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1
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Li JB, Walkley CR. Leveraging genetics to understand ADAR1-mediated RNA editing in health and disease. Nat Rev Genet 2025:10.1038/s41576-025-00830-5. [PMID: 40229561 DOI: 10.1038/s41576-025-00830-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2025] [Indexed: 04/16/2025]
Abstract
Endogenous, long double-stranded RNA (dsRNA) can resemble viral dsRNA and be recognized by cytosolic dsRNA sensors, triggering autoimmunity. Genetic studies of rare, inherited human diseases and experiments using mouse models have established the importance of adenosine-to-inosine RNA editing by the enzyme adenosine deaminase acting on RNA 1 (ADAR1) as a critical safeguard against autoinflammatory responses to cellular dsRNA. More recently, human genetic studies have revealed that dsRNA editing and sensing mechanisms are involved in common inflammatory diseases, emphasizing the broader role of dsRNA in modulating immune responses and disease pathogenesis. These findings have highlighted the therapeutic potential of targeting dsRNA editing and sensing, as exemplified by the emergence of ADAR1 inhibition in cancer therapy.
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Affiliation(s)
- Jin Billy Li
- Department of Genetics, Stanford University, Stanford, CA, USA.
| | - Carl R Walkley
- Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Victoria, Australia.
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.
- Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria, Australia.
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2
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Wang B, Singh H, Ellis M, Barisoni L, Howell DN. Hidden in the Absence: Clinicopathological Insights on Kidney Diseases Associated with Selective IgA Deficiency. J Transl Med 2025:104163. [PMID: 40199423 DOI: 10.1016/j.labinv.2025.104163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 03/06/2025] [Accepted: 03/31/2025] [Indexed: 04/10/2025] Open
Abstract
Selective IgA deficiency (sIgAD) is the most common type of primary immunodeficiency. The diagnosis of sIgAD has occasionally been suggested when a complete absence of background IgA immunofluorescent staining on renal biopsies was observed, but such findings have been described in only two patients to date. In this study, the clinical, demographic, and renal biopsy findings of 15 patients with suspected sIgAD, based on a total lack of immunofluorescence for IgA, were collected. In our cohort, most patients presented with acute kidney injury, with or without proteinuria, and had clinical histories consistent with sIgAD, including recurrent infections, autoimmune diseases, allergic disorders, and cancer. However, only one patient had a known history of sIgAD. Immunoglobulin testing was available in 10 out of 15 patients, nine of whom showed findings consistent with a diagnosis of sIgAD. Renal biopsies in most patients revealed immune-related glomerular diseases, with lupus nephritis being the most common diagnosis. Recognizing the total absence of IgA staining indicative of sIgAD is important, as it can be associated with recurrent infections, autoimmune diseases, allergic disorders, anaphylactic transfusion reactions, and rarely, malignancies.
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Affiliation(s)
- Bangchen Wang
- Department of Pathology, Duke University, Durham, NC
| | - Harpreet Singh
- Division of Nephrology, Department of Internal Medicine, Duke University, Durham, NC
| | - Matthew Ellis
- Division of Nephrology, Department of Internal Medicine, Duke University, Durham, NC
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3
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Martinez-Laso J, Cervera I, Martinez-Carrasco MS, Briz V, Crespo-Bermejo C, Sánchez-Menéndez C, Casado-Fernández G, Torres M, Coiras M. Characterisation of LGP2 complex multitranscript system in humans: role in the innate immune response and evolution from non-human primates. Hum Mol Genet 2025; 34:11-20. [PMID: 39505366 DOI: 10.1093/hmg/ddae155] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 10/09/2024] [Accepted: 10/30/2024] [Indexed: 11/08/2024] Open
Abstract
Retinoic acid inducible gene I (RIG-I)-like receptors (RLRs), including RIG-I, MDA5 and LGP2, recognize viral RNA to mount an antiviral interferon (IFN) response RLRs share three different protein domains: C-terminal domain, DExD/H box RNA helicase domain, and an N-terminal domain with two tandem repeats (CARDs). LGP2 lacks tandem CARD and is not able to induce an IFN response. However, LGP2 positively enhances MDA5 and negatively regulates RIG-I signaling. In this study, we determined the LGP2 alternative transcripts in humans to further comprehend the mechanism of its regulation, their evolutionary origin, and the isoforms functionallity. The results showed new eight alternative transcripts in the samples tested. The presence of these transcripts demonstrated that the main mechanisms for the regulation of LGP2 expression are both by insertion of introns and by the loss of exons. The phylogenetic analysis of the comparison between sequences from exon 1 to exon 3 of humans and those previously described in non-human primates showed three well-differentiated groups (lineages) originating from gorillas, suggesting that the transspecies evolution has been maintained for 10 million years. The corresponding protein models (isoforms) were also established, obtaining four isoforms: one complete and three others lacking the C-terminal domain or this domain and the partial or total He2 Helicase domain, which would compromise the functionality of LGP2. In conclusion, this is the first study that elucidate the large genomic organization and complex transcriptional regulation of human LGP2, its pattern of sequence generation, and a mode of evolutionary inheritance across species.
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Affiliation(s)
- Jorge Martinez-Laso
- Immunogenetics Unit, National Center of Microbiology, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo K2,2, Majadahonda, Madrid 28220, Spain
| | - Isabel Cervera
- Immunogenetics Unit, National Center of Microbiology, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo K2,2, Majadahonda, Madrid 28220, Spain
| | - Marina S Martinez-Carrasco
- Immunogenetics Unit, National Center of Microbiology, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo K2,2, Majadahonda, Madrid 28220, Spain
- Pediatrics Department, Hospital Universitario 12 de Octubre, Avda de Córdoba s/n 28041, Madrid, Spain
| | - Veronica Briz
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Majadahonda, 28220, Madrid, Spain
| | - Celia Crespo-Bermejo
- Viral Hepatitis Reference and Research Laboratory, National Center of Microbiology, Institute of Health Carlos III, Majadahonda, 28220, Madrid, Spain
| | - Clara Sánchez-Menéndez
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain
- PhD Program in Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia (UNED), C/ Bravo Murillo, 38 3ª, 28015 Madrid, Spain
- Hematology and Hemotherapy Service, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Hospital Universitario Ramón y Cajal, Ctra. Colmenar Viejo, Fuencarral-El Pardo, 28034 Madrid, Spain
| | - Guiomar Casado-Fernández
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain
- PhD Program in Health Sciences, Faculty of Sciences, Universidad de Alcalá, Ctra. Madrid-Barcelona, Km. 33,600. 28805 Alcalá de Henares, Madrid, Spain
| | - Montserrat Torres
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain
- Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain
| | - Mayte Coiras
- Immunopathology and Viral Reservoir Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, 28220, Madrid, Spain
- Biomedical Research Center Network in Infectious Diseases (CIBERINFEC), Instituto de Salud Carlos III, Majadahonda, 28220 Madrid, Spain
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4
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Leone F, Gori A, Cinicola BL, Brindisi G, Maglione V, Anania C, Zicari AM. Extra X, extra questions: Trisomy X syndrome and IgA deficiency - a case report. Front Immunol 2024; 15:1518076. [PMID: 39712011 PMCID: PMC11659227 DOI: 10.3389/fimmu.2024.1518076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2024] [Accepted: 11/21/2024] [Indexed: 12/24/2024] Open
Abstract
While Trisomy X syndrome is typically characterized by developmental and cognitive variations, it is not commonly associated with immunodeficiencies. We report the unique case of a 6-year-old girl with Trisomy X presenting with selective IgA deficiency, challenging the conventional understanding of this chromosomal condition. The patient exhibited recurrent respiratory infections and gastrointestinal symptoms, evaluated in the context of her genetic background of Trisomy X and significantly low levels of IgA (0.03 g/L), yet normal IgG and IgM levels. Immunological assessment revealed a poor response to vaccination to HBV, necessitating an adapted vaccination strategy. Gastrointestinal investigations indicated paradoxical diarrhea secondary to chronic constipation, managed with dietary interventions. The presence of an extra X chromosome raises questions about the potential over-expression of genes that escape X-chromosome inactivation, such as FOXP3, which is crucial for the regulation of regulatory T cells. An abnormal expression of FOXP3 could lead to either heightened immune regulation, increasing susceptibility to infections, or to immune dysregulation. Although Trisomy X is not typically associated with immunodeficiencies, this case, paralleled by another patient with Trisomy X and CVID, suggests a need for further speculative research into possible genetic links. Moreover, a 1969 study reported lower IgA levels in women with an extra X chromosome. In conclusion, this case aims to underscore the necessity for a deeper genetic and immunological evaluation in chromosomal anomalies like Trisomy X to fully understand their speculative impact on immune function.
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Affiliation(s)
- Fabrizio Leone
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Alessandra Gori
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Bianca Laura Cinicola
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Giulia Brindisi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Vittorio Maglione
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Caterina Anania
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
| | - Anna Maria Zicari
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, Rome, Italy
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5
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Willis TW, Gkrania-Klotsas E, Wareham NJ, McKinney EF, Lyons PA, Smith KGC, Wallace C. Leveraging pleiotropy identifies common-variant associations with selective IgA deficiency. Clin Immunol 2024; 268:110356. [PMID: 39241920 DOI: 10.1016/j.clim.2024.110356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/22/2024] [Accepted: 08/31/2024] [Indexed: 09/09/2024]
Abstract
Selective IgA deficiency (SIgAD) is the most common inborn error of immunity (IEI). Unlike many IEIs, evidence of a role for highly penetrant rare variants in SIgAD is lacking. Previous SIgAD studies have had limited power to identify common variants due to their small sample size. We overcame this problem first through meta-analysis of two existing GWAS. This identified four novel common-variant associations and enrichment of SIgAD-associated variants in genes linked to Mendelian IEIs. SIgAD showed evidence of shared genetic architecture with serum IgA and a number of immune-mediated diseases. We leveraged this pleiotropy through the conditional false discovery rate procedure, conditioning our SIgAD meta-analysis on large GWAS of asthma and rheumatoid arthritis, and our own meta-analysis of serum IgA. This identified an additional 18 variants, increasing the number of known SIgAD-associated variants to 27 and strengthening the evidence for a polygenic, common-variant aetiology for SIgAD.
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Affiliation(s)
- Thomas W Willis
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK.
| | - Effrossyni Gkrania-Klotsas
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK; Department of Infectious Diseases, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK
| | - Nicholas J Wareham
- Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK
| | - Eoin F McKinney
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Paul A Lyons
- Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
| | - Kenneth G C Smith
- Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; Department of Medical Biology, University of Melbourne, Melbourne, Australia
| | - Chris Wallace
- Medical Research Council Biostatistics Unit, University of Cambridge, Cambridge, UK; Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK
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6
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Fekrvand S, Abolhassani H, Rezaei N. An overview of early genetic predictors of IgA deficiency. Expert Rev Mol Diagn 2024; 24:715-727. [PMID: 39087770 DOI: 10.1080/14737159.2024.2385521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 07/24/2024] [Indexed: 08/02/2024]
Abstract
INTRODUCTION Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown. AREAS COVERED This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells. EXPERT OPINION A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.
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Affiliation(s)
- Saba Fekrvand
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hassan Abolhassani
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Division of Clinical Immunology, Department of Biosciences and Nutrition, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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7
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Altiner S, Ekinci A. Adult-Onset Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome on the Basis of Selective IgA Deficiency. Case Rep Dermatol Med 2024; 2024:9845501. [PMID: 39119144 PMCID: PMC11306723 DOI: 10.1155/2024/9845501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 06/01/2024] [Accepted: 06/15/2024] [Indexed: 08/10/2024] Open
Abstract
Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome (PFAPA) is an autoinflammatory disease that is thought to occur with the contribution of genetic and environmental factors, but its etiology has not been clearly elucidated. It is characterized by recurrent attacks with fever, pharyngitis, oral aphthous lesions, and cervical lymphadenopathy, and an increase in the level of serum acute phase reactants is observed during the attacks. Although PFAPA usually begins in childhood, adult-onset cases are also reported in the literature. In the pathogenesis of PFAPA, an increase in the expression of various inflammatory cytokines, especially interleukin-1β (IL-1β), is observed as a result of the increase in inflammasome activity. Selective IgA deficiency (SIgAD) is the most prevalent primary immunodeficiency. Although most SIgAD cases remain asymptomatic and remain undiagnosed, it is known that the risk of mucosal infection is generally increased in SIgAD cases. In addition, the frequency of autoinflammatory diseases is increased in SIgAD cases compared with the general population. We aim to present a case of adult-onset PFAPA and SIgAD coexistence.
