad of symptoms; otherwise, next-generation sequencing is recommended, given the cost-effectiveness and the advantage of excluding IPEX-like syndromes. The latter approach could be time spearing in children with severe phenotypes and candidate to advanced therapies.
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Affiliation(s)
- Federica Barzaghi
- Department of Paediatric Immunohematology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Laura Passerini
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
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14
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Consonni F, Favre C, Gambineri E. IL-2 Signaling Axis Defects: How Many Faces? Front Pediatr 2021; 9:669298. [PMID: 34277517 PMCID: PMC8282996 DOI: 10.3389/fped.2021.669298] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/31/2021] [Indexed: 11/13/2022] Open
Abstract
CD25, Signal transducer and activator of transcription 5B (STAT5B) and Forkhead box P3 (FOXP3) are critical mediators of Interleukin-2 (IL-2) signaling pathway in regulatory T cells (Tregs). CD25 (i.e., IL-2 Receptor α) binds with high affinity to IL-2, activating STAT5B-mediated signaling that eventually results in transcription of FOXP3, a master regulator of Treg function. Consequently, loss-of-function mutations in these proteins give rise to Treg disorders (i.e., Tregopathies) that clinically result in multiorgan autoimmunity. Immunodysregulation, Polyendocrinopathy Enteropathy X-linked (IPEX), due to mutations in FOXP3, has historically been the prototype of Tregopathies. This review describes current knowledge about defects in CD25, STAT5B, and FOXP3, highlighting that these disorders both share a common biological background and display comparable clinical features. However, specific phenotypes are associated with each of these syndromes, while certain laboratory findings could be helpful tools for clinicians, in order to achieve a prompt genetic diagnosis. Current treatment strategies will be outlined, keeping an eye on gene editing, an interesting therapeutic perspective that could definitely change the natural history of these disorders.
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Affiliation(s)
- Filippo Consonni
- Anna Meyer Children's Hospital, University of Florence, Florence, Italy
| | - Claudio Favre
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy
| | - Eleonora Gambineri
- Division of Pediatric Oncology/Hematology, Meyer University Children's Hospital, Florence, Italy.,Department of Neurosciences, Psychology, Drug Research and Child Health (NEUROFARBA), University of Florence, Florence, Italy
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Su N, Chen C, Zhou X, Ma GD, Chen RL, Tian C. Early-onset refractory diarrhea due to immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with a novel mutation in the FOXP3 gene: A case report. World J Clin Cases 2020; 8:1988-1994. [PMID: 32518791 PMCID: PMC7262694 DOI: 10.12998/wjcc.v8.i10.1988] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 04/01/2020] [Accepted: 04/20/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Immune dysregulation, polyendocrinopthy, enteropathy, X-linked (IPEX) syndrome is a rare X-linked recessive disease caused by mutations in the forkhead box protein 3 (FOXP3) gene, which is a master transcriptional regulator for the development and function of CD4+CD25+ regulatory T (Treg) cells. The dysfunction of these cells leads to multiple system autoimmune diseases. We present a case of IPEX due to a mutation not reported in the literature before.
CASE SUMMARY We report a male patient with IPEX syndrome who presented with refractory diarrhea and malabsorption leading to failure to thrive, as well as with hypothyroidism and nephrotic syndrome. Laboratory investigation showed increased total IgE and Treg cells, decreased free triiodothyronine (FT3) and free thyroxine (FT4), and proteinuria. Multiple dietary and supportive treatments were introduced but did not improve the diarrhea during his hospital stay. Ultimately, whole exome sequencing revealed that the patient was hemizygous for the exon 5, c.542G>A (p.Ser181Asn) mutation of the FOXP3 gene, which has not been previously reported. The patient remains on prednisone and euthyrox while awaiting hematopoietic stem cell transplantation at the time of the compilation of this case report.
CONCLUSION We report a novel FOXP3 gene mutation involved in IPEX. A high level of suspicion should be maintained in an early-onset refractory diarrhea patient.
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Affiliation(s)
- Na Su
- Department of Pediatrics, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan 528300, Guangdong Province, China
- Department of Pediatrics, Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
| | - Cheng Chen
- Department of Pediatric Internal Medicine, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan 528300, Guangdong Province, China
| | - Xia Zhou
- Department of Neurology, Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
| | - Guo-Da Ma
- Maternal and Child Research Institute, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan 528300, Guangdong Province, China
| | - Ri-Ling Chen
- Department of Pediatric Internal Medicine, Shunde Women and Children's Hospital, Guangdong Medical University, Foshan 528300, Guangdong Province, China
| | - Chuan Tian
- Department of Pediatric Hematology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524000, Guangdong Province, China
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Jamee M, Zaki-Dizaji M, Lo B, Abolhassani H, Aghamahdi F, Mosavian M, Nademi Z, Mohammadi H, Jadidi-Niaragh F, Rojas M, Anaya JM, Azizi G. Clinical, Immunological, and Genetic Features in Patients with Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) and IPEX-like Syndrome. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 8:2747-2760.e7. [PMID: 32428713 DOI: 10.1016/j.jaip.2020.04.070] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 04/06/2020] [Accepted: 04/15/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare inborn error of immunity caused by mutations in the forkhead box P3 (FOXP3) gene. OBJECTIVE In this study, we conducted a systematic review of patients with IPEX and IPEX-like syndrome to delineate differences in these 2 major groups. METHODS The literature search was performed in PubMed, Web of Science, and Scopus databases, and demographic, clinical, immunologic, and molecular data were compared between the IPEX and IPEX-like groups. RESULTS A total of 459 patients were reported in 148 eligible articles. Major clinical differences between patients with IPEX and IPEX-like syndrome were observed in rates of pneumonia (11% vs 31%, P < .001), bronchiectasis (0.3% vs 14%, P < .001), diarrhea (56% vs 42%, P = .020), and organomegaly (10% vs 23%, P = .001), respectively. Eosinophilia (95% vs 100%), low regulatory T-cell count (68% vs 50%), and elevated IgE (87% vs 61%) were the most prominent laboratory findings in patients with IPEX and IPEX-like syndrome, respectively. In the IPEX group, a lower mortality rate was observed among patients receiving hematopoietic stem cell transplantation (HSCT) (24%) compared with other patients (43%), P = .008; however, in the IPEX-like group, it was not significant (P = .189). CONCLUSIONS Patients with IPEX syndrome generally suffer from enteropathy, autoimmunity, dermatitis, eosinophilia, and elevated serum IgE. Despite similarities in their clinical presentations, patients with IPEX-like syndrome are more likely to present common variable immunodeficiency-like phenotype such as respiratory tract infections, bronchiectasis, and organomegaly. HSCT is currently the only curative therapy for both IPEX and IPEX-like syndrome and may result in favorable outcome.
