ArticleLiterature Review

Genomics and the Multifactorial Nature of Human Autoimmune Disease

October 2011
The New-England Medical Review and Journal 365(17):1612-23

October 2011
365(17):1612-23

DOI:10.1056/NEJMra1100030

Source
PubMed

Authors:

Peter K Gregersen

The Feinstein Institute for Medical Research

S. Gazal, K. Sacre, Y. Allanore, M. Teruel, A. H. Goodall, , S. Tohma, L. Alfredsson, Y. Okada, G. Xie, A. Constantin, A. Balsa, A. Kawasaki, P. Nicaise, C. Amos, L. Rodriguez-Rodriguez, G. Chiocchia, C. Boileau, J. Zhang, O. Vittecoq, T. Barnetche, M. A. G. Gay, H. Furukawa, A. Cantagrel, X. Le Loet, T. Sumida, M. Hurtado-Nedelec, C. Richez, S. Chollet-Martin, T. Schaeverbeke, B. Combe, L. Khoryati, B. Coustet, J. El-Benna, K. Siminovitch, R. Plenge, L. Padyukov, J. Martin, N. Tsuchiya, P. Dieude. (2015) Identification of secreted phosphoprotein 1 gene as a new rheumatoid arthritis susceptibility gene. Annals of the Rheumatic Diseases 74, e19-e19 CrossRef L.-M. Diaz-Gallo, C. P. Simeon, J. C. Broen, N. Ortego-Centeno, L. Beretta, M. C. Vonk, P. E. Carreira, S. Vargas, J. A. Roman-Ivorra, M. A. Gonzalez-Gay, C. Tolosa, F. J. Lopez-Longo, G. Espinosa, E. F. Vicente, R. Hesselstrand, G. Riemekasten, T. Witte, J. H. W. Distler, A. E. Voskuyl, A. J. Schuerwegh, P. G. Shiels, A. Nordin, L. Padyukov, A.-M. Hoffmann-Vold, R. Scorza, C. Lunardi, P. Airo, J. M. van Laar, N. Hunzelmann, B. S. Gathof, A. Kreuter, A. Herrick, J. Worthington, C. P. Denton, X. Zhou, F. C. Arnett, C. Fonseca, B. P. Koeleman, S. Assasi, T. R. D. J. Radstake, M. D. Mayes, J. Martin, , J. L. Callejas, R. Rios, N. Navarrete, R. G. Portales, M. T. Camps, A. Fernandez-Nebro, M. F. Gonzalez-Escribano, J. Sanchez-Roman, F. J. Garcia-Hernandez, M. J. Castillo, M. A. Aguirre, I. Gomez-Gracia, B. Fernandez-Gutierrez, L. Rodriguez-Rodriguez, J. L. Andreu, P. G. de la Pena, L. Martinez, M. A. Robles, N. Oreiro, S. de Reumatologia, V. Fonollosa, A. Pros, M. R. Carballeira, F. J. Narvaez, B. Diaz, L. Trapiella, M. Gallego, M. del Carmen Freire, I. Vaqueiro, M. V. Egurbide, L. Saez-Comet, F. Diaz, V. Hernandez, E. Beltran. (2013) Implication of IL-2/IL-21 region in systemic sclerosis genetic susceptibility. Annals of the Rheumatic Diseases 72, 1233-1238 CrossRef Lara Bossini-Castillo, Carmen P Simeon, Lorenzo Beretta, Jasper Broen, Madelon C Vonk, José Callejas, Patricia Carreira, Luis Rodríguez-Rodríguez, Rosa García-Portales, Miguel A González-Gay, Ivan Castellví, María Camps, Carlos Tolosa, Esther Vicente-Rabaneda, María Egurbide, , Annemie J Schuerwegh, Roger Hesselstrand, Claudio Lunardi, Jacob M van Laar, Paul Shiels, Ariane Herrick, Jane Worthington, Christopher Denton, Timothy RDJ Radstake, Carmen Fonseca, Javier Martin. (2012) KCNA5 gene is not confirmed as a systemic sclerosis-related pulmonary arterial hypertension genetic susceptibility factor. Arthritis Research & Therapy 14, R273 CrossRef

PheWAS and cross-disorder analysis reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

Article

Full-text available

Sep 2023

Introduction Autoimmune disorders (ADs) are a group of about 80 disorders that occur when self-attacking autoantibodies are produced due to failure in the self-tolerance mechanisms. ADs are polygenic disorders and associations with genes both in the human leukocyte antigen (HLA) region and outside of it have been described. Previous studies have shown that they are highly comorbid with shared genetic risk factors, while epidemiological studies revealed associations between various lifestyle and health-related phenotypes and ADs. Methods Here, for the first time, we performed a comparative polygenic risk score (PRS) - Phenome Wide Association Study (PheWAS) for 11 different ADs (Juvenile Idiopathic Arthritis, Primary Sclerosing Cholangitis, Celiac Disease, Multiple Sclerosis, Rheumatoid Arthritis, Psoriasis, Myasthenia Gravis, Type 1 Diabetes, Systemic Lupus Erythematosus, Vitiligo Late Onset, Vitiligo Early Onset) and 3,254 phenotypes available in the UK Biobank that include a wide range of socio-demographic, lifestyle and health-related outcomes. Additionally, we investigated the genetic relationships of the studied ADs, calculating their genetic correlation and conducting cross-disorder GWAS meta-analyses for the observed AD clusters. Results In total, we identified 508 phenotypes significantly associated with at least one AD PRS. 272 phenotypes were significantly associated after excluding variants in the HLA region from the PRS estimation. Through genetic correlation and genetic factor analyses, we identified four genetic factors that run across studied ADs. Cross-trait meta-analyses within each factor revealed pleiotropic genome-wide significant loci. Discussion Overall, our study confirms the association of different factors with genetic susceptibility for ADs and reveals novel observations that need to be further explored.