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Affiliation(s)
- Seda Altiner
- Department of Immunology and AllergyAnkara University Faculty of Medicine, Ankara, Türkiye
| | - Alper Ekinci
- Department of Immunology and AllergyAnkara University Faculty of Medicine, Ankara, Türkiye
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Manzoor S, Nabi SU, Rather TR, Gani G, Mir ZA, Wani AW, Ali S, Tyagi A, Manzar N. Advancing crop disease resistance through genome editing: a promising approach for enhancing agricultural production. Front Genome Ed 2024; 6:1399051. [PMID: 38988891 PMCID: PMC11234172 DOI: 10.3389/fgeed.2024.1399051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/22/2024] [Indexed: 07/12/2024] Open
Abstract
Modern agriculture has encountered several challenges in achieving constant yield stability especially due to disease outbreaks and lack of long-term disease-resistant crop cultivars. In the past, disease outbreaks in economically important crops had a major impact on food security and the economy. On the other hand climate-driven emergence of new pathovars or changes in their host specificity further poses a serious threat to sustainable agriculture. At present, chemical-based control strategies are frequently used to control microbial pathogens and pests, but they have detrimental impact on the environment and also resulted in the development of resistant phyto-pathogens. As a replacement, cultivating engineered disease-resistant crops can help to minimize the negative impact of regular pesticides on agriculture and the environment. Although traditional breeding and genetic engineering have been instrumental in crop disease improvement but they have certain limitations such as labour intensity, time consumption, and low efficiency. In this regard, genome editing has emerged as one of the potential tools for improving disease resistance in crops by targeting multiple traits with more accuracy and efficiency. For instance, genome editing techniques, such as CRISPR/Cas9, CRISPR/Cas13, base editing, TALENs, ZFNs, and meganucleases, have proved successful in improving disease resistance in crops through targeted mutagenesis, gene knockouts, knockdowns, modifications, and activation of target genes. CRISPR/Cas9 is unique among these techniques because of its remarkable efficacy, low risk of off-target repercussions, and ease of use. Some primary targets for developing CRISPR-mediated disease-resistant crops are host-susceptibility genes (the S gene method), resistance genes (R genes) and pathogen genetic material that prevents their development, broad-spectrum disease resistance. The use of genome editing methods has the potential to notably ameliorate crop disease resistance and transform agricultural practices in the future. This review highlights the impact of phyto-pathogens on agricultural productivity. Next, we discussed the tools for improving disease resistance while focusing on genome editing. We provided an update on the accomplishments of genome editing, and its potential to improve crop disease resistance against bacterial, fungal and viral pathogens in different crop systems. Finally, we highlighted the future challenges of genome editing in different crop systems for enhancing disease resistance.
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Affiliation(s)
- Subaya Manzoor
- Division of Plant Pathology, FOA-SKUAST-K, Wadura, Srinagar, India
| | - Sajad Un Nabi
- ICAR-Central Institute of Temperate Horticulture, Srinagar, India
| | | | - Gousia Gani
- Division of Basic Science and Humanities, FOA-SKUAST-K, Wadura, Srinagar, India
| | - Zahoor Ahmad Mir
- Department of Plant Science and Agriculture, University of Manitoba, Winnipeg, MB, Canada
| | - Ab Waheed Wani
- Department of Horticulture, LPU, Jalander, Punjab, India
| | - Sajad Ali
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Anshika Tyagi
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Nazia Manzar
- Plant Pathology Lab, ICAR-National Bureau of Agriculturally Important Microorganism, Mau, Uttar Pradesh, India
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9
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Morse ZJ, Simister RL, Crowe SA, Horwitz MS, Osborne LC. Virus induced dysbiosis promotes type 1 diabetes onset. Front Immunol 2023; 14:1096323. [PMID: 36742327 PMCID: PMC9892191 DOI: 10.3389/fimmu.2023.1096323] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/03/2023] [Indexed: 01/20/2023] Open
Abstract
Autoimmune disorders are complex diseases of unclear etiology, although evidence suggests that the convergence of genetic susceptibility and environmental factors are critical. In type 1 diabetes (T1D), enterovirus infection and disruption of the intestinal microbiota are two environmental factors that have been independently associated with T1D onset in both humans and animal models. However, the possible interaction between viral infection and the intestinal microbiota remains unknown. Here, we demonstrate that Coxsackievirus B4 (CVB4), an enterovirus that accelerates T1D onset in non-obese diabetic (NOD) mice, induced restructuring of the intestinal microbiome prior to T1D onset. Microbiome restructuring was associated with an eroded mucosal barrier, bacterial translocation to the pancreatic lymph node, and increased circulating and intestinal commensal-reactive antibodies. The CVB4-induced change in community composition was strikingly similar to that of uninfected NOD mice that spontaneously developed diabetes, implying a mutual "diabetogenic" microbiome. Notably, members of the Bifidobacteria and Akkermansia genera emerged as conspicuous members of this diabetogenic microbiome, implicating these taxa, among others, in diabetes onset. Further, fecal microbiome transfer (FMT) of the diabetogenic microbiota from CVB4-infected mice enhanced T1D susceptibility and led to diminished expression of the short chain fatty acid receptor GPR43 and fewer IL-10-expressing regulatory CD4+ T cells in the intestine of naïve NOD recipients. These findings support an overlap in known environmental risk factors of T1D, and suggest that microbiome disruption and impaired intestinal homeostasis contribute to CVB-enhanced autoreactivity and T1D.
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Affiliation(s)
- Zachary J Morse
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Rachel L Simister
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Sean A Crowe
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Earth, Ocean, and Atmospheric Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Marc S Horwitz
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Lisa C Osborne
- Department of Microbiology & Immunology, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
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Ferreira LC, Gomes CE, Rodrigues-Neto JF, Jeronimo SM. Genome-wide association studies of COVID-19: Connecting the dots. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2022; 106:105379. [PMID: 36280088 PMCID: PMC9584840 DOI: 10.1016/j.meegid.2022.105379] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 10/01/2022] [Accepted: 10/19/2022] [Indexed: 11/13/2022]
Abstract
Genome-wide association studies (GWASs) are a research approach used to identify genetic variants associated with common diseases, like COVID-19. The lead genetic variants (n = 41) reported by the eleven largest COVID-19 GWASs are mapped to 22 different chromosomal regions. The loci 3q21.31 (LZTFL1 and chemokine receptor genes) and 9q34.2 (ABO), associated with disease severity and susceptibility to infection, respectively, were the most replicated findings across studies. Genes involved with mucociliary clearance (CEP97, FOXP4), viral-entry (ACE2, SLC6A20) and mucosal immunity (MIR6891) are associated with the risk of SARS-CoV-2 infection while genes of antiviral immune response (IFNAR2, OAS1), leukocyte trafficking (CCR9, CXCR6) and lung injury (DPP9, NOTCH4) are associated with severe disease. The biological processes underlying the risk of infection occur prominently, but not exclusively, in the upper airways whereas the severe COVID-19-associated processes in alveolar-capillary interface. The COVID-19 GWASs has unraveled key genetic mechanisms of SARS-CoV-2 pathogenesis, although the genetic basis of other COVID-19 related phenotypes (long COVID and neurological impairment) remains to be elucidated.
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Affiliation(s)
- Leonardo C. Ferreira
- Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil,Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil,Corresponding author at: Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil
| | - Carlos E.M. Gomes
- Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil
| | - João F. Rodrigues-Neto
- Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil,Multicampi School of Medical Sciences, Federal University of Rio Grande do Norte, Caicó, RN 59078-900, Brazil
| | - Selma M.B. Jeronimo
- Department of Biochemistry, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil,Institute of Tropical Medicine, Federal University of Rio Grande do Norte, Natal, RN 59078-900, Brazil,Institute of Science and Technology of Tropical Diseases, Natal, RN, Brazil
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11
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Pediatric Celiac Disease and Selective IgA Deficiency: Unexpected Sequence of Events. J Clin Immunol 2022; 42:1342-1346. [PMID: 35701710 DOI: 10.1007/s10875-022-01297-3] [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: 03/25/2022] [Accepted: 05/25/2022] [Indexed: 10/18/2022]
Abstract
PURPOSE Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. METHODS Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA. RESULTS We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. CONCLUSION Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation.
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12
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Padron GT, Hernandez-Trujillo VP. Autoimmunity in Primary Immunodeficiencies (PID). Clin Rev Allergy Immunol 2022:10.1007/s12016-022-08942-0. [PMID: 35648371 DOI: 10.1007/s12016-022-08942-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/04/2022] [Indexed: 11/25/2022]
Abstract
Primary immunodeficiency (PID) may impact any component of the immune system. The number of PID and immune dysregulation disorders is growing steadily with advancing genetic detection methods. These expansive recognition methods have changed the way we characterize PID. While PID were once characterized by their susceptibility to infection, the increase in genetic analysis has elucidated the intertwined relationship between PID and non-infectious manifestations including autoimmunity. The defects permitting opportunistic infections to take hold may also lead the way to the development of autoimmune disease. In some cases, it is the non-infectious complications that may be the presenting sign of PID autoimmune diseases, such as autoimmune cytopenia, enteropathy, endocrinopathies, and arthritis among others, have been reported in PID. While autoimmunity may occur with any PID, this review will look at certain immunodeficiencies most often associated with autoimmunity, as well as their diagnosis and management strategies.
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Affiliation(s)
- Grace T Padron
- Nicklaus Children's Hospital, Miami, FL, USA.
- Allergy and Immunology Care Center of South Florida, Miami Lakes, FL, USA.
| | - Vivian P Hernandez-Trujillo
- Nicklaus Children's Hospital, Miami, FL, USA
- Allergy and Immunology Care Center of South Florida, Miami Lakes, FL, USA
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13
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Dong Z, Zhang B, Rong J, Yang X, Wang Y, Zhang Q, Su Z. The aberrant expression of CD45 isoforms and levels of sex hormones in systemic lupus erythematosus. Clin Rheumatol 2022; 41:1087-1093. [PMID: 35064423 DOI: 10.1007/s10067-021-05934-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/30/2021] [Accepted: 09/21/2021] [Indexed: 02/05/2023]
Abstract
INTRODUCTION Systemic lupus erythematosus (SLE) is a common autoimmune disease with significant gender bias in women, and sex hormones are considered to play an important role in the regulation of immune activity. The CD45 isoforms generated through alternative splicing of mRNA identify different functional status of lymphocytes and also are suggested as a biomarker for assessing the progression of SLE, while the modulation of CD45 expression in SLE patients is not clear. METHODS In this study, the peripheral blood sera of 46 SLE patients and 15 health individuals were collected for detecting the levels of sex hormones and immune associated factors. The expression of CD45 isoforms and the status of CD45 DNA methylation of the peripheral mononuclear blood cells were detected by flow cytometry and bisulfite sequencing PCR, respectively. RESULTS The levels of complement C3 and IgA decreased, especially decline of the serum IgA to the level of selective immunoglobulin A deficiency, and the C-reactive protein increased in SLE patients when compared with healthy controls, which manifested the abnormal immune activity of the SLE patients. Sex hormones detection showed a decreased testosterone and increased prolactin in SLE. An accelerated expression of CD45RO, reduced CD45RA and CD45RB, and a relative hypermethylation of CD45 DNA in SLE were also identified that provided a clue to explain the possible regulatory mechanism for the immune function in SLE. CONCLUSION The results indicated that the aberrant CD45 isoforms, DNA methylation and hormone levels might be correlated with the imbalanced immune activity of SLE patients. Key Points • Selective immunoglobulin A deficiency was significantly higher in SLE than in healthy individuals. • SLE patients had decreased testosterone and increased prolactin in the sera. • An aberrant expression of CD45 isoforms and CD45 DNA methylation were identified in SLE.