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Affiliation(s)
- Mahnaz Jamee
- Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran; Alborz Office of USERN, Universal Scientific Education and Research Network (USERN), Alborz University of Medical Sciences, Karaj, Iran
| | - Majid Zaki-Dizaji
- Legal Medicine Research Center, Legal Medicine Organization, Tehran, Iran
| | - Bernice Lo
- Sidra Medicine, Division of Translational Medicine, Research Branch, Doha, Qatar
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
| | - Fatemeh Aghamahdi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Mehdi Mosavian
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Zohreh Nademi
- Children's Bone Marrow Transplant Unit, Great North Children's Hospital, Newcastle, United Kingdom
| | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Manuel Rojas
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario, Bogotá, Colombia
| | - Gholamreza Azizi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
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Rahmani W, Sinha S, Biernaskie J. Immune modulation of hair follicle regeneration. NPJ Regen Med 2020; 5:9. [PMID: 32411394 PMCID: PMC7214459 DOI: 10.1038/s41536-020-0095-2] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Accepted: 04/15/2020] [Indexed: 12/13/2022] Open
Abstract
The mammalian hair follicle undergoes repeated bouts of regeneration orchestrated by a variety of hair follicle stem cells. The last decade has witnessed the emergence of the immune niche as a key regulator of stem cell behavior and hair follicle regeneration. Hair follicles chemotactically attract macrophages and T cells so that they are in range to regulate epithelial stem cell quiescence, proliferation and differentiation during physiologic and injured states. Disruption of this dynamic relationship leads to clinically significant forms of hair loss including scarring and non-scarring alopecias. In this review, we summarize key concepts behind immune-mediated hair regeneration, highlight gaps in the literature and discuss the therapeutic potential of exploiting this relationship for treating various immune-mediated alopecias.
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Affiliation(s)
- Waleed Rahmani
- Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4 Canada
| | - Sarthak Sinha
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4 Canada
| | - Jeff Biernaskie
- Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB T2N 1N4 Canada
- Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 1N4 Canada
- Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4 Canada
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18
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Takahashi H, Iriki H, Mukai M, Kamata A, Nomura H, Yamagami J, Amagai M. Autoimmunity and immunological tolerance in autoimmune bullous diseases. Int Immunol 2020; 31:431-437. [PMID: 30887049 DOI: 10.1093/intimm/dxz030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Accepted: 03/18/2019] [Indexed: 12/12/2022] Open
Abstract
Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell-cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.
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Affiliation(s)
- Hayato Takahashi
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hisato Iriki
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Miho Mukai
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Aki Kamata
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Hisashi Nomura
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Jun Yamagami
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
| | - Masayuki Amagai
- Department of Dermatology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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19
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Park JH, Lee KH, Jeon B, Ochs HD, Lee JS, Gee HY, Seo S, Geum D, Piccirillo CA, Eisenhut M, van der Vliet HJ, Lee JM, Kronbichler A, Ko Y, Shin JI. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: A systematic review. Autoimmun Rev 2020; 19:102526. [PMID: 32234571 DOI: 10.1016/j.autrev.2020.102526] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 01/19/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.
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Affiliation(s)
- Jae Hyon Park
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Keum Hwa Lee
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Bokyoung Jeon
- Yonsei University Wonju College of Medicine, Wonju, Republic of Korea
| | - Hans D Ochs
- Department of Pediatrics, University of Washington and Seattle Children's Research Institute, Seattle, WA, USA
| | - Joon Suk Lee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
| | - Heon Yung Gee
- Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 03772, Republic of Korea
| | - Seeun Seo
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dongil Geum
- Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Ciriaco A Piccirillo
- Department of Microbiology and Immunology, McGill University, Montréal, QC, Canada; The Research Institute of the McGill University Health Center, Montréal, QC, Canada; FOCiS Centre of Excellence in Translational Immunology (CETI), Montréal, QC H4A 3J1, Canada
| | - Michael Eisenhut
- Luton & Dunstable University Hospital NHS Foundation Trust, Lewsey Road, Luton LU4ODZ, United Kingdom
| | - Hans J van der Vliet
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit, Amsterdam, the Netherlands
| | - Jiwon M Lee
- Department of Pediatrics, Chungnam National University College of Medicine, Daejeon, Republic of Korea
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Medical University Innsbruck, Innsbruck, Austria
| | - Younhee Ko
- Division of Biomedical Engineering, Hankuk University of Foreign Studies, Gyeonggi-do, Republic of Korea
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.
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20
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Eczematous dermatitis in primary immunodeficiencies: A review of cutaneous clues to diagnosis. Clin Immunol 2020; 211:108330. [DOI: 10.1016/j.clim.2019.108330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Revised: 12/24/2019] [Accepted: 12/27/2019] [Indexed: 11/23/2022]
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21
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Huang Q, Liu X, Zhang Y, Huang J, Li D, Li B. Molecular feature and therapeutic perspectives of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. J Genet Genomics 2020; 47:17-26. [PMID: 32081609 DOI: 10.1016/j.jgg.2019.11.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Revised: 11/02/2019] [Accepted: 11/10/2019] [Indexed: 01/01/2023]
Abstract
Regulatory T (Treg) cells, a subtype of immunosuppressive CD4+ T cells, are vital for maintaining immune homeostasis in healthy people. Forkhead box protein P3 (FOXP3), a member of the forkhead-winged-helix family, is the pivotal transcriptional factor of Treg cells. The expression, post-translational modifications, and protein complex of FOXP3 present a great impact on the functional stability and immune plasticity of Treg cells in vivo. In particular, the mutation of FOXP3 can result in immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, which is a rare genetic disease mostly diagnosed in early childhood and can soon be fatal. IPEX syndrome is related to several manifestations, including dermatitis, enteropathy, type 1 diabetes, thyroiditis, and so on. Here, we summarize some recent findings on FOXP3 regulation and Treg cell function. We also review the current knowledge about the underlying mechanism of FOXP3 mutant-induced IPEX syndrome and some latest clinical prospects. At last, this review offers a novel insight into the role played by the FOXP3 complex in potential therapeutic applications in IPEX syndrome.
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Affiliation(s)
- Qianru Huang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Xu Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Yujia Zhang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Jingyao Huang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China
| | - Dan Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
| | - Bin Li
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, 200025, China.