PheWAS and cross-disorder analyses reveal genetic architecture, pleiotropic loci and phenotypic correlations across 11 autoimmune disorders

Preprint

Full-text available

Oct 2022

Autoimmune diseases (ADs) are a group of more than 80 heterogeneous disorders that occur when there is a failure in the self-tolerance mechanisms triggering self-attacking autoantibodies. Most autoimmune disorders are polygenic and associated with genes in the human leukocyte antigen (HLA) region. However, additional non-HLA genes are also found to be associated with different ADs, and often these are also implicated in more than one disorder. Previous studies have observed associations between various health-related and lifestyle phenotypes and ADs. Polygenic risk scores (PRS) allow the calculation of an individual's genetic liability to a phenotype and are estimated as the sum of the risk alleles weighted by their effect sizes in a genome-wide association study (GWAS). Here, for the first time, we conducted a comparative PRS-PheWAS analysis for 11 different ADs (Celiac Disease, Juvenile Idiopathic Arthritis, Multiple Sclerosis, Myasthenia Gravis, Primary Sclerosing Cholangitis, Psoriasis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Type 1 Diabetes, Vitiligo Early Onset, Vitiligo Late Onset) and 3,281 outcomes available in the UK Biobank that cover a wide range of lifestyle, socio-demographic and health-related phenotypes. We also explored the genetic relationships of the studied ADs, estimating their genetic correlation and performing cross-disorder GWAS meta-analyses for the identified AD clusters. In total, we observed 554 outcomes significantly associated with at least one disorder PRS, and 300 outcomes were significant after variants in the HLA region were excluded from the PRS calculations. Based on the genetic correlation and genetic factor analysis, we observed five genetic factors among studied ADs. Cross-disorder meta-analyses in each factor revealed genome-wide significant loci that are pleiotropic across multiple ADs. Overall, our analyses confirm the association of different factors with genetic risk for ADs and reveal novel observations that warrant further exploration.

Modern concept of autoimmunity in rheumatology

Article

Aug 2023

E. L. Nasonov

Two fundamental pathologic processes are central to the spectrum of chronic inflammation mechanisms: autoimmunity and autoinflammation. Autoimmunity and autoinflammation are mutually potent pathologic processes; their development is considered within the framework of the “immunoinflammatory” continuum, reflecting the close relationship between innate and acquired types of immune response. Autoimmunity is the leading mechanism of pathogenesis of a large group of chronic inflammatory human diseases, defined as autoimmune diseases, the frequency of which in the population exceeds 10%. Advances in molecular biology, pharmacogenetics and bioinformatics have created prerequisites for individualization of therapy of autoimmune rheumatic diseases within the concept of personalized medicine. The study of immunopathogenesis mechanisms, improvement of diagnostics, deciphering the nature of molecular taxonomy, development of approaches to prevention and personalized therapy of human autoimmune diseases is among the priority directions of medicine of the 21st century.

The First Case Report of Preschool-Onset SS/SLE Coexisting With NMOSD of Chinese Origin

Article

Full-text available

May 2022

Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease (CTD), the main features of which are multiple serum autoantibodies and extensive involvement of multiple systems. The onset age of patients varies from childhood to middle age, with nearly 1/5 in childhood. Sjogren’s syndrome (SS) is also an autoimmune disease characterized by high-degree lymphocytic infiltration of exocrine glands, usually occurring in middle-aged and older women, and rarely in childhood. Neuromyelitis optica spectrum disorder (NMOSD) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS) mainly involving the optic nerve and spinal cord. The coexistence of NMOSD and SLE and/or SS is well recognized by both neurologists and rheumatologists, but cases in children have been rarely reported. In this paper, we reported a case of a girl with onset at age 5 clinically featured by recurrent parotid gland enlargement, pancytopenia, hypocomplementemia, multiple positive serum antibodies, and cirrhosis. She was initially diagnosed with SS/SLE overlap syndrome at age 5. Four years later, the patient suffered a sudden vision loss and was examined to have positive AQP4 antibodies in serum and cerebrospinal fluid (CSF), and long segmental spinal swelling, in line with the diagnostic criteria for NMOSD. Up to now, the current patient is of the youngest onset age to develop SS/SLE coexisting with NMOSD, also with cirrhosis. It is important for clinicians to be aware of the possibility of CTDs coexisting with NMOSD in children, especially in those with positive anti-multiple autoantibodies, and to decrease the rate of missed diagnosis.

Causal relationship between primary sclerosing cholangitis and systemic lupus erythematosus: a bidirectional Mendelian randomization study

Article

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Jun 2024

Background Observational studies have found a link between two autoimmune diseases, namely, primary sclerosing cholangitis (PSC) and systemic lupus erythematosus (SLE). However, the relationship remains unclear. Methods Bidirectional Mendelian randomization (MR) analysis and statistical methods, including inverse variance weighting, weighted median, and MR-Egger tests, were performed using data from genome-wide association studies to detect a causal relationship between PSC and SLE. Sensitivity analyses were subsequently performed to assess the robustness of the results. Univariate MR methods were also investigated. Results Results of MR analysis suggested that PSC was associated with an increased risk for SLE (odds ratio: 1.33, 95% confidence interval: 1.10–1.61, P=0.0039) However, SLE had no significant causal relationship with PSC. Conclusion Results of MR analysis revealed that patients with PSC were at an increased risk for SLE, which provides new insights into the relationship between these two autoimmune diseases.