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Affiliation(s)
- Zhaoxia Dong
- Department of Histology and Embryology, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Bin Zhang
- Department of Histology and Embryology, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Ju Rong
- Department of Internal Medicine, The First Affiliated Hospital of Shantou University Medical College, 57 Changping Road, Shantou, 515041, Guangdong Province, China
| | - Xinran Yang
- Department of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Yongni Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Qiaoxin Zhang
- Department of Clinical Laboratory, The First Affiliated Hospital of Shantou University Medical College, Shantou, 515041, Guangdong Province, China
| | - Zhongjing Su
- Department of Histology and Embryology, Shantou University Medical College, Shantou, 515041, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, 22 Xinling Road, Shantou, 515041, Guangdong Province, China
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14
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Cinicola BL, Pulvirenti F, Capponi M, Bonetti M, Brindisi G, Gori A, De Castro G, Anania C, Duse M, Zicari AM. Selective IgA Deficiency and Allergy: A Fresh Look to an Old Story. Medicina (B Aires) 2022; 58:medicina58010129. [PMID: 35056437 PMCID: PMC8781177 DOI: 10.3390/medicina58010129] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/07/2022] [Accepted: 01/10/2022] [Indexed: 01/23/2023] Open
Abstract
Selective IgA deficiency (SIgAD) is the most common human primary immune deficiency (PID). It is classified as a humoral PID characterized by isolated deficiency of IgA (less than 7 mg/dL but normal serum IgG and IgM) in subjects greater than 4 years of age. Intrinsic defects in the maturation of B cells and a perturbation of Th cells and/or cytokine signals have been hypothesized to contribute to SIgAD pathogenesis. The genetic basis of IgA deficiency remains to be clarified. Patients with SIgAD can be either asymptomatic or symptomatic with clinical manifestations including allergy, autoimmunity and recurrent infections mainly of the respiratory and gastrointestinal tract. Studies analyzing allergy on SIgAD patients showed prevalence up to 84%, supporting in most cases the relationship between sIgAD and allergic disease. However, the prevalence of allergic disorders may be influenced by various factors. Thus, the question of whether allergy is more common in SIgAD patients compared to healthy subjects remains to be defined. Different hypotheses support an increased susceptibility to allergy in subjects with SIgAD. Recurrent infections due to loss of secretory IgA might have a role in the pathogenesis of allergy, and vice versa. Perturbation of microbiota also plays a role. The aim of this review is to examine the association between SIgAD and atopic disease and to update readers on advances over time at this important interface between allergy and SIgAD.
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Affiliation(s)
- Bianca Laura Cinicola
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
- Department of Molecular Medicine, Sapienza University of Rome, 00185 Rome, Italy
- Correspondence:
| | - Federica Pulvirenti
- Primary Immune Deficiencies Unit, Department of Internal Medicine and Infectious Diseases, Azienda Ospedaliera Universitaria Policlinico Umberto I, 00185 Rome, Italy;
| | - Martina Capponi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Marta Bonetti
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Giulia Brindisi
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy
| | - Alessandra Gori
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Giovanna De Castro
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Caterina Anania
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Marzia Duse
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
| | - Anna Maria Zicari
- Department of Maternal Infantile and Urological Sciences, Sapienza University of Rome, 00185 Rome, Italy; (M.C.); (M.B.); (G.B.); (A.G.); (G.D.C.); (C.A.); (M.D.); (A.M.Z.)
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15
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Lim CK, Bronson PG, Varade J, Behrens TW, Hammarström L. STXBP6 and B3GNT6 Genes are Associated With Selective IgA Deficiency. Front Genet 2022; 12:736235. [PMID: 34976003 PMCID: PMC8718598 DOI: 10.3389/fgene.2021.736235] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Accepted: 11/11/2021] [Indexed: 12/24/2022] Open
Abstract
Immunoglobulin A Deficiency (IgAD) is a polygenic primary immune deficiency, with a strong genetic association to the human leukocyte antigen (HLA) region. Previous genome-wide association studies (GWAS) have identified five non-HLA risk loci (IFIH1, PVT1, ATG13-AMBRA1, AHI1 and CLEC16A). In this study, we investigated the genetic interactions between different HLA susceptibility haplotypes and non-MHC genes in IgAD. To do this, we stratified IgAD subjects and healthy controls based on HLA haplotypes (N = 10,993), and then performed GWAS to identify novel genetic regions contributing to IgAD susceptibility. After replicating previously published HLA risk haplotypes, we compared individuals carrying at least one HLA risk allele (HLA-B*08:01-DRB1*03:01-DQB1*02:01 or HLA-DRB1*07:01-DQB1*02:02 or HLA-DRB1*01-DQB1*05:01) with individuals lacking an HLA risk allele. Subsequently, we stratified subjects based on the susceptibility alleles/haplotypes and performed gene-based association analysis using 572,856 SNPs and 24,125 genes. A significant genome-wide association in STXBP6 (rs4097492; p = 7.63 × 10-9) was observed in the cohort carrying at least one MHC risk allele. We also identified a significant gene-based association for B3GNT6 (P Gene = 2.1 × 10-6) in patients not carrying known HLA susceptibility alleles. Our findings indicate that the etiology of IgAD differs depending on the genetic background of HLA susceptibility haplotypes.
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Affiliation(s)
- Che Kang Lim
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University, Hospital Huddinge, Stockholm, Sweden.,Department Clinical Translation Research, Singapore General Hospital, Singapore, Singapore
| | - Paola G Bronson
- RED OMNI Human Genetics, Genentech, South San Francisco, CA, United States
| | - Jezabel Varade
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University, Hospital Huddinge, Stockholm, Sweden.,Biomedical Research Center (CINBIO) Singular Research Center, University of Vigo, Vigo, Spain
| | | | - Lennart Hammarström
- Department of Laboratory Medicine, Karolinska Institutet, Karolinska University, Hospital Huddinge, Stockholm, Sweden.,Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.,BGI-Shenzhen, Shenzhen, China
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16
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Koenen MH, Bosma M, Roorda UA, Wopereis FM, Roos A, van der Vries E, Bogaert D, Sanders EA, Boes M, Heidema J, van Montfrans JM, Balemans WA, van Holten TC, Verhagen LM. A novel method to standardise serum IgA measurements shows an increased prevalence of IgA deficiency in young children with recurrent respiratory tract infections. Clin Transl Immunology 2021; 10:e1344. [PMID: 34745609 PMCID: PMC8556141 DOI: 10.1002/cti2.1344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 09/03/2021] [Accepted: 09/05/2021] [Indexed: 11/17/2022] Open
Abstract
Objectives While physicians are often confronted with immunoglobulin A (IgA) deficiency in children with recurrent infections, the clinical relevance of this finding is unclear. Large‐scale studies examining the significance of IgA deficiency in children are hampered by differences in techniques for measuring IgA and the physiological increase of IgA with age. Both result in a variety of reference values used for diagnosing IgA deficiency. We propose a new laboratory‐independent method to accurately compare IgA measurements in children of varying ages. Methods We present a method to standardise IgA values for age and laboratory differences. We applied this method to a multicentre case–control study of children under the age of seven suffering from recurrent respiratory tract infections (rRTI, cases) and children who had IgA measured as part of coeliac disease screening (controls). We defined IgA deficiency as serum IgA measurements < 2.5% for age‐specific reference values. Results We developed reference values for IgA for seven age groups and five different laboratory assays. Using these reference values, IgA measurements from 417 cases and 224 controls were standardised to compare groups. In children aged 2 years and older, IgA deficiency was observed in 2.9% (7/242) of cases and 0% (0/189) of controls (P = 0.02). Conclusion We present a method to compare IgA values in cohorts that vary in age and laboratory assay. This way, we showed that IgA deficiency was more prevalent in children with rRTI compared with controls. This implicates that IgA deficiency may be a clinically relevant condition, even in young children.
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Affiliation(s)
- Mischa H Koenen
- Center of Translational Immunology University Medical Center Utrecht Utrecht The Netherlands
| | - Madeleen Bosma
- Department of Clinical Chemistry St Antonius Hospital Nieuwegein The Netherlands
| | - Udo A Roorda
- Department of Research Data Management Pediatrics, Woman & Baby UMC Utrecht Utrecht The Netherlands
| | - Fabiënne My Wopereis
- Department of General Practice University Medical Center Utrecht Utrecht The Netherlands
| | - Anja Roos
- Department of Medical Microbiology and Immunology St Antonius Hospital Nieuwegein The Netherlands
| | - Erhard van der Vries
- Department of Research & Development GD Animal Health Deventer The Netherlands.,Department of Clinical Chemistry and Hematology University Medical Center Utrecht Utrecht The Netherlands
| | - Debby Bogaert
- Department of Pediatric Infectious Diseases and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht The Netherlands.,Center for Inflammation Research Queen's Medical Research Institute University of Edinburgh Edinburgh UK
| | - Elisabeth Am Sanders
- Department of Pediatric Infectious Diseases and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht The Netherlands.,Centre for Infectious Disease Control National Institute of Public Health and the Environment Bilthoven The Netherlands
| | - Marianne Boes
- Center of Translational Immunology University Medical Center Utrecht Utrecht The Netherlands.,Department of Pediatric Infectious Diseases and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht The Netherlands
| | - Jojanneke Heidema
- Department of Pediatrics St Antonius Hospital Nieuwegein The Netherlands
| | - Joris M van Montfrans
- Department of Pediatric Infectious Diseases and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht The Netherlands
| | - Walter Af Balemans
- Department of Pediatrics St Antonius Hospital Nieuwegein The Netherlands
| | - Thijs C van Holten
- Department of Clinical Chemistry St Antonius Hospital Nieuwegein The Netherlands
| | - Lilly M Verhagen
- Department of Pediatric Infectious Diseases and Immunology Wilhelmina Children's Hospital, University Medical Center Utrecht Utrecht The Netherlands.,Section of Pediatric Infectious Diseases Laboratory of Medical Immunology Radboud University Medical Center Radboud Center for Infectious Diseases Nijmegen The Netherlands.,Department of Paediatric Infectious Diseases and Immunology Radboud University Medical Center Amalia Children's Hospital Nijmegen The Netherlands
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17
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Morse ZJ, Horwitz MS. Virus Infection Is an Instigator of Intestinal Dysbiosis Leading to Type 1 Diabetes. Front Immunol 2021; 12:751337. [PMID: 34721424 PMCID: PMC8554326 DOI: 10.3389/fimmu.2021.751337] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Accepted: 09/28/2021] [Indexed: 12/12/2022] Open
Abstract
In addition to genetic predisposition, environmental determinants contribute to a complex etiology leading to onset of type 1 diabetes (T1D). Multiple studies have established the gut as an important site for immune modulation that can directly impact development of autoreactive cell populations against pancreatic self-antigens. Significant efforts have been made to unravel how changes in the microbiome function as a contributor to autoimmune responses and can serve as a biomarker for diabetes development. Large-scale longitudinal studies reveal that common environmental exposures precede diabetes pathology. Virus infections, particularly those associated with the gut, have been prominently identified as risk factors for T1D development. Evidence suggests recent-onset T1D patients experience pre-existing subclinical enteropathy and dysbiosis leading up to development of diabetes. The start of these dysbiotic events coincide with detection of virus infections. Thus viral infection may be a contributing driver for microbiome dysbiosis and disruption of intestinal homeostasis prior to T1D onset. Ultimately, understanding the cross-talk between viral infection, the microbiome, and the immune system is key for the development of preventative measures against T1D.
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Affiliation(s)
| | - Marc S. Horwitz
- Department of Microbiology and Immunology, University of British Columbia, Vancouver, BC, Canada
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18
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Lee M, Lee G, Kang HG, Suh JS. New susceptible locus, rs9428555, is associated with pediatric-onset immunoglobulin A nephropathy and immunoglobulin A vasculitis in Koreans. Genes Genomics 2021; 43:1049-1057. [PMID: 34146253 DOI: 10.1007/s13258-021-01120-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 06/06/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN) is one of the most common primary forms of glomerulonephritis, while IgA vasculitis (IgAV) is the most common systemic vasculitis in children. OBJECTIVE Herein we aimed to uncover single nucleotide polymorphism (SNP) markers associated with these two related diseases by applying association tests and Sanger sequencing. METHODS Within the discovery stage, genomic DNA in blood samples from 101 enrolled patients were genotyped by the Korean Biobank Array. Association tests were performed with 397 Korean reference genomes. In the validation stage, 26 independent samples were genotyped by Sanger sequencing. RESULTS Four SNPs were identified (P < 5 × 10-8) in the discovery stage. To determine whether the genotypes determined by SNP array were accurate, additional genotyping via Sanger sequencing was performed. As a result, only one SNP, rs9428555, was properly genotyped. In the validation stage, the minor allele (A > G) was found in as many as 15 out of 26 samples (minor allele frequency = 0.288), even though this minor allele is rare in East Asians (< 3%). CONCLUSIONS We found rs9428555 as a novel susceptible locus associated with the development of both IgAN and IgAV in Koreans. Though we cannot conclude rs9428555 is the unique susceptible locus of IgAN and IgAV, it is likely a good marker as the minor allele of this SNP occurred much more often in the patient group here versus within East Asians as a whole.