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22
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Érythrodermie révélatrice d’un syndrome IPEX. Ann Dermatol Venereol 2019; 146:807-811. [DOI: 10.1016/j.annder.2019.04.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Revised: 10/15/2018] [Accepted: 04/29/2019] [Indexed: 11/20/2022]
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23
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Martuszewski A, Paluszkiewicz P, Wawrzyniak-Dzierżek E, Drożyńska-Duklas M, Bąbol-Pokora K, Myśliwiec M, Szymczak D, Irga-Jaworska N, Młynarski W, Kałwak K, Ussowicz M. Successful Salvage Haploidentical Alpha-Beta T Cell-Depleted Stem Cell Transplantation After Busulfan-Based Myeloablation in a Patient With IPEX Syndrome: A Case Report. Transplant Proc 2019; 51:3150-3154. [PMID: 31611124 DOI: 10.1016/j.transproceed.2019.07.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Accepted: 07/28/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND X-linked immunodysregulation syndrome with polyendocrinopathy and enteropathy (IPEX) is caused by FOXP3 gene mutations that block the generation of regulatory T lymphocytes. We report an 18-month-old boy with classic IPEX who underwent 2 hematopoietic stem cell transplantations (HSCTs). METHODS The first HSCT from an unrelated 8/10 HLA-matched umbilical cord blood donor (UCB) was performed after a conditioning regimen consisting of treosulfan, fludarabine, thiotepa, and thymoglobulin. Due to complete rejection of the UCB transplant, a second transplantation from a 6/10 HLA-matched mother was performed after alpha-beta T-cell depletion. The second conditioning regimen consisted of busulfan, fludarabine, a single dose of cyclophosphamide 1 g/m2, and Grafalon (Neovii Pharmaceuticals, Rapperswil, Switzerland). The T-cell depletion product contained 15.06 x 106 CD34+ cells per kilogram body weight (BW) and 4.19 x 105 alpha-beta T lymphocytes per kilogram BW. Due to acute graft rejection, the boy was treated with thymoglobulin, and full donor chimerism in both T lymphocytes and mononuclear cells was achieved. The immunosuppressive therapy was stopped 1 year after transplantation. To date, the patient remains free from graft-vs-host disease (GVHD) and immunosuppression. CONCLUSIONS HSCT after busulfan-based reduced-toxicity conditioning in patients with IPEX syndrome is feasible and well tolerated and can result in full donor engraftment. Monitoring of chimerism and aggressive therapy in cases of graft rejection are warranted due to the high reactivity of residual autologous T lymphocytes. T-cell depletion reduces the risk of GVHD and the need for steroid therapy, which is especially challenging in patients with diabetes.
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Affiliation(s)
- Adrian Martuszewski
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wrocław Medical University, Wrocław, Poland
| | - Patrycja Paluszkiewicz
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wrocław Medical University, Wrocław, Poland
| | - Elżbieta Wawrzyniak-Dzierżek
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wrocław Medical University, Wrocław, Poland
| | | | - Katarzyna Bąbol-Pokora
- Laboratory of Immunopathology and Genetics, Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Łódź, Łódź, Poland
| | - Małgorzata Myśliwiec
- Department of Paediatrics, Diabetology and Endocrinology, Medical University of Gdańsk, Gdańsk, Poland
| | - Donata Szymczak
- Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wrocław Medical University, Wrocław, Poland
| | - Ninela Irga-Jaworska
- Department of Paediatrics, Haematology and Oncology, Medical University of Gdańsk, Gdańsk, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Łódź, Łódź, Poland
| | - Krzysztof Kałwak
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wrocław Medical University, Wrocław, Poland
| | - Marek Ussowicz
- Department of Paediatric Bone Marrow Transplantation, Oncology and Hematology, Wrocław Medical University, Wrocław, Poland.
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Mathur AN, Zirak B, Boothby IC, Tan M, Cohen JN, Mauro TM, Mehta P, Lowe MM, Abbas AK, Ali N, Rosenblum MD. Treg-Cell Control of a CXCL5-IL-17 Inflammatory Axis Promotes Hair-Follicle-Stem-Cell Differentiation During Skin-Barrier Repair. Immunity 2019; 50:655-667.e4. [PMID: 30893588 PMCID: PMC6507428 DOI: 10.1016/j.immuni.2019.02.013] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 11/16/2018] [Accepted: 02/14/2019] [Indexed: 12/11/2022]
Abstract
Restoration of barrier-tissue integrity after injury is dependent on the function of immune cells and stem cells (SCs) residing in the tissue. In response to skin injury, hair-follicle stem cells (HFSCs), normally poised for hair generation, are recruited to the site of injury and differentiate into cells that repair damaged epithelium. We used a SC fate-mapping approach to examine the contribution of regulatory T (Treg) cells to epidermal-barrier repair after injury. Depletion of Treg cells impaired skin-barrier regeneration and was associated with a Th17 inflammatory response and failed HFSC differentiation. In this setting, damaged epithelial cells preferentially expressed the neutrophil chemoattractant CXCL5, and blockade of CXCL5 or neutrophil depletion restored barrier function and SC differentiation after epidermal injury. Thus, Treg-cell regulation of localized inflammation enables HFSC differentiation and, thereby, skin-barrier regeneration, with implications for the maintenance and repair of other barrier tissues.
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Affiliation(s)
- Anubhav N Mathur
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Bahar Zirak
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Ian C Boothby
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Madge Tan
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Jarish N Cohen
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Thea M Mauro
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Pooja Mehta
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Margaret M Lowe
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Abul K Abbas
- Department of Pathology, University of California, San Francisco, CA, USA
| | - Niwa Ali
- Department of Dermatology, University of California, San Francisco, CA, USA
| | - Michael D Rosenblum
- Department of Dermatology, University of California, San Francisco, CA, USA.
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25
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Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. J Allergy Clin Immunol 2018; 142:1909-1921.e9. [DOI: 10.1016/j.jaci.2018.03.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 02/14/2018] [Accepted: 03/19/2018] [Indexed: 01/10/2023]
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Gambineri E, Ciullini Mannurita S, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, Segundo GRS, Allenspach EJ, Favre C, Ochs HD, Torgerson TR. Clinical, Immunological, and Molecular Heterogeneity of 173 Patients With the Phenotype of Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-Linked (IPEX) Syndrome. Front Immunol 2018; 9:2411. [PMID: 30443250 PMCID: PMC6223101 DOI: 10.3389/fimmu.2018.02411] [Citation(s) in RCA: 127] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 09/28/2018] [Indexed: 12/22/2022] Open
Abstract
Background: Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) Syndrome is a rare recessive disorder caused by mutations in the FOXP3 gene. In addition, there has been an increasing number of patients with wild-type FOXP3 gene and, in some cases, mutations in other immune regulatory genes. Objective: To molecularly asses a cohort of 173 patients with the IPEX phenotype and to delineate the relationship between the clinical/immunologic phenotypes and the genotypes. Methods: We reviewed the clinical presentation and laboratory characteristics of each patient and compared clinical and laboratory data of FOXP3 mutation-positive (IPEX patients) with those from FOXP3 mutation-negative patients (IPEX-like). A total of 173 affected patients underwent direct sequence analysis of the FOXP3 gene while 85 IPEX-like patients with normal FOXP3 were investigated by a multiplex panel of "Primary Immune Deficiency (PID-related) genes." Results: Forty-four distinct FOXP3 variants were identified in 88 IPEX patients, 9 of which were not previously reported. Among the 85 IPEX-like patients, 19 different disease-associated variants affecting 9 distinct genes were identified. Conclusions: We provide a comprehensive analysis of the clinical features and molecular bases of IPEX and IPEX-like patients. Although we were not able to identify major distinctive clinical features to differentiate IPEX from IPEX-like syndromes, we propose a simple flow-chart to effectively evaluate such patients and to focus on the most likely molecular diagnosis. Given the large number of potential candidate genes and overlapping phenotypes, selecting a panel of PID-related genes will facilitate a molecular diagnosis.