The gut microbiota posttranslationally modifies IgA1 in autoimmune glomerulonephritis

Article

Mar 2024
Sci Transl Med

Mechanisms underlying the disruption of self-tolerance in acquired autoimmunity remain unclear. Immunoglobulin A (IgA) nephropathy is an acquired autoimmune disease where deglycosylated IgA1 (IgA subclass 1) auto-antigens are recognized by IgG auto-antibodies, forming immune complexes that are deposited in the kidneys, leading to glomerulonephritis. In the intestinal microbiota of patients with IgA nephropathy, there was increased relative abundance of mucin-degrading bacteria, including Akkermansia muciniphila . IgA1 was deglycosylated by A. muciniphila both in vitro and in the intestinal lumen of mice. This generated neo-epitopes that were recognized by autoreactive IgG from the sera of patients with IgA nephropathy. Mice expressing human IgA1 and the human Fc α receptor I (α1 KI -CD89 tg ) that underwent intestinal colonization by A. muciniphila developed an aggravated IgA nephropathy phenotype. After deglycosylation of IgA1 by A. muciniphila in the mouse gut lumen, IgA1 crossed the intestinal epithelium into the circulation by retrotranscytosis and became deposited in the glomeruli of mouse kidneys. Human α-defensins—a risk locus for IgA nephropathy—inhibited growth of A. muciniphila in vitro. A negative correlation observed between stool concentration of α-defensin 6 and quantity of A. muciniphila in the guts of control participants was lost in patients with IgA nephropathy. This study demonstrates that gut microbiota dysbiosis contributes to generation of auto-antigens in patients with IgA nephropathy and in a mouse model of this disease.

Maternal‐driven immune education in offspring

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Mar 2024
IMMUNOL REV

Maternal environmental exposures, particularly during gestation and lactation, significantly influence the immunological development and long‐term immunity of offspring. Mammalian immune systems develop through crucial inputs from the environment, beginning in utero and continuing after birth. These critical developmental windows are essential for proper immune system development and, once closed, may not be reopened. This review focuses on the mechanisms by which maternal exposures, particularly to pathogens, diet, and microbiota, impact offspring immunity. Mechanisms driving maternal‐offspring immune crosstalk include transfer of maternal antibodies, changes in the maternal microbiome and microbiota‐derived metabolites, and transfer of immune cells and cytokines via the placenta and breastfeeding. We further discuss the role of transient maternal infections, which are common during pregnancy, in providing tissue‐specific immune education to offspring. We propose a “maternal‐driven immune education” hypothesis, which suggests that offspring can use maternal encounters that occur during a critical developmental window to develop optimal immune fitness against infection and inflammation.

Prevalence and Factors Associated with Positivity of Antinuclear Antibodies (ANA) Patterns, Native Anti-DNA and Extractable Nuclear Antigens (ENA) Antibodies: Experience from a Laboratory in Dakar

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Jan 2024

Endocrine Autoimmunity in Association with Female Infertility

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Oct 2023

Infertility is the inability to conceive after a year of regular unprotected sexual intercourse, affecting 10-15% of couples. Advanced age, obesity, and certain medications can hinder fertility. Endocrine autoimmunity is increasingly recognized as a significant contributor to female infertility, often complicating various gynecological conditions. Autoimmune issues involving the hypothalamus, pituitary gland, thyroid, adrenal glands, and ovaries can impact fertility. A multidisciplinary approach is essential for diagnosing infertility, with a crucial focus on identifying potential endocrine disorders. Here we discuss how to identify endocrine autoimmune patients with ovulatory dysfunction. Women must be advised about limiting factors to be avoided, to protect their fertility. A comprehensive understanding of the underlying mechanisms, coupled with appropriate diagnostic and therapeutic approaches, is crucial for effectively managing this complex condition and helping women achieve their reproductive goals.

Consequences of errors in the functioning of the immune system Descriptive review [ Running title: Consequences of misstep of the immune system ]

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Aug 2023

The immune system is a very complex network of cells, tissues and organs that work together to defend the body against pathogens. Its two main components are: the innate immune system and the adaptive immune system. However, when this system is compromised, the body's ability to defend itself is impaired, which can increase the risk of developing at least one of the more than 80 autoimmune diseases that affect a significant proportion of the world's population. These illnesses can cause a range of symptoms, including pain, fatigue, rashes, nausea, headaches and dizziness. They can also affect different parts of the body, such as the skin, muscles, joints, tendons, blood and blood vessels, and even other organs. Also, it is not uncommon to suffer from more than one type of autoimmune disease, as they share similarities in their basic immunological mechanisms. In this review, we aim to provide a more comprehensive understanding of the impact and severity of immune dysfunction. We will also describe the advantages and disadvantages of factors considered to promote immune function and summarize current knowledge about the mechanisms of certain autoimmune diseases. We hope to shed light on this complex subject and provide valuable insights into potential treatments and preventive measures for these diseases.

AutoCore: A network-based definition of the core module of human autoimmunity and autoinflammation

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Sep 2023

Although research on rare autoimmune and autoinflammatory diseases has enabled definition of nonredundant regulators of homeostasis in human immunity, because of the single gene-single disease nature of many of these diseases, contributing factors were mostly unveiled in sequential and noncoordinated individual studies. We used a network-based approach for integrating a set of 186 inborn errors of immunity with predominant autoimmunity/autoinflammation into a comprehensive map of human immune dysregulation, which we termed "AutoCore." The AutoCore is located centrally within the interactome of all protein-protein interactions, connecting and pinpointing multidisease markers for a range of common, polygenic autoimmune/autoinflammatory diseases. The AutoCore can be subdivided into 19 endotypes that correspond to molecularly and phenotypically cohesive disease subgroups, providing a molecular mechanism-based disease classification and rationale toward systematic targeting for therapeutic purposes. Our study provides a proof of concept for using network-based methods to systematically investigate the molecular relationships between individual rare diseases and address a range of conceptual, diagnostic, and therapeutic challenges.