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Affiliation(s)
- Minho Lee
- Department of Life Science, Dongguk University-Seoul, Ilsandong-gu, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Gunhee Lee
- Department of Biomedicine & Health Sciences, Graduate School, The Catholic University of Korea, Seoul, Republic of Korea
| | - Hee Gyung Kang
- Department of Pediatrics, Seoul National University, College of Medicine and Seoul National University Children's Hospital, Seoul, Republic of Korea
| | - Jin-Soon Suh
- Department of Pediatrics, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon-Si, Gyeonggi-do, Republic of Korea.
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19
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Moll JM, Myers PN, Zhang C, Eriksen C, Wolf J, Appelberg KS, Lindberg G, Bahl MI, Zhao H, Pan-Hammarström Q, Cai K, Jia H, Borte S, Nielsen HB, Kristiansen K, Brix S, Hammarström L. Gut Microbiota Perturbation in IgA Deficiency Is Influenced by IgA-Autoantibody Status. Gastroenterology 2021; 160:2423-2434.e5. [PMID: 33662387 DOI: 10.1053/j.gastro.2021.02.053] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 02/01/2021] [Accepted: 02/22/2021] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS IgA exerts its primary function at mucosal surfaces, where it binds microbial antigens to regulate bacterial growth and epithelial attachment. One third of individuals with IgA deficiency (IgAD) suffers from recurrent mucosal infections, possibly related to an altered microbiota. We aimed to delineate the impact of IgAD and the IgA-autoantibody status on the composition and functional capacity of the gut microbiota. METHODS We performed a paired, lifestyle-balanced analysis of the effect of IgA on the gut microbiota composition and functionality based on fecal samples from individuals with IgAD and IgA-sufficient household members (n = 100), involving quantitative shotgun metagenomics, species-centric functional annotation of gut bacteria, and strain-level analyses. We supplemented the data set with 32 individuals with IgAD and examined the influence of IgA-autoantibody status on the composition and functionality of the gut microbiota. RESULTS The gut microbiota of individuals with IgAD exhibited decreased richness and diversity and was enriched for bacterial species encoding pathogen-related functions including multidrug and antimicrobial peptide resistance, virulence factors, and type III and VI secretion systems. These functional changes were largely attributed to Escherichia coli but were independent of E coli strain variations and most prominent in individuals with IgAD with IgA-specific autoreactive antibodies. CONCLUSIONS The microbiota of individuals with IgAD is enriched for species holding increased proinflammatory potential, thereby potentially decreasing the resistance to gut barrier-perturbing events. This phenotype is especially pronounced in individuals with IgAD with IgA-specific autoreactive antibodies, thus warranting a screening for IgA-specific autoreactive antibodies in IgAD to identify patients with IgAD with increased risk for gastrointestinal implications.
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Affiliation(s)
- Janne Marie Moll
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Pernille Neve Myers
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | | | - Carsten Eriksen
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Johannes Wolf
- ImmunoDeficiencyCenter Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at the Municipal Hospital St. Georg Leipzig, Leipzig, Germany
| | - K Sofia Appelberg
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Greger Lindberg
- Department of Medicine, Karolinska Institutet and Department of Gastroenterology at Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | - Martin Iain Bahl
- National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
| | | | | | - Kaiye Cai
- BGI-Shenzhen, Shenzhen, China; Shenzhen Engineering Laboratory for Detection and Intervention of Human Intestinal Microbiome, BGI-Shenzhen, Shenzhen, China
| | - Huijue Jia
- BGI-Shenzhen, Shenzhen, China; Shenzhen Key Laboratory for Human Commensals and Health Research, BGI-Shenzhen, Shenzhen, China
| | - Stephan Borte
- ImmunoDeficiencyCenter Leipzig, Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies at the Municipal Hospital St. Georg Leipzig, Leipzig, Germany; Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden
| | | | - Karsten Kristiansen
- BGI-Shenzhen, Shenzhen, China; Laboratory of Genomics and Molecular Biomedicine, Department of Biology, University of Copenhagen, Copenhagen, Denmark; Qingdao-Europe Advanced Institute for Life Sciences, Qingdao, Shandong, China.
| | - Susanne Brix
- Department of Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark; Qingdao-Europe Advanced Institute for Life Sciences, Qingdao, Shandong, China.
| | - Lennart Hammarström
- Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institutet at Karolinska University Hospital, Huddinge, Stockholm, Sweden.
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20
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Zhang J, van Oostrom D, Li J, Savelkoul HFJ. Innate Mechanisms in Selective IgA Deficiency. Front Immunol 2021; 12:649112. [PMID: 33981304 PMCID: PMC8107477 DOI: 10.3389/fimmu.2021.649112] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 04/07/2021] [Indexed: 12/12/2022] Open
Abstract
Selective IgA deficiency (SIgAD), characterized by a serum IgA level below 0.07 mg/ml, while displaying normal serum levels of IgM and IgG antibodies, is the most frequently occurring primary immunodeficiency that reveals itself after the first four years after birth. These individuals with SIgAD are for the majority healthy and even when they are identified they are usually not investigated further or followed up. However, recent studies show that newborns and young infants already display clinical manifestations of this condition due to aberrancies in their immune defense. Interestingly, there is a huge heterogeneity in the clinical symptoms of the affected individuals. More than 50% of the affected individuals do not have clinical symptoms, while the individuals that do show clinical symptoms can suffer from mild to severe infections, allergies and autoimmune diseases. However, the reason for this heterogeneity in the manifestation of clinical symptoms of the individuals with SIgAD is unknown. Therefore, this review focusses on the characteristics of innate immune system driving T-cell independent IgA production and providing a mechanism underlying the development of SIgAD. Thereby, we focus on some important genes, including TNFRSF13B (encoding TACI), associated with SIgAD and the involvement of epigenetics, which will cover the methylation degree of TNFRSF13B, and environmental factors, including the gut microbiota, in the development of SIgAD. Currently, no specific treatment for SIgAD exists and novel therapeutic strategies could be developed based on the discussed information.
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Affiliation(s)
- Jingyan Zhang
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China
| | - Dèlenn van Oostrom
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
| | - JianXi Li
- Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences (CAAS), Lanzhou, China
| | - Huub F. J. Savelkoul
- Cell Biology and Immunology Group, Wageningen University & Research, Wageningen, Netherlands
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21
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Onomoto K, Onoguchi K, Yoneyama M. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors. Cell Mol Immunol 2021; 18:539-555. [PMID: 33462384 PMCID: PMC7812568 DOI: 10.1038/s41423-020-00602-7] [Citation(s) in RCA: 230] [Impact Index Per Article: 57.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 11/17/2020] [Indexed: 01/31/2023] Open
Abstract
Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are RNA sensor molecules that play essential roles in innate antiviral immunity. Among the three RLRs encoded by the human genome, RIG-I and melanoma differentiation-associated gene 5, which contain N-terminal caspase recruitment domains, are activated upon the detection of viral RNAs in the cytoplasm of virus-infected cells. Activated RLRs induce downstream signaling via their interactions with mitochondrial antiviral signaling proteins and activate the production of type I and III interferons and inflammatory cytokines. Recent studies have shown that RLR-mediated signaling is regulated by interactions with endogenous RNAs and host proteins, such as those involved in stress responses and posttranslational modifications. Since RLR-mediated cytokine production is also involved in the regulation of acquired immunity, the deregulation of RLR-mediated signaling is associated with autoimmune and autoinflammatory disorders. Moreover, RLR-mediated signaling might be involved in the aberrant cytokine production observed in coronavirus disease 2019. Since the discovery of RLRs in 2004, significant progress has been made in understanding the mechanisms underlying the activation and regulation of RLR-mediated signaling pathways. Here, we review the recent advances in the understanding of regulated RNA recognition and signal activation by RLRs, focusing on the interactions between various host and viral factors.
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Affiliation(s)
- Koji Onomoto
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan
| | - Kazuhide Onoguchi
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan
| | - Mitsutoshi Yoneyama
- Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, 1-8-1, Inohana, Chuo-ku, Chiba, 260-8673, Japan.
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22
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King HW, Orban N, Riches JC, Clear AJ, Warnes G, Teichmann SA, James LK. Single-cell analysis of human B cell maturation predicts how antibody class switching shapes selection dynamics. Sci Immunol 2021; 6:6/56/eabe6291. [PMID: 33579751 DOI: 10.1126/sciimmunol.abe6291] [Citation(s) in RCA: 152] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 01/14/2021] [Indexed: 12/21/2022]
Abstract
Protective humoral memory forms in secondary lymphoid organs where B cells undergo affinity maturation and differentiation into memory or plasma cells. Here, we provide a comprehensive roadmap of human B cell maturation with single-cell transcriptomics matched with bulk and single-cell antibody repertoires to define gene expression, antibody repertoires, and clonal sharing of B cell states at single-cell resolution, including memory B cell heterogeneity that reflects diverse functional and signaling states. We reconstruct gene expression dynamics during B cell activation to reveal a pre-germinal center state primed to undergo class switch recombination and dissect how antibody class-dependent gene expression in germinal center and memory B cells is linked with a distinct transcriptional wiring with potential to influence their fate and function. Our analyses reveal the dynamic cellular states that shape human B cell-mediated immunity and highlight how antibody isotype may play a role during their antibody-based selection.
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Affiliation(s)
- Hamish W King
- Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK. .,Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK
| | - Nara Orban
- Barts Health Ear, Nose and Throat Service, Royal London Hospital, London E1 1BB, UK
| | - John C Riches
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.,Francis Crick Institute, London NW1 1AT, UK
| | - Andrew J Clear
- Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK
| | - Gary Warnes
- Flow Cytometry Core Facility, Blizard Institute, Queen Mary University of London, London E1 2AT, UK
| | - Sarah A Teichmann
- Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge CB10 1SA, UK.,Theory of Condensed Matter, Cavendish Laboratory, Department of Physics, University of Cambridge, Cambridge CB3 0EH, UK
| | - Louisa K James
- Centre for Immunobiology, Blizard Institute, Queen Mary University of London, London E1 2AT, UK.
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Mishra R, Joshi RK, Zhao K. Base editing in crops: current advances, limitations and future implications. PLANT BIOTECHNOLOGY JOURNAL 2020; 18:20-31. [PMID: 31365173 PMCID: PMC6920333 DOI: 10.1111/pbi.13225] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 07/23/2019] [Accepted: 07/29/2019] [Indexed: 05/19/2023]
Abstract
Targeted mutagenesis via genome-editing technologies holds great promise in developing improved crop varieties to meet future demands. Point mutations or single nucleotide polymorphisms often determine important agronomic traits of crops. Genome-editing-based single-base changes could generate elite trait variants in crop plants which help in accelerating crop improvement. Among the genome-editing technologies, base editing has emerged as a novel and efficient genome-editing approach which enables direct and irreversible conversion of one target base into another in a programmable manner. A base editor is a fusion of catalytically inactive CRISPR-Cas9 domain (Cas9 variants) and cytosine or adenosine deaminase domain that introduces desired point mutations in the target region enabling precise editing of genomes. In the present review, we have summarized the development of different base-editing platforms. Then, we have focussed on the current advances and the potential applications of this precise technology in crop improvement. The review also sheds light on the limitations associated with this technology. Finally, the future perspectives of this emerging technology towards crop improvement have been highlighted.