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Affiliation(s)
- Eleonora Gambineri
- Department of NEUROFARBA, University of Florence, Florence, Italy
- Oncology/Hematology Department, “Anna Meyer” Children's Hospital, Florence, Italy
| | - Sara Ciullini Mannurita
- Department of NEUROFARBA, University of Florence, Florence, Italy
- Oncology/Hematology Department, “Anna Meyer” Children's Hospital, Florence, Italy
| | - David Hagin
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Marina Vignoli
- Department of NEUROFARBA, University of Florence, Florence, Italy
- Oncology/Hematology Department, “Anna Meyer” Children's Hospital, Florence, Italy
| | | | - Stacey DeBoer
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Gesmar R. S. Segundo
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Eric J. Allenspach
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Claudio Favre
- Oncology/Hematology Department, “Anna Meyer” Children's Hospital, Florence, Italy
| | - Hans D. Ochs
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
| | - Troy R. Torgerson
- Seattle Children's Research Institute, University of Washington, Seattle, WA, United States
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27
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Muramatsu K, Ujiie H, Kobayashi I, Nishie W, Izumi K, Ito T, Yoshimoto N, Natsuga K, Iwata H, Shimizu H. Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects. J Allergy Clin Immunol 2018; 142:1818-1830.e6. [PMID: 29704593 DOI: 10.1016/j.jaci.2018.03.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 02/12/2018] [Accepted: 03/28/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T-cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo.
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Affiliation(s)
- Ken Muramatsu
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hideyuki Ujiie
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
| | - Ichiro Kobayashi
- Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Wataru Nishie
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Kentaro Izumi
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takamasa Ito
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Norihiro Yoshimoto
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Ken Natsuga
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroaki Iwata
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hiroshi Shimizu
- Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
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Passerini L, Bacchetta R. Forkhead-Box-P3 Gene Transfer in Human CD4 + T Conventional Cells for the Generation of Stable and Efficient Regulatory T Cells, Suitable for Immune Modulatory Therapy. Front Immunol 2017; 8:1282. [PMID: 29075264 PMCID: PMC5643480 DOI: 10.3389/fimmu.2017.01282] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 09/25/2017] [Indexed: 12/17/2022] Open
Abstract
The development of novel approaches to control immune responses to self- and allogenic tissues/organs represents an ambitious goal for the management of autoimmune diseases and in transplantation. Regulatory T cells (Tregs) are recognized as key players in the maintenance of peripheral tolerance in physiological and pathological conditions, and Treg-based cell therapies to restore tolerance in T cell-mediated disorders have been designed. However, several hurdles, including insufficient number of Tregs, their stability, and their antigen specificity, have challenged Tregs clinical applicability. In the past decade, the ability to engineer T cells has proven a powerful tool to redirect specificity and function of different cell types for specific therapeutic purposes. By using lentivirus-mediated gene transfer of the thymic-derived Treg transcription factor forkhead-box-P3 (FOXP3) in conventional CD4+ T cells, we converted effector T cells into Treg-like cells, endowed with potent in vitro and in vivo suppressive activity. The resulting CD4FOXP3 T-cell population displays stable phenotype and suppressive function. We showed that this strategy restores Treg function in T lymphocytes from patients carrying mutations in FOXP3 [immune-dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX)], in whom CD4FOXP3 T cell could be used as therapeutics to control autoimmunity. Here, we will discuss the potential advantages of using CD4FOXP3 T cells for in vivo application in inflammatory diseases, where tissue inflammation may undermine the function of natural Tregs. These findings pave the way for the use of engineered Tregs not only in IPEX syndrome but also in autoimmune disorders of different origin and in the context of stem cell and organ transplantation.
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Affiliation(s)
- Laura Passerini
- Mechanisms of Peripheral Tolerance Unit, San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Rosa Bacchetta
- Department of Stem Cell Transplantation and Regenerative Medicine, Division of Pediatrics, Stanford School of Medicine, Stanford, CA, United States
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29
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Bin Dhuban K, d’Hennezel E, Nagai Y, Xiao Y, Shao S, Istomine R, Alvarez F, Ben-Shoshan M, Ochs H, Mazer B, Li B, Sekine C, Berezov A, Hancock W, Torgerson TR, Greene MI, Piccirillo CA. Suppression by human FOXP3
+
regulatory T cells requires FOXP3-TIP60 interactions. Sci Immunol 2017; 2. [DOI: 10.1126/sciimmunol.aai9297] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Targeting the FOXP3-TIP60 interaction may modulate T
reg
activity in IPEX and other autoimmune and inflammatory diseases.
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Affiliation(s)
- Khalid Bin Dhuban
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - Eva d’Hennezel
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
| | - Yasuhiro Nagai
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | - Yan Xiao
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | - Steven Shao
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - Roman Istomine
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - Fernando Alvarez
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - Moshe Ben-Shoshan
- Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montréal, Québec H3H 1P3, Canada
| | - Hans Ochs
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA 98101–1304, USA
| | - Bruce Mazer
- Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montréal, Québec H3H 1P3, Canada
- FOCiS Centre of Excellence in Translational Immunology (CETI), Montréal, Québec H4A 3J1, Canada
| | - Bin Li
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | | | - Alan Berezov
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | - Wayne Hancock
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | - Troy R. Torgerson
- Division of Pediatric Allergy and Clinical Immunology, Department of Pediatrics, McGill University Health Center, Montréal, Québec H3H 1P3, Canada
| | - Mark I. Greene
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104–6082, USA
| | - Ciriaco A. Piccirillo
- Department of Microbiology and Immunology, McGill University and Research Institute of McGill University Health Centre, Montréal, Québec H3A 2B4, Canada
- Program in Infectious Diseases and Immunology in Global Health, Centre for Translational Biology, Research Institute of McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
- FOCiS Centre of Excellence in Translational Immunology (CETI), Montréal, Québec H4A 3J1, Canada
- Division of Allergy and Clinical Immunology, Department of Medicine, McGill University and McGill University Health Centre, Montreal, Quebec, Canada
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30
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Louie RJ, Tan QKG, Gilner JB, Rogers RC, Younge N, Wechsler SB, McDonald MT, Gordon B, Saski CA, Jones JR, Chapman SJ, Stevenson RE, Sleasman JW, Friez MJ. Novel pathogenic variants in FOXP3 in fetuses with echogenic bowel and skin desquamation identified by ultrasound. Am J Med Genet A 2017; 173:1219-1225. [PMID: 28317311 DOI: 10.1002/ajmg.a.38144] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 12/05/2016] [Accepted: 12/30/2016] [Indexed: 11/12/2022]
Abstract
Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare, X-linked recessive disease that affects regulatory T cells (Tregs) resulting in diarrhea, enteropathy, eczema, and insulin-dependent diabetes mellitus. IPEX syndrome is caused by pathogenic alterations in FOXP3 located at Xp11.23. FOXP3 encodes a transcription factor that interacts with several partners, including NFAT and NF-κB, and is necessary for the proper cellular differentiation of Tregs. Although variable, the vast majority of IPEX syndrome patients have onset of disease during infancy with severe enteropathy. Only five families with prenatal presentation of IPEX syndrome have been reported. Here, we present two additional prenatal onset cases with novel inherited frameshift pathogenic variants in FOXP3 that generate premature stop codons. Ultrasound findings in the first patient identified echogenic bowel, echogenic debris, scalp edema, and hydrops. In the second patient, ultrasound findings included polyhydramnios with echogenic debris, prominent fluid-filled loops of bowel, and echogenic bowel. These cases further broaden the phenotypic spectrum of IPEX syndrome by describing previously unappreciated prenatal ultrasound findings associated with the disease.