Autoimmunity to synovial extracellular matrix proteins in patients with postinfectious Lyme arthritis

Article

Full-text available

Jul 2023
J CLIN INVEST

Background: Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked up-regulation of HLA-DR molecules, including in post-infectious Lyme arthritis (LA). However, the identity of HLA-DR-presented peptides and therefore, the reasons for these associations have frequently remained elusive. Methods: Using immunopeptidomics to detect HLA-DR-presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with post-infectious LA, identified potential Borreliella burgdorferi (Bb)-mimic epitopes, and characterized T and B cell responses to these peptides or proteins. Results: Of 24 post-infectious LA patients, 58% had CD4+ T cell responses to ≥1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to >1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet-expressing Th1 cells, a small percentage were RoRyt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Treg cells. Conclusion: Autoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of post-infectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.

Prediction of a Positive ANA Result for a Rheumatological Diagnosis in an Outpatient Setting

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Jul 2023

Objective: To study the predictive value of a positive anti-nuclear antibody (ANA) for a rheumatological diagnosis in an outpatient setting. Methods: Individuals who were referred to the rheumatology outpatient clinics because of a positive ANA between July 2014 and June 2015 were retrospectively reviewed. Presenting symptoms in addition to a positive ANA and whether a final rheumatological diagnosis was made were recorded. The positive predictive value of a positive ANA and its titer for a rheumatological diagnosis, with and without accompanying symptoms was evaluated. Results: A total of 230 patients were included (82% women, age 47.7 ± 14.1 years [range 18-84]). Family medicine and the general outpatient clinic were the main sources of referral (32.2%), followed by ophthalmology (13.0%) and otorhinolaryngology (11.7%). A final rheumatological diagnosis was made in 54 (23.5%) patients, with rheumatoid arthritis being the commonest diagnosis (40.7%). In the absence of any associated symptoms, the predictive value of a positive ANA was 0%. The presence of Raynaud’s phenomenon (100%), joint swelling (59.5%), and joint stiffness (48.9%) predicted a better final rheumatological diagnosis along with a positive ANA. ANA titers of 1:80 or less had a low sensitivity for rheumatic diseases. A receiver operating characteristic (ROC) curve analysis showed that an ANA titer of [Formula: see text]1:128 best predicted a rheumatological diagnosis (AUC 0.78 [0.71–0.85]; sensitivity 0.78; specificity 0.64). Conclusions: To improve the prediction for a rheumatological diagnosis, referral for a positive ANA test should be more appropriately done with compatible symptoms.

The Crosstalk between Covid-19 and Autoimmune Diseases: An Overview

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The COVID-19 pandemic has created significant public health challenges, and one of the major concerns is its potential association with pre-existing medical conditions. Our comprehensive review aims to provide the latest information on the relationship between COVID-19 and autoimmune diseases, shedding light on current knowledge, emerging concepts, and underlying mechanisms that may exacerbate viral infections and even trigger autoimmunity. We delve into the complex interplay between the immune system and the virus, exploring how COVID-19 impacts individuals with autoimmune diseases and the potential implications for disease severity, clinical outcomes, and management strategies. Additionally, we investigate the potential impact of autoimmune therapy on COVID-19 prognosis, discussing the latest findings and insights on the benefits and risks of immunosuppressive and immunomodulatory agents in COVID-19 patients with underlying autoimmune diseases.

Ferroptosis: A potential therapeutic target in autoimmune disease (Review)

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Jun 2023

Ferroptosis is a distinct type of regulated cell death characterized by iron overload and lipid peroxidation. Ferroptosis is regulated by numerous factors and controlled by several mechanisms. This cell death type has a relationship with the immune system, which may be regulated by damage-associated molecular patterns. Ferroptosis participates in the progression of autoimmune diseases, including autoimmune hepatitis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, multiple sclerosis, Parkinson's Disease, psoriasis and insulin-dependent diabetes mellitus. The present review summarizes the role of ferroptosis in autoimmune disorders and discusses ferroptosis as a potential therapeutic target for autoimmune disease.

Use of autoprobiotics in the complex therapy of axial spondyloarthritis

Article

Mar 2023

Spondyloarthritis (SpA) is a group of chronic inflammatory diseases of the musculoskeletal system involving of the axial skeleton and extra-articular manifestations such as inflammatory bowel diseases. Some violations of the intestinal microbiome often occur during the course of spondyloarthritis. Also, intestinal dysbiosis can be enhanced by ongoing therapy. The aim of the study was to evaluate the effectiveness of combined therapy with nonsteroidal anti-inflammatory drugs (NSAIDs) and autoprobiotics supplementation. SpA patients treated with NSAID were divided into two groups: group A which took autoprobiotic based on indigenous culture of Enterococcus faecium , and group S which took only Supra medium, which is the basis used for making of autoprobiotic. Reducing of pain intensity, dyspeptic phenomena were observed to a greater extent in group A compared to group S. PCRRT testing revealed no significant changes in intestinal microbiocenosis in patients with SpA, except of a decrease in the Lactobacillus population, which was restored only in group A. A feature of the changes in group S was a decrease in the total bacterial mass, amounts of Bacteroides, Faecalibacterium, Enterobacter and expansion of Methanobrevibacter population. The tendency to restore the quantitative content of Lactobacillus , correlating with a decrease of IL-10 concentration, was found only in group A. In our study the effectiveness of enterococcal auprobiotic supplementation as an element of complex therapy of patient suffering from SpA has been proven. The use of an autoprobiotic leads to a decrease in the severity of the symptoms of the disease, the leveling of dyspeptic symptoms and microbiota disorders.

The Role of Viral Infections in the Onset of Autoimmune Diseases

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Mar 2023

Autoimmune diseases (AIDs) are the consequence of a breach in immune tolerance, leading to the inability to sufficiently differentiate between self and non-self. Immune reactions that are targeted towards self-antigens can ultimately lead to the destruction of the host’s cells and the development of autoimmune diseases. Although autoimmune disorders are comparatively rare, the worldwide incidence and prevalence is increasing, and they have major adverse implications for mortality and morbidity. Genetic and environmental factors are thought to be the major factors contributing to the development of autoimmunity. Viral infections are one of the environmental triggers that can lead to autoimmunity. Current research suggests that several mechanisms, such as molecular mimicry, epitope spreading, and bystander activation, can cause viral-induced autoimmunity. Here we describe the latest insights into the pathomechanisms of viral-induced autoimmune diseases and discuss recent findings on COVID-19 infections and the development of AIDs.