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Affiliation(s)
- Rukmini Mishra
- National Key Facility for Crop Gene Resources and Genetic Improvement (NFCRI), Institute of Crop ScienceChinese Academy of Agriculture Sciences (CAAS)BeijingChina
| | - Raj Kumar Joshi
- Department of BiotechnologyRama Devi Women's UniversityBhubaneswarOdishaIndia
| | - Kaijun Zhao
- National Key Facility for Crop Gene Resources and Genetic Improvement (NFCRI), Institute of Crop ScienceChinese Academy of Agriculture Sciences (CAAS)BeijingChina
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25
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Swain S, Selmi C, Gershwin ME, Teuber SS. The clinical implications of selective IgA deficiency. J Transl Autoimmun 2019; 2:100025. [PMID: 32743511 PMCID: PMC7388344 DOI: 10.1016/j.jtauto.2019.100025] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 11/21/2019] [Indexed: 01/06/2023] Open
Abstract
Selective IgA deficiency (SIgAD) is the most common primary immunodeficiency but does not always result in clinical disease. This may in part be due to the definition based on serum IgA, while most IgA is secreted at mucosal surfaces, not amenable to measurement. Clinical complications include increased risk of sinopulmonary infections with bacteria and viruses, gastrointestinal infections with a predilection for Giardia lamblia, a myriad of autoimmune diseases including systemic lupus erythematosus, hyper- and hypo-thyroidism, Type 1 diabetes, celiac disease, and rarely, malignancy. SIgAD must be differentiated from IgA deficiency that may be seen with IgG2 or IgG4 deficiency, specific antibody deficiency, or as an early manifestation prior to a diagnosis of common variable immunodeficiency. Secondary IgA deficiency is increasingly recognized and may be due to medications such as anti-epileptics, or antibiotics with disruption of the microbiome which can influence IgA levels, infections or malignancies. Patients with SIgAD should be monitored at regular intervals and educated to be aware of particular complications. There is a rare chance of development of anti-IgA IgE antibodies in patients with complete deficiency, which can result in anaphylaxis if blood products with IgA are administered. Prophylactic antibiotics may be indicated in some cases, and very rarely, supplemental IgG infusions.
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Affiliation(s)
- Samantha Swain
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
- Veterans Affairs Northern California Healthcare System, Mather, CA, USA
| | - Carlo Selmi
- Rheumatology and Clinical Immunology, Humanitas Research Hospital, Rozzano, Milan, Italy
- BIOMETRA Department, University of Milan, Milan, Italy
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
| | - Suzanne S. Teuber
- Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA
- Veterans Affairs Northern California Healthcare System, Mather, CA, USA
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26
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Sparks AM, Watt K, Sinclair R, Pilkington JG, Pemberton JM, McNeilly TN, Nussey DH, Johnston SE. The genetic architecture of helminth-specific immune responses in a wild population of Soay sheep (Ovis aries). PLoS Genet 2019; 15:e1008461. [PMID: 31697674 PMCID: PMC6863570 DOI: 10.1371/journal.pgen.1008461] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Revised: 11/19/2019] [Accepted: 10/04/2019] [Indexed: 12/22/2022] Open
Abstract
Much of our knowledge of the drivers of immune variation, and how these responses vary over time, comes from humans, domesticated livestock or laboratory organisms. While the genetic basis of variation in immune responses have been investigated in these systems, there is a poor understanding of how genetic variation influences immunity in natural, untreated populations living in complex environments. Here, we examine the genetic architecture of variation in immune traits in the Soay sheep of St Kilda, an unmanaged population of sheep infected with strongyle gastrointestinal nematodes. We assayed IgA, IgE and IgG antibodies against the prevalent nematode Teladorsagia circumcincta in the blood plasma of > 3,000 sheep collected over 26 years. Antibody levels were significantly heritable (h2 = 0.21 to 0.57) and highly stable over an individual’s lifespan. IgA levels were strongly associated with a region on chromosome 24 explaining 21.1% and 24.5% of heritable variation in lambs and adults, respectively. This region was adjacent to two candidate loci, Class II Major Histocompatibility Complex Transactivator (CIITA) and C-Type Lectin Domain Containing 16A (CLEC16A). Lamb IgA levels were also associated with the immunoglobulin heavy constant loci (IGH) complex, and adult IgE levels and lamb IgA and IgG levels were associated with the major histocompatibility complex (MHC). This study provides evidence of high heritability of a complex immunological trait under natural conditions and provides the first evidence from a genome-wide study that large effect genes located outside the MHC region exist for immune traits in the wild. Understanding how immune responses vary in natural populations can give an insight into how infection affects the ability of hosts and parasites to survive and reproduce, and how this drives evolutionary and ecological dynamics. Yet, very little is known about how immune responses vary over an individual’s lifetime and how genes contribute to this variation under natural conditions. Our study investigates the genetic architecture of variation in three antibody types, IgA, IgE and IgG in a wild population of Soay sheep on the St Kilda archipelago in North-West Scotland. Using data collected over 26 years, we show that antibody levels have a heritable basis in lambs and adults and are stable over an individual’s lifetime. We also identify several genomic regions with large effects on immune responses. Our study offers the first insights into the genetic control of immunity in a wild population, which is essential to understand how immune profiles vary in challenging natural conditions and how natural selection maintains genetic variation in complex immune traits.
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Affiliation(s)
- Alexandra M. Sparks
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
- Faculty of Biological Sciences, School of Biology, University of Leeds, Leeds, United Kingdom
- * E-mail:
| | - Kathryn Watt
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Rona Sinclair
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Jill G. Pilkington
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Josephine M. Pemberton
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Tom N. McNeilly
- Moredun Research Institute, Pentlands Science Park, Bush Loan, Midlothian, United Kingdom
| | - Daniel H. Nussey
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
| | - Susan E. Johnston
- Institutes of Evolutionary Biology and Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, Edinburgh, United Kingdom
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Abstract
Primary immunodeficiency diseases are a heterogeneous group of rare inherited disorders of innate or adaptive immune system function. Patients with primary immunodeficiencies typically present with recurrent and severe infections in infancy or young adulthood. More recently, the co-occurrence of autoimmune, benign lymphoproliferative, atopic, and malignant complications has been described. The diagnosis of a primary immunodeficiency disorder requires a thorough assessment of a patient's underlying immune system function. Historically, this has been accomplished at the time of symptomatic presentation by measuring immunoglobulins, complement components, protective antibody titers, or immune cell counts in the peripheral blood. Although these data can be used to critically assess the degree of immune dysregulation in the patient, this approach fall short in at least 2 regards. First, this assessment often occurs after the patient has suffered life-threatening infectious or autoinflammatory complications. Second, these data fail to uncover an underlying molecular cause of the patient's primary immune dysfunction, prohibiting the use of molecularly targeted therapeutic interventions. Within the last decade, the field of primary immunodeficiency diagnostics has been revolutionized by 2 major molecular advancements: (1) the onset of newborn screening in 2008, and (2) the onset of next-generation sequencing in 2010. In this article, the techniques of newborn screening and next-generation sequencing are reviewed and their respective impacts on the field of primary immunodeficiency disorders are discussed with a specific emphasis on severe combined immune deficiency and common variable immune deficiency.
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Affiliation(s)
- Jocelyn R Farmer
- Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Boston, MA, USA; Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA.
| | - Vinay S Mahajan
- Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA; Center for Advanced Molecular Diagnostics, Brigham and Women's Hospital, Boston, MA, USA
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28
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Jeong KH, Kim JS, Lee YH, Kim YG, Moon JY, Kim SK, Kang SW, Kim TH, Lee SH, Kim YH. Genome-wide association study identifies new susceptible loci of IgA nephropathy in Koreans. BMC Med Genomics 2019; 12:122. [PMID: 31426789 PMCID: PMC6700823 DOI: 10.1186/s12920-019-0568-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 07/31/2019] [Indexed: 12/27/2022] Open
Abstract
Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Recent evidence suggests that genetic factors are related to the pathogenesis of IgAN. We conducted a genome-wide association study (GWAS) to identify novel genetic susceptibility loci for IgAN in a Korean population. Methods We enrolled 188 biopsy-confirmed IgAN cases and 455 healthy controls for the discovery stage and explored associations between IgAN and single nucleotide polymorphisms (SNPs) using a customized DNA chip. The significant SNPs from the discovery samples were then selected for replication in an independent cohort with 310 biopsy-confirmed IgAN cases and 438 healthy controls. Results In the first stage, two SNPs (rs10172700 in LOC105373592 and rs2296136 in ANKRD16) were selected for further association analysis in the next stage. In the replication cohort, rs2296136 in ANKRD16 was significantly associated with IgAN (odds ratio [OR] = 1.40, 95% confidence interval [CI] 0.99–1.98, p = 0.05 in log-additive model, OR = 1.55, 95% CI = 1.06–−2.27, p = 0.02 in dominant model, and OR = 0.70, 95% CI = 0.17–−2.84, p = 0.62 in recessive model). rs2296136 in ANKRD16 also showed a significant association with IgAN in the entire study population combining GWAS and replication study (p = 0.0045 in log-additive model, p = 0.0027 in dominant model, and p = 0.76 in recessive model). Conclusions The SNPs identified in the present study could be good candidate markers for predicting IgAN in Koreans, although further experimental validation is needed.
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Affiliation(s)
- Kyung Hwan Jeong
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea
| | - Jin Sug Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea
| | - Yu Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea
| | - Yang Gyun Kim
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea
| | - Ju-Young Moon
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea
| | - Su Kang Kim
- Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung, 25601, Republic of Korea
| | - Sun Woo Kang
- Division of Nephrology, Department of Internal Medicine, Inje University College of Medicine, 633-165, Gaegum-dong, Busanjin-gu, Busan, Republic of Korea
| | - Tae Hee Kim
- Division of Nephrology, Department of Internal Medicine, Inje University College of Medicine, 633-165, Gaegum-dong, Busanjin-gu, Busan, Republic of Korea
| | - Sang Ho Lee
- Division of Nephrology, Department of Internal Medicine, Kyung Hee University School of Medicine, 26, Kyungheedae-ro, Dongdaemun-gu, Seoul, South Korea.
| | - Yeong Hoon Kim
- Division of Nephrology, Department of Internal Medicine, Inje University College of Medicine, 633-165, Gaegum-dong, Busanjin-gu, Busan, Republic of Korea.
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Bagheri Y, Sanaei R, Yazdani R, Shekarabi M, Falak R, Mohammadi J, Abolhassani H, Aghamohammadi A. The Heterogeneous Pathogenesis of Selective Immunoglobulin A Deficiency. Int Arch Allergy Immunol 2019; 179:231-246. [DOI: 10.1159/000499044] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 02/18/2019] [Indexed: 11/19/2022] Open
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Zhang B, Zhuang Z, Wang X, Huang H, Fu Q, Yan Q. Dual RNA-Seq reveals the role of a transcriptional regulator gene in pathogen-host interactions between Pseudomonas plecoglossicida and Epinephelus coioides. FISH & SHELLFISH IMMUNOLOGY 2019; 87:778-787. [PMID: 30776540 DOI: 10.1016/j.fsi.2019.02.025] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/26/2019] [Accepted: 02/15/2019] [Indexed: 06/09/2023]
Abstract
Pseudomonas plecoglossicida is a highly pathogenic bacterium for maricultured fish and causes serious losses. A transcriptional regulator gene RK21_RS10315 was found up-regulated during the whole infection process, which was confirmed by qRT-PCR. Five shRNA were designed to silence RK21_RS10315 gene, and the gene expression was reduced up to 96.1%. Compared with the counterpart infected with wild type strain, the infection of RK21_RS10315-RNAi strain resulted in the death time delay, and 90% reduction in mortality of Epinephelus coioides, as well as the alleviation in the symptoms of E. coioides spleen. Moreover, compared with the fish infected with wild type strain, the infection of RK21_RS10315-RNAi strain of P. plecoglossicida resulted in a significant change both in transcriptome of spleen of infected E. coioides and P. plecoglossicida. The KEGG analysis showed that genes of 16 immune pathways in E. coioides were affected by the silence of RK21_RS10315 of P. plecoglossicida. Among them, intestinal immune network for IgA production pathway and leukocyte transendothelial migration pathway were more prominent than other pathways. 19 euk-DEMs in these immune pathways had varying degrees of correlation with 19 pro-DEMs, and the expression of ipxA, grpE, yhbJ, truD and suhB from 19 pro-DEMs were predicted more related to RK21_RS10315 in P. plecoglossicida.