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Affiliation(s)
| | | | | | | | - Noelle Younge
- Duke University School of Medicine, Durham, North Carolina
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Abstract
Eczema and urticaria are common disorders encountered in pediatric patients, but they may occasionally be the presenting complaint in a child with an underlying rare disease. Immunodeficiency syndromes should be suspected when eczema is associated with neonatal onset, recurrent infections, chronic lymphadenopathy, or failure to thrive. Nutritional deficiencies and mycosis fungoides are in the differential diagnosis for a child with a recalcitrant eczematous eruption. Autoinflammatory syndromes should be suspected in a child with chronic urticaria, fever, and other systemic signs of inflammation. Although these disorders are rare, early recognition allows for appropriate treatment and decreased morbidity for the child.
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Affiliation(s)
- Molly J Youssef
- Department of Dermatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA
| | - Yvonne E Chiu
- Section of Pediatric Dermatology, Department of Dermatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA; Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.
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32
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Gaudinski MR, Milner JD. Atopic Dermatitis and Allergic Urticaria: Cutaneous Manifestations of Immunodeficiency. Immunol Allergy Clin North Am 2016; 37:1-10. [PMID: 27886899 DOI: 10.1016/j.iac.2016.08.016] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Atopic dermatitis and allergic urticaria are common conditions of the skin that can also be the presenting symptoms of uncommon diseases. Defects leading to immunodeficiency may be associated with atopic dermatitis or allergic urticaria. Unusually severe or otherwise atypical presentations of atopic dermatitis or allergic urticaria may lead to clinical suspicion of an underlying immunodeficiency.
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Affiliation(s)
- Martin Robert Gaudinski
- National Institute of Allergy and Infectious Diseases, Genetics and Pathogenesis of Allergy Section, 10 Center Drive, Building 10 Room 11N240A, Bethesda, MD 20814, USA
| | - Joshua D Milner
- National Institute of Allergy and Infectious Diseases, Genetics and Pathogenesis of Allergy Section, 10 Center Drive, Building 10 Room 11N240A, Bethesda, MD 20814, USA.
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33
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Jacobsen AA, Tosti A. Trachyonychia and Twenty-Nail Dystrophy: A Comprehensive Review and Discussion of Diagnostic Accuracy. Skin Appendage Disord 2016; 2:7-13. [PMID: 27843915 DOI: 10.1159/000445544] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2016] [Accepted: 03/16/2016] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND/AIMS The term trachyonychia, also known as twenty-nail dystrophy, is used to describe thin, brittle nails with excessive longitudinal ridging. The term twenty-nail dystrophy has been incorrectly applied to other conditions that can affect all twenty nails. Therefore, we have conducted a comprehensive review of the clinical features of trachyonychia and have included a discussion regarding the diagnostic accuracy of this condition in the literature. METHODS In November and December 2015, we conducted a thorough literature search using the following search terms: 'trachyonychia', 'twenty nail dystrophy', and 'sandpaper nails'. Articles that reported the epidemiology, disease associations, clinical presentation, histopathology, and treatment options for trachyonychia were included. Particular attention was given to case reports to identify misdiagnosed cases of twenty-nail dystrophy. RESULTS Our preliminary search yielded 184 results with 72 unique articles ultimately selected for review. Excluded articles included 27 articles in languages other than English, 18 commentaries or reviews, and 67 irrelevant articles. Twelve additional articles described nail abnormalities clinically different from trachyonychia. CONCLUSION Many other conditions can cause widespread nail dystrophy. The specific characteristics of trachyonychia need to be considered to make the diagnosis of twenty-nail dystrophy.
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Affiliation(s)
| | - Antonella Tosti
- Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Fla., USA
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34
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Bacchetta R, Barzaghi F, Roncarolo MG. From IPEX syndrome to FOXP3
mutation: a lesson on immune dysregulation. Ann N Y Acad Sci 2016; 1417:5-22. [DOI: 10.1111/nyas.13011] [Citation(s) in RCA: 210] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Revised: 11/29/2015] [Accepted: 01/06/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Rosa Bacchetta
- Department of Pediatrics; Division of Pediatric Stem Cells, Transplantation and Regenerative Medicine; Stanford University Medical School; Stanford California
| | - Federica Barzaghi
- San Raffaele Telethon Institute for Gene Therapy; Division of Regenerative Medicine; Stem Cells and Gene Therapy; San Raffaele Scientific Institute; Milan Italy
| | - Maria-Grazia Roncarolo
- Department of Pediatrics; Division of Pediatric Stem Cells, Transplantation and Regenerative Medicine; Stanford University Medical School; Stanford California
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35
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Passerini L, Santoni de Sio FR, Porteus MH, Bacchetta R. Gene/cell therapy approaches for Immune Dysregulation Polyendocrinopathy Enteropathy X-linked syndrome. Curr Gene Ther 2015; 14:422-8. [PMID: 25274247 PMCID: PMC4443799 DOI: 10.2174/1566523214666141001123828] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2014] [Revised: 08/19/2014] [Accepted: 08/25/2014] [Indexed: 01/23/2023]
Abstract
Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome is a rare autoimmune disease due to mutations in the gene encoding for Forkhead box P3 (FOXP3), a transcription factor fundamental for the function of thymus-derived (t) regulatory T (Treg) cells. The dysfunction of Treg cells results in the development of devastating autoimmune manifestations affecting multiple organs, eventually leading to premature death in infants, if not promptly treated by hematopoietic stem cell transplantation (HSCT). Novel gene therapy strategies can be developed for IPEX syndrome as more definitive cure than allogeneic HSCT. Here we describe the therapeutic approaches, alternative to HSCT, currently under development. We described that effector T cells can be converted in regulatory T cells by LV-mediated FOXP3-gene transfer in differentiated T lymphocytes. Despite FOXP3 mutations mainly affect a highly specific T cell subset, manipulation of stem cells could be required for long-term remission of the disease. Therefore, we believe that a more comprehensive strategy should aim at correcting FOXP3-mutated stem cells. Potentials and hurdles of both strategies will be highlighted here.