Secondary Fisher–Evans syndrome in a child with activated PI(3)kd syndrome and lymphoma

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Feb 2023

Evans syndrome, a combination of autoimmune hemolytic anemia and immune thrombocytopenia, is a rare disease in children. In childhood, it may turn out to be one of the first manifestations of a primary immunodeficiency or an immune dysregulation syndrome. Here we present a clinical case of a patient who was initially diagnosed with Evans syndrome and did not respond well to therapy. Based on the results of genetic testing, the child was then diagnosed with primary immunodeficiency, namely, activated PI(3)kd syndrome. During follow-up, the patient developed lymphoma and had to undergo radical treatment (allogeneic hematopoietic stem cell transplantation). The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Future on a Flashdrive: Timely Considerations for the Imminent Adoption of Whole Genome Sequencing in Pediatric Healthcare

Article

Jan 2023

In just twenty years, humanity has progressed from the first sequenced human genome to the ability to sequence one in a matter of hours and for only hundreds of dollars. This rise in affordability and speed has enabled physicians to use whole genome sequencing (WGS) as a diagnostic tool, particularly in cases of rare disease in pediatric patients where it has already demonstrated immense potential. However, such a rapid development in technology powerful enough to unlock a person’s genetic information has also led to necessary questions regarding when and how it is applied. In this assessment, we discuss the implications of WGS adoption in pediatric healthcare, focusing specifically on ensuring ethical and equitable collection and communication of genomic data as well as the need for secure and accessible data storage methods. We identify several key areas where further policy is most pressing and provide value-driven recommendations centered on guaranteeing pediatric patient safety, equity, and empowerment during the broader introduction of WGS tools. In particular, we advocate for legal frameworks that limit present usage of WGS to only those patients with a clear and present need, guidelines that expand the labor force that can conduct WGS, increasing access and equity, improved standards for storage, access, and sharing of WGS data, and finally expanding Medicaid coverage to include WGS use in critical care settings.

Epigenetic changes in inflammatory arthritis monocytes contribute to disease and can be targeted by JAK inhibition

Article

Full-text available

Jan 2023

Objectives How the local inflammatory environment regulates epigenetic changes in the context of inflammatory arthritis remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying inflammatory arthritis. Methods RNA-sequencing and H3K27me3 chromatin immunoprecipitation sequencing (ChIP-seq) were used to analyze the transcriptional and epigenetic profile, respectively, of JIA synovial fluid-derived monocytes. Results Synovial-derived monocytes display an activated phenotype, which is regulated on the epigenetic level. IFN signalling-associated genes are increased and epigenetically altered in synovial monocytes, indicating a driving role for IFN in establishing the local inflammatory phenotype. Treatment of synovial monocytes with the Janus-associated kinase (JAK) inhibitor ruxolitinib, which inhibits IFN signalling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. Conclusion This study provides novel insights into epigenetic regulation of inflammatory arthritis patient-derived monocytes and highlights the therapeutic potential of epigenetic modulation for the treatment of inflammatory rheumatic diseases.

Phenotypic subtyping via contrastive learning

Preprint

Full-text available

Jan 2023

Defining and accounting for subphenotypic structure has the potential to increase statistical power and provide a deeper understanding of the heterogeneity in the molecular basis of complex disease. Existing phenotype subtyping methods primarily rely on clinically observed heterogeneity or metadata clustering. However, they generally tend to capture the dominant sources of variation in the data, which often originate from variation that is not descriptive of the mechanistic heterogeneity of the phenotype of interest; in fact, such dominant sources of variation, such as population structure or technical variation, are, in general, expected to be independent of subphenotypic structure. We instead aim to find a subspace with signal that is unique to a group of samples for which we believe that subphenotypic variation exists (e.g., cases of a disease). To that end, we introduce Phenotype Aware Components Analysis (PACA), a contrastive learning approach leveraging canonical correlation analysis to robustly capture weak sources of subphenotypic variation. In the context of disease, PACA learns a gradient of variation unique to cases in a given dataset, while leveraging control samples for accounting for variation and imbalances of biological and technical confounders between cases and controls. We evaluated PACA using an extensive simulation study, as well as on various subtyping tasks using genotypes, transcriptomics, and DNA methylation data. Our results provide multiple strong evidence that PACA allows us to robustly capture weak unknown variation of interest while being calibrated and well-powered, far superseding the performance of alternative methods. This renders PACA as a state-of-the-art tool for defining de novo subtypes that are more likely to reflect molecular heterogeneity, especially in challenging cases where the phenotypic heterogeneity may be masked by a myriad of strong unrelated effects in the data. Code Availability PACA is available as an open source R package on GitHub: https://github.com/Adigorla/PACA

The Frequency of Immunofluorescence Antinuclear Antibody Patterns and Extractable Nuclear Antigen: Experience From a Large Laboratory in Pakistan