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Affiliation(s)
- Beibei Zhang
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen, Fujian, 361024, China; Fisheries College, Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Jimei University, Xiamen, Fujian, 361021, China
| | - Zhixia Zhuang
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen, Fujian, 361024, China
| | - Xiaoru Wang
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen, Fujian, 361024, China
| | - Huabin Huang
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen, Fujian, 361024, China
| | - Qi Fu
- College of Environment and Public Health, Xiamen Huaxia University, Xiamen, Fujian, 361024, China
| | - Qingpi Yan
- Fisheries College, Key Laboratory of Healthy Mariculture for the East China Sea, Ministry of Agriculture, Jimei University, Xiamen, Fujian, 361021, China.
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Abstract
Gastrointestinal (GI) allergic disease is an umbrella term used to describe a variety of adverse, food antigen-driven, immune-mediated diseases. Although these diseases vary mechanistically, common elements include a breakdown of immunologic tolerance, a biased type 2 immune response, and an impaired mucosal barrier. These pathways are influenced by diverse factors such as diet, infections, exposure to antibiotics and chemicals, GI microbiome composition, and genetic and epigenetic elements. Early childhood has emerged as a critical period when these factors have a dramatic impact on shaping the immune system and therefore triggering or protecting against the onset of GI allergic diseases. In this Review, we will discuss the latest findings on the molecular and cellular mechanisms that govern GI allergic diseases and how these findings have set the stage for emerging preventative and treatment strategies.
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32
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Qi YY, Zhou XJ, Zhang H. Autophagy and immunological aberrations in systemic lupus erythematosus. Eur J Immunol 2019; 49:523-533. [PMID: 30776086 DOI: 10.1002/eji.201847679] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2018] [Revised: 11/22/2018] [Accepted: 02/15/2019] [Indexed: 12/13/2022]
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease, in which immune defects can occur at multiple points of the cascading auto-aggressive immune reactions, resulting in a striking heterogeneity of clinical presentations. The clinical manifestations of such autoimmune response can be severe: common manifestations symptoms include rash and renal inflammation progressing to kidney failure. Autophagy, the cellular "self-digestion" process, is a key factor in the interplay between innate and adaptive immunity. Dysregulation of autophagy has been implicated in numerous autoimmune diseases. Several lines of evidence from genomic studies, cell culture systems, animal models, and human patients are emerging to support the role of autophagy in progression and pathogenesis of SLE. In this review, we summarize recent key findings on the aberrations of autophagy in SLE, with a special focus on how deregulated autophagy promotes autoimmunity and renal damage. We will also discuss how the observed findings may be translated into therapeutic settings.
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Affiliation(s)
- Yuan-Yuan Qi
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China
| | - Xu-Jie Zhou
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China
| | - Hong Zhang
- Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Ministry of Education, Beijing, 100034, People's Republic of China
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Moschese V, Chini L, Graziani S, Sgrulletti M, Gallo V, Di Matteo G, Ferrari S, Di Cesare S, Cirillo E, Pession A, Pignata C, Specchia F. Follow-up and outcome of symptomatic partial or absolute IgA deficiency in children. Eur J Pediatr 2019; 178:51-60. [PMID: 30269248 DOI: 10.1007/s00431-018-3248-1] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 08/07/2018] [Accepted: 09/10/2018] [Indexed: 12/18/2022]
Abstract
Selective IgA deficiency is defined as absolute or partial when serum IgA level is < 7 mg/dl or 2 SD below normal for age, respectively. Few data are available on partial selective IgA deficiency, as probably most children with low serum IgA are seldom referred to a specialist clinic in common pediatric practice. The aim of our study was to better define the profile of both symptomatic forms and their clinical outcome in a pediatric immunology setting. Thus, clinical and immunological data from 103 symptomatic patients with selective IgA deficiency (53 absolute and 50 partial), 4-18 years of age, were collected at diagnosis and 80 patients (44 absolute and 36 partial) were monitored for a mean period of 5 years. Also, the prevalence of TNFRSF13B mutations has been assessed in 56 patients. The most common clinical features were infections (86/103; 83%), allergy (39/103; 38%), and autoimmunity (13/103; 13%). No significative differences were observed between absolute and partial selective IgA deficiency patients. However, a significative difference in the rate of IgA normalization between partial and absolute selective IgA deficiency patients (33 vs 9%, p = 0.01) was detected. Furthermore, a lower incidence of infections was associated to a normalization reversal compared to a final absolute or partial defect status (12 vs 53 and 64% respectively, p < 0.01).Conclusions: Regardless of a diagnosis of absolute or partial defect, monitoring of symptomatic patients with selective IgA deficiency is recommended overtime for prompt identification and treatment of associated diseases. Further, diagnostic workup protocols should be revisited in children with IgA deficiency. What is Known: ● Selective IgA Deficiency is the most common primary immunodeficiency and is usually asymptomatic. ● Symptomatic pediatric patients with selective IgA deficiency mostly suffer with respiratory and gastrointestinal infections. What is New: ● Symptomatic children with partial IgA defect may have similar clinical, immunological, and genetic features than symptomatic children with absolute IgA deficiency. ● Symptomatic children with partial IgA deficiency deserve accurate monitoring for associated diseases as per children with absolute IgA deficiency.
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Affiliation(s)
- Viviana Moschese
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.
| | - Loredana Chini
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Simona Graziani
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Mayla Sgrulletti
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Vera Gallo
- Department of Translational Medical Sciences- Section of Pediatrics, Federico II University, Naples, Italy
| | - Gigliola Di Matteo
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Simona Ferrari
- Medical Genetics Unit, S.Orsola-Malpighi University Hospital, Bologna, Italy
| | - Silvia Di Cesare
- Pediatric Immunopathology and Allergology Unit, University of Rome Tor Vergata, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Emilia Cirillo
- Department of Translational Medical Sciences- Section of Pediatrics, Federico II University, Naples, Italy
| | - Andrea Pession
- Pediatric Unit, Department of Woman, Child and Urologic Diseases, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
| | - Claudio Pignata
- Department of Translational Medical Sciences- Section of Pediatrics, Federico II University, Naples, Italy
| | - Fernando Specchia
- Pediatric Unit, Department of Woman, Child and Urologic Diseases, University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy
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Khan S, Godfrey V, Zaki MH. Cytosolic Nucleic Acid Sensors in Inflammatory and Autoimmune Disorders. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2018; 344:215-253. [PMID: 30798989 DOI: 10.1016/bs.ircmb.2018.10.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Innate immunity employs germline-encoded pattern recognition receptors (PRRs) to sense microbial pattern molecules. Recognition of pathogen-associated molecular patterns (PAMPs) by various PPRs located on the cell membrane or in the cytosol leads to the activation of cell signaling pathways and production of inflammatory mediators. Nucleic acids including DNA, RNA, and their derivatives are potent PAMPs which can be recognized by multiple PRRs to induce inflammatory responses. While nucleic acid sensors can also sense endogenous nucleic acids, they are capable of discriminating self from non-self. However, defects in nucleic acid sensing PRRs or dysregulation of nucleic acid sensing signaling pathways may cause excessive activation of the immune system resulting in the development of inflammatory and autoimmune diseases. This review will discuss the major pathways for sensing intracellular nucleic acids and how defects in these nucleic acid sensing are associated with different kinds of autoimmune and inflammatory disorders.
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Affiliation(s)
- Shahanshah Khan
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Victoria Godfrey
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Md Hasan Zaki
- Department of Pathology, UT Southwestern Medical Center, Dallas, TX, United States.
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35
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Crow MK, Olferiev M, Kirou KA. Type I Interferons in Autoimmune Disease. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2018; 14:369-393. [PMID: 30332560 DOI: 10.1146/annurev-pathol-020117-043952] [Citation(s) in RCA: 189] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Type I interferons, which make up the first cytokine family to be described and are the essential mediators of antivirus host defense, have emerged as central elements in the immunopathology of systemic autoimmune diseases, with systemic lupus erythematosus as the prototype. Lessons from investigation of interferon regulation following virus infection can be applied to lupus, with the conclusion that sustained production of type I interferon shifts nearly all components of the immune system toward pathologic functions that result in tissue damage and disease. We review recent data, mainly from studies of patients with systemic lupus erythematosus, that provide new insights into the mechanisms of induction and the immunologic consequences of chronic activation of the type I interferon pathway. Current concepts implicate endogenous nucleic acids, driving both cytosolic sensors and endosomal Toll-like receptors, in interferon pathway activation and suggest targets for development of novel therapeutics that may restore the immune system to health.
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Affiliation(s)
- Mary K Crow
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York 10021, USA;
| | - Mikhail Olferiev
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York 10021, USA;
| | - Kyriakos A Kirou
- Mary Kirkland Center for Lupus Research, Hospital for Special Surgery, New York, New York 10021, USA;
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Zhang J, Liu X, Meng Y, Wu H, Wu Y, Yang B, Wang L. Autoimmune disease associated IFIH1 single nucleotide polymorphism related with IL-18 serum levels in Chinese systemic lupus erythematosus patients. Sci Rep 2018; 8:9442. [PMID: 29930297 PMCID: PMC6013496 DOI: 10.1038/s41598-018-27782-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 06/08/2018] [Indexed: 02/05/2023] Open
Abstract
Systemic lupus erythematosus (SLE) has heterogeneous clinical manifestations. IFIH1 (interferon induced with helicase C domain 1) as one of antiviral helicase genes mediating type I interferon production, plays an essential role in the pathogenesis of SLE. The gene variants in IFIH1 could abnormally activate antiviral defenses and increased type I interferon signaling. The present study aimed to validate associations between single nucleotide polymorphisms (SNP) in IFIH1 and the pathogenesis of SLE. In total, rs1990760, rs3747517 and rs10930046 in IFIH1 are genotyped in 400 SLE patients and 659 health controls in Chinese cohort by an improved multiplex ligation detection reaction (iMLDR) technique. Significant associations were observed between alleles of IFIH1 (rs1990760 C > T, P = 0.005, OR = 1.36, 95%CI = 1.10–1.69; rs3747517 T > C, P = 0.004, OR = 1.31, 95%CI = 1.09–1.58, respectively) and SLE susceptibility. IFIH1 rs1990760 TT genotype carriers had lower serum levels of IL-18 (P < 0.001) and granzyme B (P < 0.001) than CC and CT genotype carriers. IFIH1 rs1990760 CT genotype carriers had higher anti-dsDNA–positive than CC and TT genotype carriers. In conclusion, IFIH1 polymorphisms (rs1990760 and rs3747517) were associated with SLE susceptibility and rs1990760 risk T allele related with IL-18 and granzyme B serum levels in SLE patients.
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Affiliation(s)
- Junlong Zhang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Xinle Liu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yanming Meng
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Hengxu Wu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Yongkang Wu
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China
| | - Bin Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
| | - Lanlan Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
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Cox DBT, Gootenberg JS, Abudayyeh OO, Franklin B, Kellner MJ, Joung J, Zhang F. RNA editing with CRISPR-Cas13. Science 2017; 358:1019-1027. [PMID: 29070703 DOI: 10.1126/science.aaq0180] [Citation(s) in RCA: 1197] [Impact Index Per Article: 149.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Accepted: 10/16/2017] [Indexed: 12/15/2022]
Abstract
Nucleic acid editing holds promise for treating genetic disease, particularly at the RNA level, where disease-relevant sequences can be rescued to yield functional protein products. Type VI CRISPR-Cas systems contain the programmable single-effector RNA-guided ribonuclease Cas13. We profiled type VI systems in order to engineer a Cas13 ortholog capable of robust knockdown and demonstrated RNA editing by using catalytically inactive Cas13 (dCas13) to direct adenosine-to-inosine deaminase activity by ADAR2 (adenosine deaminase acting on RNA type 2) to transcripts in mammalian cells. This system, referred to as RNA Editing for Programmable A to I Replacement (REPAIR), which has no strict sequence constraints, can be used to edit full-length transcripts containing pathogenic mutations. We further engineered this system to create a high-specificity variant and minimized the system to facilitate viral delivery. REPAIR presents a promising RNA-editing platform with broad applicability for research, therapeutics, and biotechnology.