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Affiliation(s)
| | | | | | - Rosa Bacchetta
- San Raffaele Telethon Institute for Gene Therapy (HSR-TIGET), Division of Regenerative Medicine, Stem Cells and Gene Therapy, IRCCS San Raffaele Scientific Institute, Via Olgettina 58, 20131, Milan, Italy.
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36
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Bis S, Maguiness SM, Gellis SE, Schneider LC, Lee PY, Notarangelo LD, Keles S, Chatila TA, Schmidt BA, Miller DD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome associated with neonatal epidermolysis bullosa acquisita. Pediatr Dermatol 2015; 32:e74-7. [PMID: 25790289 DOI: 10.1111/pde.12550] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
We report the case of a 2-week-old boy who presented with a vesiculopustular, bullous eruption in the setting of autoimmune enteropathy, hypothyroidism, membranous nephropathy, Coombs-positive hemolytic anemia, and persistent eosinophilia. Immunologic testing revealed a deficiency of FOXP3-expressing regulatory T cells, and a diagnosis of immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome was made. Histologic analysis, immunofluorescence, and enzyme-linked immunosorbent assay confirmed the bullous eruption as epidermolysis bullosa acquisita with associated collagen VII autoantibody production. The skin lesions responded to systemic immunosuppressant therapy and have regressed after allogeneic bone marrow transplantation.
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Affiliation(s)
- Sabina Bis
- Harvard Combined Dermatology Program, Boston, Massachusetts
| | - Sheilagh M Maguiness
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Stephen E Gellis
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Lynda C Schneider
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Pui Y Lee
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Luigi D Notarangelo
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Sevgi Keles
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Talal A Chatila
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Birgitta A Schmidt
- Division of Immunology, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts
| | - Daniel D Miller
- Department of Dermatology, School of Medicine, Boston University, Boston, Massachusetts
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37
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Foxp3 gene polymorphisms and haplotypes associate with susceptibility of Graves' disease in Chinese Han population. Int Immunopharmacol 2015; 25:425-31. [DOI: 10.1016/j.intimp.2015.02.020] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 02/08/2015] [Accepted: 02/11/2015] [Indexed: 01/13/2023]
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Xavier-da-Silva MM, Moreira-Filho CA, Suzuki E, Patricio F, Coutinho A, Carneiro-Sampaio M. Fetal-onset IPEX: Report of two families and review of literature. Clin Immunol 2015; 156:131-40. [DOI: 10.1016/j.clim.2014.12.007] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/20/2014] [Accepted: 12/18/2014] [Indexed: 12/16/2022]
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Disease specificity of anti-tryptophan hydroxylase-1 and anti-AIE-75 autoantibodies in APECED and IPEX syndrome. Clin Immunol 2015; 156:36-42. [PMID: 25463430 DOI: 10.1016/j.clim.2014.10.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 10/27/2014] [Accepted: 10/30/2014] [Indexed: 11/18/2022]
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Locke BA, Dasu T, Verbsky JW. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol 2014; 46:154-68. [PMID: 24569953 DOI: 10.1007/s12016-014-8412-4] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Primary immune deficiency disorders represent a highly heterogeneous group of disorders with an increased propensity to infections and other immune complications. A careful history to delineate the pattern of infectious organisms and other complications is important to guide the workup of these patients, but a focused laboratory evaluation is essential to the diagnosis of an underlying primary immunodeficiency. Initial workup of suspected immune deficiencies should include complete blood counts and serologic tests of immunoglobulin levels, vaccine titers, and complement levels, but these tests are often insufficient to make a diagnosis. Recent advancements in the understanding of the immune system have led to the development of novel immunologic assays to aid in the diagnosis of these disorders. Classically utilized to enumerate lymphocyte subsets, flow cytometric-based assays are increasingly utilized to test immune cell function (e.g., neutrophil oxidative burst, NK cytotoxicity), intracellular cytokine production (e.g., TH17 production), cellular signaling pathways (e.g., phosphor-STAT analysis), and protein expression (e.g., BTK, Foxp3). Genetic testing has similarly expanded greatly as more primary immune deficiencies are defined, and the use of mass sequencing technologies is leading to the identification of novel disorders. In order to utilize these complex assays in clinical care, one must have a firm understanding of the immunologic assay, how the results are interpreted, pitfalls in the assays, and how the test affects treatment decisions. This article will provide a systematic approach of the evaluation of a suspected primary immunodeficiency, as well as provide a comprehensive list of testing options and their results in the context of various disease processes.
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Affiliation(s)
- Bradley A Locke
- Department of Pediatrics, Division of Allergy and Clinical Immunology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
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41
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Uhlig HH, Schwerd T, Koletzko S, Shah N, Kammermeier J, Elkadri A, Ouahed J, Wilson DC, Travis SP, Turner D, Klein C, Snapper SB, Muise AM. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology 2014; 147:990-1007.e3. [PMID: 25058236 PMCID: PMC5376484 DOI: 10.1053/j.gastro.2014.07.023] [Citation(s) in RCA: 468] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Revised: 07/13/2014] [Accepted: 07/15/2014] [Indexed: 02/07/2023]
Abstract
Patients with a diverse spectrum of rare genetic disorders can present with inflammatory bowel disease (monogenic IBD). Patients with these disorders often develop symptoms during infancy or early childhood, along with endoscopic or histological features of Crohn's disease, ulcerative colitis, or IBD unclassified. Defects in interleukin-10 signaling have a Mendelian inheritance pattern with complete penetrance of intestinal inflammation. Several genetic defects that disturb intestinal epithelial barrier function or affect innate and adaptive immune function have incomplete penetrance of the IBD-like phenotype. Several of these monogenic conditions do not respond to conventional therapy and are associated with high morbidity and mortality. Due to the broad spectrum of these extremely rare diseases, a correct diagnosis is frequently a challenge and often delayed. In many cases, these diseases cannot be categorized based on standard histological and immunologic features of IBD. Genetic analysis is required to identify the cause of the disorder and offer the patient appropriate treatment options, which include medical therapy, surgery, or allogeneic hematopoietic stem cell transplantation. In addition, diagnosis based on genetic analysis can lead to genetic counseling for family members of patients. We describe key intestinal, extraintestinal, and laboratory features of 50 genetic variants associated with IBD-like intestinal inflammation. In addition, we provide approaches for identifying patients likely to have these disorders. We also discuss classic approaches to identify these variants in patients, starting with phenotypic and functional assessments that lead to analysis of candidate genes. As a complementary approach, we discuss parallel genetic screening using next-generation sequencing followed by functional confirmation of genetic defects.