Article

Full-text available

Jan 2023

Background Autoimmune disorders have shown an increasing incidence in the last few years. The systemic response to the disorder is characterized by the expression of antinuclear antibody (ANA), which serves as the serological hallmark of autoimmunity. Its presence may indicate either a systemic autoimmune disease such as systemic lupus erythematosus (SLE), scleroderma, and polymyositis/dermatomyositis or an organ-specific condition such as autoimmune thyroiditis and hepatitis. The systemic response may vary from one individual to another in each population. Several specific autoantibodies are also found to be associated with specific rheumatic diseases. Aim We aim to report the frequency of ANA positivity, ANA immunofluorescence patterns, and the presence of extractable nuclear antigen (ENA) among the general Pakistani population from one of the largest laboratories in Pakistan. Material and methods A total of 1,966 blood samples from a random Pakistani population were included, who were referred by their physicians with suspicion of autoimmune disease. These blood samples were subjected to ANA testing by indirect immunofluorescence method, and subsequently, positive samples were further analyzed for ENA detection in the Section of Chemical Pathology, Department of Pathology at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. An ANA titer of ≥1:80 was taken as positive. ANA was divided into subgroups based on titer: negative, weakly positive (titer of 1:80 or 1:160), moderately positive (titer of 1:320 or 1:640), and strongly positive (titer of ≥1:1280). Further, the frequency of ANA in male and female participants was studied in different age groups (2 to <10, 10 to <20, 20 to <30, 30 to <40, 40 to <50, 50 to <60, 60 to <70, 70 to <80, and 80+ years). Results This study included 1,966 participants, out of which 1,100 (55%) were ANA-positive at a titer of ≥1:80. Out of these ANA positives, the proportion of weakly positive (titer of 1:80 or 1:160), moderately positive (titer of 1:320 or 1:640), and strongly positive (titer of ≥1:1280) were 48.7%, 2.6%, and 4.2%, respectively. The ages ranged from two to 91 years, with a mean age of 43.64 ± 17.4 years. Females (75.5%) showed predominance over males (24.5%) in all age groups, with a ratio of 3:1. The age group in which most ANA positivity was found was 30 to <40 years. Among 1,100 ANA-positive sera, 383 (34.8%) participants tested positive for at least one out of 15 ENA. The most frequent autoantibodies noticed were anti-recombinant Ro52 (Ro52) (19.8%), anti-Sjogren’s syndrome type A (SSA) (17.2%), and anti-ribonucleoprotein (RNP) (13.3%). The most prevalent ANA patterns were nuclear homogeneous (27.7%), followed by nuclear speckled (26.5%). Conclusion The frequency of ANA positivity is high in the Pakistani population and differs in different sex and age groups.

Population genetic research of the mutation in ugt1a1 gene associated with reduced activity of liver UDP-glucuronosyltransferase A1

Article

Sep 2020

A. N. Volkov

Aim. To explore allele and genotype frequencies of the rs8175347 polymorphism within the UGT1A1 gene in Kemerovo Region. Materials and Methods. The study sample included 64 male and 68 female inhabitants of the Kemerovo Region. Upon DNA isolation from the peripheral blood leukocytes, we conducted allele-specific polymerase chain reaction followed by electrophoretic detection of the genotype. Results. The frequency of minor allele *28 of rs8175347 polymorphism, which is associated with the downregulation of UDP-glucuronosyltransferase А1 in the liver, was 33.3%, while the frequency of *28/*28 genotype was 13.6% and did not significantly differ in the examined men and women. Conclusion. High frequency of the *28/*28 genotype in the studied sample suggests a high prevalence of reduced UDP-glucuronosyltransferase А1 activity and associated conditions including Gilbert’s syndrome and adverse drug reactions.

Type 2 autoimmune hepatitis: Genetic susceptibility

Article

Full-text available

Sep 2022

Two types of autoimmune hepatitis (AIH) are recognized; AIH-1 is characterized by the presence of anti-nuclear and/or anti-smooth muscle autoantibodies, while AIH-2 is associated with the presence of anti-Liver kidney microsome and/or anti-Liver Cytosol antibodies. The autoantigens targeted by AIH-2 autoantibodies are the cytochrome P450 2D6 and Formiminotransferase-cyclodeaminase for anti-LKM1 and anti-LC1 respectively. Both autoantigens are expressed in hepatocytes at higher levels than in any other cell type. Therefore, compared to AIH-1, the autoantigens targeted in AIH-2 are predominantly tissue-specific. Distinct clinical features are specific to AIH-2 compared to AIH-1, including diagnosis in younger patients (mean age 6.6 years), onset as fulminant hepatitis in very young patients (3 years of age or less), higher frequency in children than in adults and is frequently associated with extrahepatic T cell-mediated autoimmune diseases. AIH-2 is also often diagnosed in patients with primary immunodeficiency. AIH-2 is associated with specific HLA class II susceptibility alleles; DQB1*0201 is considered the main determinant of susceptibility while DRB1*07/DRB1*03 is associated with the type of autoantibody present. HLA DQB1*0201 is in strong linkage disequilibrium with both HLA DRB1*03 and DRB1*07. Interestingly, as in humans, MHC and non-MHC genes strongly influence the development of the disease in an animal model of AIH-2. Altogether, these findings suggest that AIH-2 incidence is likely dependent on specific genetic susceptibility factors combined with distinct environmental triggers.

Human islet T cells are highly reactive to preproinsulin in type 1 diabetes

Article

Sep 2022

Internal Ribosome Entry Site (IRES)-Mediated Translation and Its Potential for Novel mRNA-Based Therapy Development

Article

Full-text available

Aug 2022

Many conditions can benefit from RNA-based therapies, namely, those targeting internal ribosome entry sites (IRESs) and their regulatory proteins, the IRES trans-acting factors (ITAFs). IRES-mediated translation is an alternative mechanism of translation initiation, known for maintaining protein synthesis when canonical translation is impaired. During a stress response, it contributes to cell reprogramming and adaptation to the new environment. The relationship between IRESs and ITAFs with tumorigenesis and resistance to therapy has been studied in recent years, proposing new therapeutic targets and treatments. In addition, IRES-dependent translation initiation dysregulation is also related to neurological and cardiovascular diseases, muscular atrophies, or other syndromes. The participation of these structures in the development of such pathologies has been studied, yet to a far lesser extent than in cancer. Strategies involving the disruption of IRES–ITAF interactions or the modification of ITAF expression levels may be used with great impact in the development of new therapeutics. In this review, we aim to comprehend the current data on groups of human pathologies associated with IRES and/or ITAF dysregulation and their application in the designing of new therapeutic approaches using them as targets or tools. Thus, we wish to summarise the evidence in the field hoping to open new promising lines of investigation toward personalised treatments.