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Affiliation(s)
- David B T Cox
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.,Department of Biology, MIT, Cambridge, MA 02139, USA.,Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA
| | - Jonathan S Gootenberg
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.,Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Omar O Abudayyeh
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA.,Harvard-MIT Division of Health Sciences and Technology, MIT, Cambridge, MA 02139, USA
| | - Brian Franklin
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Max J Kellner
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Julia Joung
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA.,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
| | - Feng Zhang
- Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. .,McGovern Institute for Brain Research, MIT, Cambridge, MA 02139, USA.,Department of Brain and Cognitive Science, MIT, Cambridge, MA 02139, USA.,Department of Biological Engineering, MIT, Cambridge, MA 02139, USA
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38
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Pott MC, Frede N, Wanders J, Hammarström L, Glocker EO, Glocker C, Tahami F, Grimbacher B. Autoantibodies against BAFF, APRIL or IL21 - an alternative pathogenesis for antibody-deficiencies? BMC Immunol 2017. [PMID: 28651547 PMCID: PMC5485583 DOI: 10.1186/s12865-017-0217-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
BACKGROUND The ability of anti-cytokine antibodies to play a disease-causing role in the pathogenesis of immunodeficiencies is widely accepted. The aim of this study was to investigate whether autoantibodies against BAFF (important B cell survival signal), APRIL (important plasma cell survival signal), or Interleukin-21 (important cytokine for immunoglobulin class switch) present an alternative mechanism for the development of the following primary antibody deficiencies (PADs): common variable immune deficiency (CVID) or selective IgA deficiency (sIgAD). RESULTS Two hundred thirty-two sera from patients with PADs were screened for autoantibodies against cytokines by ELISA. Statistical data analysis yielded a significant difference (p < 0.01) between the healthy donor sera and both PAD cohorts. The analysis was deepened by subdividing the patient collective into groups with distinct B cell phenotypes but no significant differences were found. For selected sera with notable high ELISA-read outs functional analysis ensued. Anti-BAFF and anti-APRIL antibodies were further examined by a B cell survival assay, whilst the functional relevance of putative anti-IL-21 autoantibodies was investigated by means of a STAT3 phosphorylation assay. However, the results of these experiments revealed no discernible functional effect. CONCLUSION Whilst statistical analysis of ELISA results showed significant differences between patients and healthy controls, in our set of patients functional tests yielded no evidence for an involvement of autoantibodies against BAFF, APRIL, or IL-21 in the pathogenesis of CVID or sIgAD.
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Affiliation(s)
- Marian-Christopher Pott
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Natalie Frede
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Jennifer Wanders
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | | | - Erik-Oliver Glocker
- Institute of Medical Microbiology and Hygiene, University Medical Center Freiburg, Freiburg, Germany.,Institute of Laboratory Medicine, Brandenburg Hospital, Brandenburg Medical School, Brandenburg, Germany
| | - Cristina Glocker
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany
| | - Fariba Tahami
- Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK
| | - Bodo Grimbacher
- Centre for Chronic Immunodeficiency, Medical Centre University Hospital, Medical Faculty of Freiburg, Freiburg, Germany. .,Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, UK.
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39
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Kato H, Oh SW, Fujita T. RIG-I-Like Receptors and Type I Interferonopathies. J Interferon Cytokine Res 2017; 37:207-213. [PMID: 28475461 PMCID: PMC5439449 DOI: 10.1089/jir.2016.0095] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 12/28/2016] [Indexed: 12/24/2022] Open
Abstract
Type I interferon (IFN) production by the proper activation of nucleic acid sensors is essential for hosts to eliminate invading viruses. Among these sensors, RIG-I-like receptors (RLRs) are well-known viral RNA sensors in the cytoplasm that recognize the nonself signatures of viral RNAs to trigger IFN responses. Recent accumulating evidence has clarified that some specific and atypical self-RNAs also cause activation of RLRs independently of virus infection. Importantly, when RLR-activation by these RNAs or a conformational change via missense mutations is sustained, the resulting continuous production of type I IFN will lead to autoimmune disorders. We, herein, focus on autoimmune diseases caused by chronic activation of RLRs and discuss possible mechanisms of their onset.
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Affiliation(s)
- Hiroki Kato
- Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University , Kyoto, Japan
| | - Seong-Wook Oh
- Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University , Kyoto, Japan
| | - Takashi Fujita
- Laboratory of Molecular Genetics, Institute for Virus Research, Kyoto University , Kyoto, Japan
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40
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Langlais D, Fodil N, Gros P. Genetics of Infectious and Inflammatory Diseases: Overlapping Discoveries from Association and Exome-Sequencing Studies. Annu Rev Immunol 2017; 35:1-30. [DOI: 10.1146/annurev-immunol-051116-052442] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- David Langlais
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada;, ,
- Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Nassima Fodil
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada;, ,
- Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada
| | - Philippe Gros
- McGill University Research Centre on Complex Traits, McGill University, Montreal, Quebec H3G 0B1, Canada;, ,
- Department of Biochemistry, McGill University, Montreal, Quebec H3G 0B1, Canada
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41
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Pettersson M, Bergendal B, Norderyd J, Nilsson D, Anderlid BM, Nordgren A, Lindstrand A. Further evidence for specific IFIH1 mutation as a cause of Singleton-Merten syndrome with phenotypic heterogeneity. Am J Med Genet A 2017; 173:1396-1399. [PMID: 28319323 DOI: 10.1002/ajmg.a.38214] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Accepted: 02/17/2017] [Indexed: 01/09/2023]
Abstract
Singleton-Merten syndrome (MIM 182250) is an autosomal dominant inherited disorder characterized by early onset periodontitis, root resorption, osteopenia, osteoporosis, and aortic valve or thoracic aorta calcification. The disorder can have significant intrafamilial phenotypic variability. Here, we present a mother and daughter with Singleton-Merten syndrome harboring a previously described pathogenic missense mutation, c.2465G>A p.(Arg822Gln), in IFIH1 (interferon induced with helicase C domain 1), encoding MDA5 (Melanoma Differentiation-Associated protein 5). These data confirm the pathogenicity of IFIH1 c.2465G>A p.(Arg822Gln) for Singleton-Merten syndrome and affirm the striking phenotypic heterogeneity of this disorder. In addition, we expand the Singleton-Merten phenotype by adding severe systemic lupus erythematosus (SLE) to the clinical picture. Investigations of known SLE genes as well as a single nucleotide polymorphism suggested to be involved in development of SLE were normal.
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Affiliation(s)
- Maria Pettersson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Birgitta Bergendal
- National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, Jönköping, Sweden.,School of Health and Welfare, Jönköping University, Jönköping, Sweden
| | - Johanna Norderyd
- National Oral Disability Centre for Rare Disorders, The Institute for Postgraduate Dental Education, Jönköping, Sweden.,School of Health and Welfare, Jönköping University, Jönköping, Sweden
| | - Daniel Nilsson
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.,Science for Life Laboratory, Karolinska Institutet Science Park, Solna, Sweden
| | - Britt-Marie Anderlid
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Ann Nordgren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Anna Lindstrand
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
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Abstract
During viral and bacterial infections, pathogen-derived cytosolic nucleic acids are recognized by the intracellular RNA sensors retinoic acid-inducible gene I and melanoma-differentiated gene 5 and intracellular DNA sensors, including cyclic-di-GMP-AMP synthase, absent in melanoma 2, interferon (IFN)-gamma inducible protein 16, polymerase III, and so on. Binding of intracellular nucleic acids to these sensors activates downstream signaling cascades, resulting in the production of type I IFNs and pro-inflammatory cytokines to induce appropriate systematic immune responses. While these sensors also recognize endogenous nucleic acids and activate immune responses, they can discriminate between self- and non-self-nucleic acids. However, dysfunction of these sensors or failure of regulatory mechanisms causes aberrant activation of immune response and autoimmune disorders. In this review, we focus on how intracellular immune sensors recognize exogenous nucleic acids and activate the innate immune system, and furthermore, how autoimmune diseases result from dysfunction of these sensors.
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Affiliation(s)
- Daisuke Ori
- a Laboratory of Molecular Immunobiology , Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Takayama-cho , Ikoma , Nara , Japan
| | - Motoya Murase
- a Laboratory of Molecular Immunobiology , Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Takayama-cho , Ikoma , Nara , Japan
| | - Taro Kawai
- a Laboratory of Molecular Immunobiology , Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), Takayama-cho , Ikoma , Nara , Japan
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GWAS for serum galactose-deficient IgA1 implicates critical genes of the O-glycosylation pathway. PLoS Genet 2017; 13:e1006609. [PMID: 28187132 PMCID: PMC5328405 DOI: 10.1371/journal.pgen.1006609] [Citation(s) in RCA: 106] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 02/27/2017] [Accepted: 01/27/2017] [Indexed: 12/12/2022] Open
Abstract
Aberrant O-glycosylation of serum immunoglobulin A1 (IgA1) represents a heritable pathogenic defect in IgA nephropathy, the most common form of glomerulonephritis worldwide, but specific genetic factors involved in its determination are not known. We performed a quantitative GWAS for serum levels of galactose-deficient IgA1 (Gd-IgA1) in 2,633 subjects of European and East Asian ancestry and discovered two genome-wide significant loci, in C1GALT1 (rs13226913, P = 3.2 x 10−11) and C1GALT1C1 (rs5910940, P = 2.7 x 10−8). These genes encode molecular partners essential for enzymatic O-glycosylation of IgA1. We demonstrated that these two loci explain approximately 7% of variability in circulating Gd-IgA1 in Europeans, but only 2% in East Asians. Notably, the Gd-IgA1-increasing allele of rs13226913 is common in Europeans, but rare in East Asians. Moreover, rs13226913 represents a strong cis-eQTL for C1GALT1 that encodes the key enzyme responsible for the transfer of galactose to O-linked glycans on IgA1. By in vitro siRNA knock-down studies, we confirmed that mRNA levels of both C1GALT1 and C1GALT1C1 determine the rate of secretion of Gd-IgA1 in IgA1-producing cells. Our findings provide novel insights into the genetic regulation of O-glycosylation and are relevant not only to IgA nephropathy, but also to other complex traits associated with O-glycosylation defects, including inflammatory bowel disease, hematologic disease, and cancer. O-glycosylation is a common type of post-translational modification of proteins; specific abnormalities in the mechanism of O-glycosylation have been implicated in cancer, inflammatory and blood diseases. However, the molecular basis of abnormal O-glycosylation in these complex disorders is not known. We studied the genetic basis of defective O-glycosylation of serum immunoglobulin A1 (IgA1), that represents the key pathogenic defect in IgA nephropathy, the most common form of primary glomerulonephritis worldwide. We report our results of the first genome-wide association study for this trait using serum assays in 2,633 individuals of European and East-Asian ancestry. In our genome scan, we observed two significant signals with large effects, on chromosomes 7p21.3 and Xq24, jointly explaining about 7% of trait variability. These signals implicate two genes that encode molecular partners essential for enzymatic O-glycosylation of IgA1 and mucins, and represent potential new targets for therapy.
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Nititham J, Gupta R, Zeng X, Hartogensis W, Nixon DF, Deeks SG, Hecht FM, Liao W. Psoriasis risk SNPs and their association with HIV-1 control. Hum Immunol 2017; 78:179-184. [PMID: 27810495 PMCID: PMC5253078 DOI: 10.1016/j.humimm.2016.10.018] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 10/14/2016] [Accepted: 10/28/2016] [Indexed: 12/12/2022]
Abstract
Human evolution has resulted in selection for genetic polymorphisms beneficial in the defense against pathogens. However, such polymorphisms may have the potential to heighten the risk of autoimmune disease. Here, we investigated whether psoriasis-associated single nucleotide polymorphisms influence host control of HIV-1 infection. We studied psoriasis and viral immune response variants in three HIV-positive cohorts: (1) HIV-1 controllers and non-controllers in the Study of the Consequences of the Protease Inhibitor Era (SCOPE) cohort (n=366), (2) Individuals with primary HIV infection in the Options cohort (n=675), and (3) HIV-positive injection drug users from the Urban Health Study (UHS) (n=987). We found a strong association of two psoriasis MHC variants, rs9264942 and rs3021366, with both HIV-1 controller status and viral load, and identified another Class III MHC variant rs9368699 to be strongly associated with viral load. A number of genetic variants outside the MHC (SOX5, TLR9, SDC4, PROX1, IL12B, TLR4, MBL-2, TYK2, IFIH1) demonstrated nominal significance. Overall, our data suggest that several psoriasis variants within the MHC have a robust impact on HIV-1 control, while variants outside the MHC require further investigation.