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Affiliation(s)
- Holm H Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, England; Department of Pediatrics, University of Oxford, Oxford, England.
| | - Tobias Schwerd
- Translational Gastroenterology Unit, University of Oxford, Oxford, England
| | - Sibylle Koletzko
- Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany
| | - Neil Shah
- Great Ormond Street Hospital London, London, England; Catholic University, Leuven, Belgium
| | | | - Abdul Elkadri
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Jodie Ouahed
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - David C Wilson
- Child Life and Health, University of Edinburgh, Edinburgh, Scotland; Department of Pediatric Gastroenterology, Hepatology, and Nutrition, Royal Hospital for Sick Children, Edinburgh, Scotland
| | - Simon P Travis
- Translational Gastroenterology Unit, University of Oxford, Oxford, England
| | - Dan Turner
- Pediatric Gastroenterology Unit, Shaare Zedek Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Christoph Klein
- Dr von Hauner Children's Hospital, Ludwig Maximilians University, Munich, Germany
| | - Scott B Snapper
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts; Division of Gastroenterology and Hepatology, Brigham & Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts
| | - Aleixo M Muise
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada; Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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42
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Zama D, Cocchi I, Masetti R, Specchia F, Alvisi P, Gambineri E, Lima M, Pession A. Late-onset of immunodysregulation, polyendocrinopathy, enteropathy, x-linked syndrome (IPEX) with intractable diarrhea. Ital J Pediatr 2014; 40:68. [PMID: 25326164 PMCID: PMC4421998 DOI: 10.1186/s13052-014-0068-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 07/07/2014] [Indexed: 11/10/2022] Open
Abstract
The syndrome of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) is a rare disorder caused by mutations in the FOXP3 gene. Diarrhea, diabetes and dermatitis are the hallmark of the disease, with a typical onset within the first months of life. We describe the case of a twelve-year old male affected by a very late-onset IPEX with intractable enteropathy, which markedly improved after starting Sirolimus as second-line treatment. This case suggests that IPEX should always be considered in the differential diagnosis of watery intractable diarrhea, despite its unusual onset.
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Affiliation(s)
- Daniele Zama
- Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.
| | - Ilaria Cocchi
- Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.
| | - Riccardo Masetti
- Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.
| | - Fernando Specchia
- Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.
| | | | - Eleonora Gambineri
- Department of 'NEUROFARBA', Section of Child's Health, University of Florence, Florence, Italy. .,BMT Unit, Department of Hematology-Oncology, Anna Meyer Children's Hospital, Florence, Italy.
| | - Mario Lima
- Department of Pediatric Surgery, University of Bologna, Bologna, Italy.
| | - Andrea Pession
- Pediatric Oncology and Haematology Unit "Lalla Seràgnoli", Department of Pediatrics, University of Bologna Sant'Orsola-Malpighi Hospital, Via Massarenti, 11, Bologna, 40138, Italy.
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43
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Michel M. Warm autoimmune hemolytic anemia: Advances in pathophysiology and treatment. Presse Med 2014; 43:e97-e104. [DOI: 10.1016/j.lpm.2014.02.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 02/18/2014] [Accepted: 02/20/2014] [Indexed: 10/25/2022] Open
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Passerini L, Santoni de Sio FR, Roncarolo MG, Bacchetta R. Forkhead box P3: the peacekeeper of the immune system. Int Rev Immunol 2013; 33:129-45. [PMID: 24354325 DOI: 10.3109/08830185.2013.863303] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
Ten years ago Forkhead box P3 (FOXP3) was discovered as master gene driving CD4(+)CD25(+) T cell regulatory (Treg) function. Since then, several layers of complexity have emerged in the regulation of its expression and function, which is not only exerted in Treg cells. While the mechanisms leading to the highly selective expression of FOXP3 in thymus-derived Treg cells still remain to be elucidated, we review here the current knowledge on the role of FOXP3 in the development of Treg cells and the direct and indirect consequences of FOXP3 mutations on multiple arms of the immune response. Finally, we summarize the newly acquired knowledge on the epigenetic regulation of FOXP3, still largely undefined in human cells.
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Affiliation(s)
- Laura Passerini
- 1Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy
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45
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Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr 2013; 25:708-14. [PMID: 24240290 PMCID: PMC4047515 DOI: 10.1097/mop.0000000000000029] [Citation(s) in RCA: 110] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
PURPOSE OF REVIEW To summarize recent progress in our understanding of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders. RECENT FINDINGS A number of Mendelian disorders of immune dysregulation and autoimmunity have been noted to result from defects in T regulatory cell, development and function. The best characterized of these is IPEX, resulting from mutations affecting FOXP3. A number of other gene defects that affect T regulatory cell function also give rise to IPEX-related phenotypes, including loss-of-function mutations in CD25, STAT5b and ITCH. Recent progress includes the identification of gain-of-function mutations in STAT1 as a cause of an IPEX-like disease, emerging FOXP3 genotype/phenotype relationships in IPEX, and the elucidation of a role for the microbiota in the immune dysregulation associated with regulatory T cell deficiency. SUMMARY An expanding spectrum of genetic defects that compromise T regulatory cell function underlies human disorders of immune dysregulation and autoimmunity. Collectively, these disorders offer novel insights into pathways of peripheral tolerance and their disruption in autoimmunity.
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Martín-Santiago A, Hervás JA, Hervás D, Rosell A, Caimari M, de Carlos JC, Matamoros N. Diagnostic value of the skin lesions in immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Dermatol 2013; 30:e221-2. [PMID: 23534934 DOI: 10.1111/pde.12126] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
We report a child with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome due to a de novo c.1190G>A (p.R397Q) mutation in exon 11 of the forkhead domain of the FOXP3 gene. He had chronic dermatitis with an eczematous and ichthyosiform appearance and had an allogeneic bone marrow transplantation. IPEX syndrome is a rare, often fatal recessive disease caused by mutations in the FOXP3 gene on the X chromosome (Xp11.23-q13.3).