Influence of Disease Severity and Gender on HLA-C Methylation in COVID-19 Patients

Article

Jul 2022

In the pathophysiology of COVID-19, immunomodulatory factors play a vital role. Viruses have epigenetic effects on various genes, particularly methylation. Explaining the changes in immunological factor methylation levels during viral infections requires substantial consideration. HLA-C is a crucial determinant of immune function and NK cell activity and is primarily implicated in viral infections. This research focused on studying HLA-C methylation in COVID-19 patients with different severity. Peripheral blood samples were collected from 470 patients (235 men and 235 women) with RT-qPCR-confirmed COVID-19 test and classified into moderate, severe, and critical groups based on WHO criteria. Also, one hundred (50 men and 50 women) healthy subjects were selected as the control group. Peripheral blood mononuclear cells were used for DNA extraction, and the methylation-specific PCR (MSP) method and gel electrophoresis were used to determine the methylation status of the HLA-C. Significant statistical differences in HLA-C methylation were observed among cases and controls and various stages of the disease. HLA-C methylation in men and women has decreased in all stages (p < 0.05). In comparison with control, HLA-C methylation in both genders were as follows: moderate (women: 41.0%, men: 52.33%), severe (women: 43.42%, men: 64.86%), critical (women: 42.33%, men: 60.07%), and total patients (women: 45.52%, men: 56.97%). Furthermore, the methylation levels in men were higher than in women in all groups (p < 0.05). Significantly, among all groups, the severe group of men participants showed the highest methylation percentage (p < 0.05). No significant differences were detected for different disease severity in the women group (p > 0.1). This study found that HLA-C methylation was significantly lower in COVID-19 patients with different disease severity. There were also significant differences in HLA-C methylation between men and women patients with different severity. Therefore, during managing viral infections, particularly COVID-19, it is critical to consider patient gender and disease severity.

COVID-19 2022 update: transition of the pandemic to the endemic phase

Article

Full-text available

Jun 2022
Hum Genom

COVID-19, which is caused by the SARS-CoV-2, has ravaged the world for the past 2 years. Here, we review the current state of research into the disease with focus on its history, human genetics and genomics and the transition from the pandemic to the endemic phase. We are particularly concerned by the lack of solid information from the initial phases of the pandemic that highlighted the necessity for better preparation to face similar future threats. On the other hand, we are gratified by the progress into human genetic susceptibility investigations and we believe now is the time to explore the transition from the pandemic to the endemic phase. The latter will require worldwide vigilance and cooperation, especially in emerging countries. In the transition to the endemic phase, vaccination rates have lagged and developed countries should assist, as warranted, in bolstering vaccination rates worldwide. We also discuss the current status of vaccines and the outlook for COVID-19.

Association of Neuromyelitis Optica Spectrum Disease and Sjogren Syndrome in a Tunisian Patient

Article

Jul 2021

Development of a Machine Learning Model to Distinguish between Ulcerative Colitis and Crohn’s Disease Using RNA Sequencing Data

Article

Full-text available

Dec 2021

Crohn’s disease (CD) and ulcerative colitis (UC) can be difficult to differentiate. As differential diagnosis is important in establishing a long-term treatment plan for patients, we aimed to develop a machine learning model for the differential diagnosis of the two diseases using RNA sequencing (RNA-seq) data from endoscopic biopsy tissue from patients with inflammatory bowel disease (n = 127; CD, 94; UC, 33). Biopsy samples were taken from inflammatory lesions or normal tissues. The RNA-seq dataset was processed via mapping to the human reference genome (GRCh38) and quantifying the corresponding gene models that comprised 19,596 protein-coding genes. An unsupervised learning model showed distinct clusters of four classes: CD inflammatory, CD normal, UC inflammatory, and UC normal. A supervised learning model based on partial least squares discriminant analysis was able to distinguish inflammatory CD from inflammatory UC after pruning the strong classifiers of normal CD vs. normal UC. The error rate was minimal and affected only two components: 20 and 50 genes for the first and second components, respectively. The corresponding overall error rate was 0.147. RNA-seq analysis of tissue and the two components revealed in this study may be helpful for distinguishing CD from UC.

Epigenetic changes in autoimmune monocytes contribute to disease and can be targeted by JAK inhibition

Preprint

Full-text available

Nov 2021

How the local inflammatory environment regulates epigenetic changes in the context of autoimmune diseases remains unclear. Here we assessed the transcriptional and active enhancer profile of monocytes derived from the inflamed joints of Juvenile Idiopathic Arthritis (JIA) patients, a model well-suited for studying autoimmune diseases. RNA-sequencing analysis demonstrated that synovial-derived monocytes display an activated phenotype, characterized by increased expression of surface activation markers and multiple chemokines and cytokines. This increased expression is regulated on the epigenetic level, as ChIP-sequencing indicated increased H3K27 acetylation of genes upregulated in synovial monocytes. IFN signaling-associated genes are increased and epigenetically altered in synovial monocytes, suggesting a role for IFN in establishing the inflammatory phenotype. Treatment of human synovial monocytes with the Janus-associated kinase (JAK) inhibitor Ruxolitinib, which inhibits IFN signaling, transformed the activated enhancer landscape and reduced disease-associated gene expression, thereby inhibiting the inflammatory phenotype. Taken together, these data provide novel insight into epigenetic regulation of autoimmune disease-patient derived monocytes and suggest that altering the epigenetic profile can be a therapeutic approach for the treatment of autoimmune diseases.