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Affiliation(s)
- Joanne Nititham
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Rashmi Gupta
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Xue Zeng
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA
| | - Wendy Hartogensis
- Division of HIV/AIDS, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
| | - Douglas F Nixon
- Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC, USA
| | - Steven G Deeks
- Division of HIV/AIDS, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
| | - Frederick M Hecht
- Division of HIV/AIDS, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, CA, USA
| | - Wilson Liao
- Department of Dermatology, University of California San Francisco, San Francisco, CA, USA.
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45
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Azizi G, Ahmadi M, Abolhassani H, Yazdani R, Mohammadi H, Mirshafiey A, Rezaei N, Aghamohammadi A. Autoimmunity in Primary Antibody Deficiencies. Int Arch Allergy Immunol 2016; 171:180-193. [DOI: 10.1159/000453263] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
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46
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Giza S, Kotanidou E, Papadopoulou-Alataki E, Antoniou MC, Maggana I, Kyrgios I, Galli-Tsinopoulou A. Prevalence of selective immunoglobulin A deficiency in Greek children and adolescents with type 1 diabetes. World J Pediatr 2016; 12:470-476. [PMID: 27286692 DOI: 10.1007/s12519-016-0039-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 02/03/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND The association of selective immunoglobulin A (IgA) deficiency with type 1 diabetes (T1D) remains unclear. This study was to evaluate serum IgA concentrations in Greek children and adolescents with T1D. METHODS In two hundred individuals with T1D, serum IgA concentrations were quantitatively determined using nephelometry. RESULTS Immunoglobulin A deficiency was detected in 6 (3.0%) of 200 patients who were subjected to immunological evaluation. Recurrent infections were not recorded, but human papilloma virus infection was clinically suspected and confirmed by laboratory examination in a 5-year-old girl. In regard to coincidence of selective IgA deficiency with autoimmune diseases, celiac disease was detected in a girl and juvenile idiopathic arthritis in a boy. Serum IgA concentrations differed significantly when patients were grouped according to age at the beginning of the study (P<0.001), age at diagnosis of T1D (P=0.015) and coincidence of celiac disease (CD) (P=0.038). However, when the age of the patients was adjusted, difference in serum IgA concentrations was not statistically significant despite CD was present or not. Moreover, serum IgA concentrations were positively correlated with serum IgG (P<0.001) and IgE (P=0.001) concentrations and negatively correlated with serum antigliadin antibody IgG (P=0.035) concentrations. There was no association or correlation of serum IgA concentrations with glycemic control. CONCLUSION The prevalence of selective IgA deficiency in Greek children and adolescents with T1D is high (3.0%). The correlation of serum IgA concentrations with serum IgG, IgE and anti-gliadin antibody IgG concentrations needs further investigation.
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Affiliation(s)
- Styliani Giza
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Eleni Kotanidou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Efimia Papadopoulou-Alataki
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Maria Christina Antoniou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Ioanna Maggana
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Ioannis Kyrgios
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece
| | - Assimina Galli-Tsinopoulou
- 4th Department of Pediatrics, Faculty of Medicine, Aristotle University of Thessaloniki, Papageorgiou General Hospital, Ring Road Nea Efkarpia, 56403, Thessaloniki, Greece.
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47
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Bronson PG, Chang D, Bhangale T, Seldin MF, Ortmann W, Ferreira RC, Urcelay E, Pereira LF, Martin J, Plebani A, Lougaris V, Friman V, Freiberger T, Litzman J, Thon V, Pan-Hammarström Q, Hammarström L, Graham RR, Behrens TW. Common variants at PVT1, ATG13-AMBRA1, AHI1 and CLEC16A are associated with selective IgA deficiency. Nat Genet 2016; 48:1425-1429. [PMID: 27723758 PMCID: PMC5086090 DOI: 10.1038/ng.3675] [Citation(s) in RCA: 56] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2015] [Accepted: 08/24/2016] [Indexed: 12/18/2022]
Abstract
Selective immunoglobulin A deficiency (IgAD) is the most common primary immunodeficiency in Europeans. Our genome-wide association study (GWAS) meta-analysis of 1,635 patients with IgAD and 4,852 controls identified four new significant (P < 5 × 10-8) loci and association with a rare IFIH1 variant (p.Ile923Val). Peak new variants (PVT1, P = 4.3 × 10-11; ATG13-AMBRA1, P = 6.7 × 10-10; AHI1, P = 8.4 × 10-10; CLEC16A, P = 1.4 × 10-9) overlapped with autoimmune markers (3/4) and correlated with 21 putative regulatory variants, including expression quantitative trait loci (eQTLs) for AHI1 and DEXI and DNase hypersensitivity sites in FOXP3+ regulatory T cells. Pathway analysis of the meta-analysis results showed striking association with the KEGG pathway for IgA production (pathway P < 0.0001), with 22 of the 30 annotated pathway genes containing at least one variant with P ≤ 0.05 in the IgAD meta-analysis. These data suggest that a complex network of genetic effects, including genes known to influence the biology of IgA production, contributes to IgAD.
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Affiliation(s)
- Paola G. Bronson
- Department of Human Genetics, Genentech, Inc., South San
Francisco, CA, USA
| | - Diana Chang
- Department of Human Genetics, Genentech, Inc., South San
Francisco, CA, USA
| | - Tushar Bhangale
- Department of Bioinformatics and Computational Biology,
Genentech, Inc., South San Francisco, CA, USA
| | - Michael F. Seldin
- Department of Biochemistry, School of Medicine, University
of California, Davis, CA, USA
| | - Ward Ortmann
- Department of Human Genetics, Genentech, Inc., South San
Francisco, CA, USA
| | - Ricardo C. Ferreira
- Juvenile Diabetes Research Foundation/Wellcome Trust
Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research,
Cambridge, UK
| | - Elena Urcelay
- Department of Immunology, Instituto de Investigación
Sanitaria del Hospital Clínico San Carlos, IdISSC, Madrid, Spain
| | | | - Javier Martin
- Instituto de Parasitología y Biomedicina
López-Neyra, CSIC, Granada, Spain
| | - Alessandro Plebani
- Pediatrics Clinic, Department of Clinical and Experimental
Sciences, University of Brescia, Spedali Civili di Brescia, Italy
- Institute for Molecular Medicine, A. Nocivelli, Department
of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di
Brescia, Italy
| | - Vassilios Lougaris
- Pediatrics Clinic, Department of Clinical and Experimental
Sciences, University of Brescia, Spedali Civili di Brescia, Italy
- Institute for Molecular Medicine, A. Nocivelli, Department
of Clinical and Experimental Sciences, University of Brescia, Spedali Civili di
Brescia, Italy
| | - Vanda Friman
- Department of Infectious Diseases, University of
Gothenburg, Gothenburg, Sweden
| | - Tomáš Freiberger
- Molecular Genetics Laboratory, Centre for Cardiovascular
Surgery and Transplantation, Brno, Czech Republic
- Central European Institute of Technology, Masaryk
University, Brno, Czech Republic
| | - Jiri Litzman
- Department of Clinical Immunology and Allergy, Faculty of
Medicine, Masaryk University, St. Anne’s Univ. Hospital, Brno, Czech
Republic
| | - Vojtech Thon
- Department of Clinical Immunology and Allergy, Faculty of
Medicine, Masaryk University, St. Anne’s Univ. Hospital, Brno, Czech
Republic
- Research Centre for Toxic Compounds in the Environment,
Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Qiang Pan-Hammarström
- Division of Clinical Immunology & Transfusion
Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Lennart Hammarström
- Division of Clinical Immunology & Transfusion
Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Robert R. Graham
- Department of Human Genetics, Genentech, Inc., South San
Francisco, CA, USA
| | - Timothy W. Behrens
- Department of Human Genetics, Genentech, Inc., South San
Francisco, CA, USA
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48
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Inflammatory bowel disease: exploring gut pathophysiology for novel therapeutic targets. Transl Res 2016; 176:38-68. [PMID: 27220087 DOI: 10.1016/j.trsl.2016.04.009] [Citation(s) in RCA: 134] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2015] [Revised: 03/17/2016] [Accepted: 04/28/2016] [Indexed: 12/14/2022]
Abstract
Ulcerative colitis and Crohn's disease are the 2 major phenotypes of inflammatory bowel disease (IBD), which are influenced by a complex interplay of immunological and genetic elements, though the precise etiology still remains unknown. With IBD developing into a globally prevailing disease, there is a need to explore new targets and a thorough understanding of the pathophysiological differences between the healthy and diseased gut could unearth new therapeutic opportunities. In this review, we provide an overview of the major aspects of IBD pathogenesis and thereafter present a comprehensive analysis of the gut pathophysiology leading to a discussion on some of the most promising targets and biologic therapies currently being explored. These include various gut proteins (CXCL-10, GATA-3, NKG2D, CD98, microRNAs), immune cells recruited to the gut (mast cells, eosinophils, toll-like receptors 2, 4), dysregulated proinflammatory cytokines (interleukin-6, -13, -18, -21), and commensal microbiota (probiotics and fecal microbiota transplantation). We also evaluate some of the emerging nonconventional therapies being explored in IBD treatment focusing on the latest developments in stem cell research, oral targeting of the gut-associated lymphoid tissue, novel anti-inflammatory signaling pathway targeting, adenosine deaminase inhibition, and the beneficial effects of antioxidant and nutraceutical therapies. In addition, we highlight the growth of biologics and their targets in IBD by providing information on the preclinical and clinical development of over 60 biopharmaceuticals representing the state of the art in ulcerative colitis and Crohn's disease drug development.
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49
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Wong GK, Millar D, Penny S, Heather JM, Mistry P, Buettner N, Bryon J, Huissoon AP, Cobbold M. Accelerated Loss of TCR Repertoire Diversity in Common Variable Immunodeficiency. THE JOURNAL OF IMMUNOLOGY 2016; 197:1642-9. [PMID: 27481850 PMCID: PMC4991247 DOI: 10.4049/jimmunol.1600526] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/25/2016] [Accepted: 06/30/2016] [Indexed: 11/19/2022]
Abstract
Although common variable immunodeficiency (CVID) has long been considered as a group of primary Ab deficiencies, growing experimental data now suggest a global disruption of the entire adaptive immune response in a segment of patients. Oligoclonality of the TCR repertoire was previously demonstrated; however, the manner in which it relates to other B cell and T cell findings reported in CVID remains unclear. Using a combination approach of high-throughput TCRβ sequencing and multiparametric flow cytometry, we compared the TCR repertoire diversity between various subgroups of CVID patients according to their B cell immunophenotypes. Our data suggest that the reduction in repertoire diversity is predominantly restricted to those patients with severely reduced class-switched memory B cells and an elevated level of CD21lo B cells (Freiburg 1a), and may be driven by a reduced number of naive T cells unmasking underlying memory clonality. Moreover, our data indicate that this loss in repertoire diversity progresses with advancing age far exceeding the expected physiological rate. Radiological evidence supports the loss in thymic volume, correlating with the decrease in repertoire diversity. Evidence now suggests that primary thymic failure along with other well-described B cell abnormalities play an important role in the pathophysiology in Freiburg group 1a patients. Clinically, our findings emphasize the integration of combined B and T cell testing to identify those patients at the greatest risk for infection. Future work should focus on investigating the link between thymic failure and the severe reduction in class-switched memory B cells, while gathering longitudinal laboratory data to examine the progressive nature of the disease.
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Affiliation(s)
- Gabriel K Wong
- Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom; West Midlands Primary Immunodeficiency Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom
| | - David Millar
- Cancer Center, Massachusetts General Hospital, Boston MA 02114; Department of Medicine, Harvard Medical School, Charlestown, MA 02129
| | - Sarah Penny
- Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom
| | - James M Heather
- Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom; and
| | - Punam Mistry
- Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom
| | - Nico Buettner
- Medical Research Council Centre for Immune Regulation, University of Birmingham, Edgbaston B15 2TT, United Kingdom
| | - Jane Bryon
- Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham B15 2TG, United Kingdom
| | - Aarnoud P Huissoon
- West Midlands Primary Immunodeficiency Centre, Birmingham Heartlands Hospital, Birmingham B9 5SS, United Kingdom
| | - Mark Cobbold
- Cancer Center, Massachusetts General Hospital, Boston MA 02114; Department of Medicine, Harvard Medical School, Charlestown, MA 02129;
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50
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Abolhassani H, Aghamohammadi A, Hammarström L. Monogenic mutations associated with IgA deficiency. Expert Rev Clin Immunol 2016; 12:1321-1335. [DOI: 10.1080/1744666x.2016.1198696] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
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