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Affiliation(s)
- Ana Martín-Santiago
- Department of Dermatology, Son Espases University Hospital, Palma de Mallorca, Spain
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47
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Jyonouchi S, Orange J, Sullivan KE, Krantz I, Deardorff M. Immunologic features of Cornelia de Lange syndrome. Pediatrics 2013; 132:e484-9. [PMID: 23821697 PMCID: PMC4074671 DOI: 10.1542/peds.2012-3815] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/03/2013] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVES Cornelia de Lange syndrome (CdLS) is a genetic syndrome with multisystem abnormalities. Infections are a significant cause of morbidity and mortality. The goals of our study were to identify the frequency and types of infections in CdLS and to determine if underlying immunodeficiency contributes to the clinical spectrum of this syndrome. METHODS We assessed infectious histories in 45 patients with CdLS and evaluated conventional immunologic screening tests in 27 patients. Among these 27 subjects, additional phenotypic enumeration of T-cell subsets, expression of activation markers in T cells, and production of cytokines in response to T-cell stimulants were studied in 12 CdLS subjects compared with 12 normal case control subjects. RESULTS Recurrent infections were reported at high frequency in CdLS patients and included chronic ear infections (53%), chronic viral respiratory infections (46%), pneumonia (42%), sinus infections (33%), oral candidiasis (13%), sepsis (6%), and bacterial skin infections (4%). Full immune evaluation in 27 subjects led to identification of 9 cases of antibody deficiency syndrome in patients with severe forms of CdLS. Subjects with CdLS had decreased percentages of T regulatory cells and T follicular helper cells compared with normal control subjects (P < .05). CONCLUSIONS This study identified for the first time a high frequency of antibody deficiency in CdLS subjects, indicating a critical need for screening and management of immunodeficiency in CdLS patients with a history of well-documented severe or recurrent infections. Furthermore, our results indicate that impaired T-cell populations may be associated with antibody deficiency in CdLS.
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Affiliation(s)
- Soma Jyonouchi
- Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
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48
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Katoh H, Zheng P, Liu Y. FOXP3: genetic and epigenetic implications for autoimmunity. J Autoimmun 2013; 41:72-8. [PMID: 23313429 DOI: 10.1016/j.jaut.2012.12.004] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2012] [Accepted: 12/16/2012] [Indexed: 12/12/2022]
Abstract
FOXP3 plays an essential role in the maintenance of self-tolerance and, thus, in preventing autoimmune diseases. Inactivating mutations of FOXP3 cause immunodysregulation, polyendocrinopathy, and enteropathy, X-linked syndrome. FOXP3-expressing regulatory T cells attenuate autoimmunity as well as immunity against cancer and infection. More recent studies demonstrated that FOXP3 is an epithelial cell-intrinsic tumor suppressor for breast, prostate, ovary and other cancers. Corresponding to its broad function, FOXP3 regulates a broad spectrum of target genes. While it is now well established that FOXP3 binds to and regulates thousands of target genes in mouse and human genomes, the fundamental mechanisms of its broad impact on gene expression remain to be established. FOXP3 is known to both activate and repress target genes by epigenetically regulating histone modifications of target promoters. In this review, we first focus on germline mutations found in the FOXP3 gene among IPEX patients, then outline possible molecular mechanisms by which FOXP3 epigenetically regulates its targets. Finally, we discuss clinical implications of the function of FOXP3 as an epigenetic modifier. Accumulating results reveal an intriguing functional convergence between FOXP3 and inhibitors of histone deacetylases. The essential epigenetic function of FOXP3 provides a foundation for experimental therapies against autoimmune diseases.
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Affiliation(s)
- Hiroto Katoh
- Division of Molecular Oncology, Institute for Genetic Medicine, Hokkaido University, Hokkaido, Japan
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Zhang J, Chen Y, Jia G, Chen X, Lu J, Yang H, Zhou W, Xiao B, Zhang N, Li J. FOXP3 -3279 and IVS9+459 polymorphisms are associated with genetic susceptibility to myasthenia gravis. Neurosci Lett 2012; 534:274-8. [PMID: 23228687 DOI: 10.1016/j.neulet.2012.11.048] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Revised: 11/26/2012] [Accepted: 11/30/2012] [Indexed: 01/08/2023]
Abstract
Myasthenia gravis (MG) is an autoimmune disorder in which CD4(+)CD25(+) FOXP3(+)regulatory T cells (Tregs) are thought to play important roles in driving the ongoing autoimmune response. Although it is known that single-nucleotide polymorphisms (SNPs) in the fork head/winged-helix transcription factor 3 (FOXP3) gene contribute to some autoimmune diseases, information about the role of this gene in MG is limited. We therefore evaluated the association between FOXP3 gene SNPs and susceptibility to MG in a Han Chinese population. In a hospital-based, case-control study, two SNPs in the FOXP3 gene (-3279 and IVS9+459) were investigated in 118 MG and 124 healthy controls, and their relationship with the four parameters of gender, onset age, thymus pathology, and clinical classification of MG were performed with a stratified analysis. We found that the frequency of the FOXP3 IVS9+459 G allele was significantly lower in MG patients than in healthy controls (P=0.041), while the frequency of the FOXP3 -3279 polymorphisms was not significantly different between the two groups. Our results suggest that FOXP3 IVS9+459 polymorphisms appear to have an effect on the risk of MG in a Han Chinese population, and the G allele may be a genetic protective factor to MG.
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Affiliation(s)
- Junmei Zhang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China
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50
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Barzaghi F, Passerini L, Bacchetta R. Immune dysregulation, polyendocrinopathy, enteropathy, x-linked syndrome: a paradigm of immunodeficiency with autoimmunity. Front Immunol 2012; 3:211. [PMID: 23060872 PMCID: PMC3459184 DOI: 10.3389/fimmu.2012.00211] [Citation(s) in RCA: 227] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 07/01/2012] [Indexed: 12/15/2022] Open
Abstract
Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare monogenic primary immunodeficiency (PID) due to mutations of FOXP3, a key transcription factor for naturally occurring (n) regulatory T (Treg) cells. The dysfunction of Treg cells is the main pathogenic event leading to the multi-organ autoimmunity that characterizes IPEX syndrome, a paradigm of genetically determined PID with autoimmunity. IPEX has a severe early onset and can become rapidly fatal within the first year of life regardless of the type and site of the mutation. The initial presenting symptoms are severe enteritis and/or type-1 diabetes mellitus, alone or in combination with eczema and elevated serum IgE. Other autoimmune symptoms, such as hypothyroidism, cytopenia, hepatitis, nephropathy, arthritis, and alopecia can develop in patients who survive the initial acute phase. The current therapeutic options for IPEX patients are limited. Supportive and replacement therapies combined with pharmacological immunosuppression are required to control symptoms at onset. However, these procedures can allow only a reduction of the clinical manifestations without a permanent control of the disease. The only known effective cure for IPEX syndrome is hematopoietic stem cell transplantation, but it is always limited by the availability of a suitable donor and the lack of specific guidelines for bone marrow transplant in the context of this disease. This review aims to summarize the clinical histories and genomic mutations of the IPEX patients described in the literature to date. We will focus on the clinical and immunological features that allow differential diagnosis of IPEX syndrome and distinguish it from other PID with autoimmunity. The efficacy of the current therapies will be reviewed, and possible innovative approaches, based on the latest highlights of the pathogenesis to treat this severe primary autoimmune disease of childhood, will be discussed.
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Affiliation(s)
- Federica Barzaghi
- Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute Milan, Italy ; Vita Salute San Raffaele University Milan, Italy
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