The Human Genetic Differences in the Outcomes of mRNA Vaccination against COVID-19: A Prospective Cohort Study

Article

Full-text available

Jun 2024

Background: This study aimed to explore how genetic variations in individuals impact neutralization activity post-mRNA vaccination, recognizing the critical role vaccination plays in curbing COVID-19 spread and the necessity of ensuring vaccine efficacy amidst genetic diversity. Methods: In a 4-week clinical pilot study, 534 healthy subjects received their first COVID vaccine dose, followed by the second dose. Antibody levels were evaluated thrice. From this pool, 120 participants were selected and divided into high- and low-antibody groups based on their levels. Genomic DNA was isolated from peripheral blood mononuclear cells for pilot genome-wide association studies (GWAS) conducted on a single platform. Real-time PCR was used to confirm differences in gene expression identified via GWAS analysis. Results: Three SNPs exceeded the level of p < 1.0 × 10⁻³. The rs7795433 SNP of the HDAC9 gene (7q21.1) showed the strongest association with COVID-19 vaccination under the additive model (OR = 5.63; p = 3 × 10⁻⁵). In the PCR experiments, the AA genotype group showed that the gene expression level of HDAC9 was likely to be decreased in the low-antibody-formation group at the time of vaccination. Conclusion: We found that AA genotype holders (rs7795433 SNP of the HDAC9 gene) have a high probability of having a higher antibody count when vaccinated, and GG type holders have a high probability of the opposite. These findings show that the genetic characteristics of vaccinated people may affect antibody production after COVID vaccination.

Pathogenesis of autoimmune diseases caused by genetic variants of co-stimulatory molecules for antigen presentation抗原提示補助シグナル分子の遺伝的バリアントに起因する自己免疫疾患の発症機序

Article

Apr 2024

Yuki Hitomi

Autoimmune diseases are caused by a breakdown in the tolerance that evades immune responses to self-antigens, and it is assumed that genetic and environmental factors collectively contribute to their development. To date, numerous disease susceptibility gene loci have been identified using comprehensive genome analysis methods such as genome-wide association studies (GWAS). Among these, genes encoding co-stimulatory molecules that play an important role in antigen presentation from Human Leukocyte Antigen (HLA) to T cell antigen receptor (TCR) have relatively many disease susceptibility gene loci common to multiple autoimmune diseases. It has been revealed that CD80, ICOSLG, CD40, CD58, CD28, CTLA4, and PDCD1, are involved in autoimmune diseases because of specific genetic variants by the post-GWAS analyses using in silico analyses and the genome editing technologies such as CRISPR/Cas9.

Genetic Factors

Chapter

Apr 2024

Systemic sclerosis (SSc) occurs more frequently in families with SSc than in the general population. International collaborations have enabled sufficiently powered, genome-wide association studies, leading to substantial progress in the field of SSc genetics. In the HLA region, the strongest associations are with the antibody subgroups of SSc. Outside the HLA region, up to 30 robustly replicated, susceptibility loci have been identified. The majority of these susceptibility loci are involved in innate and adaptive immunity, underscoring the role of immune dysregulation for the SSc pathogenesis. More recently, several loci involved in autophagy and apoptosis have been implicated in SSc susceptibility. The functional implication of the associated gene variants is often unclear as most of them are located in the non-coding regions. These loci might directly influence the transcription of non-coding regulatory RNAs or be in linkage disequilibrium with genetic variants in coding areas. Further functional and fine-mapping studies (including sequencing) are required to elucidate the impact of the associated variants on gene expression and protein production.

Immune tolerance and the prevention of autoimmune diseases essentially depend on thymic tissue homeostasis

Article

Full-text available

Mar 2024

The intricate balance of immune reactions towards invading pathogens and immune tolerance towards self is pivotal in preventing autoimmune diseases, with the thymus playing a central role in establishing and maintaining this equilibrium. The induction of central immune tolerance in the thymus involves the elimination of self-reactive T cells, a mechanism essential for averting autoimmunity. Disruption of the thymic T cell selection mechanisms can lead to the development of autoimmune diseases. In the dynamic microenvironment of the thymus, T cell migration and interactions with thymic stromal cells are critical for the selection processes that ensure self-tolerance. Thymic epithelial cells are particularly significant in this context, presenting self-antigens and inducing the negative selection of autoreactive T cells. Further, the synergistic roles of thymic fibroblasts, B cells, and dendritic cells in antigen presentation, selection and the development of regulatory T cells are pivotal in maintaining immune responses tightly regulated. This review article collates these insights, offering a comprehensive examination of the multifaceted role of thymic tissue homeostasis in the establishment of immune tolerance and its implications in the prevention of autoimmune diseases. Additionally, the developmental pathways of the thymus are explored, highlighting how genetic aberrations can disrupt thymic architecture and function, leading to autoimmune conditions. The impact of infections on immune tolerance is another critical area, with pathogens potentially triggering autoimmunity by altering thymic homeostasis. Overall, this review underscores the integral role of thymic tissue homeostasis in the prevention of autoimmune diseases, discussing insights into potential therapeutic strategies and examining putative avenues for future research on developing thymic-based therapies in treating and preventing autoimmune conditions.

Metabolic dysregulation of lymphocytes in autoimmune diseases

Article

Feb 2024
TRENDS ENDOCRIN MET

Tracking the role of Aire in immune tolerance to the eye with a TCR transgenic mouse model

Article

Jan 2024
P NATL ACAD SCI USA

Roughly one-half of mice with partial defects in two immune tolerance pathways (Aire GW/+ Lyn −/− mice) spontaneously develop severe damage to their retinas due to T cell reactivity to Aire-regulated interphotoreceptor retinoid–binding protein (IRBP). Single-cell T cell receptor (TCR) sequencing of CD4 ⁺ T cells specific for a predominate epitope of IRBP showed a remarkable diversity of autoantigen-specific TCRs with greater clonal expansions in mice with disease. TCR transgenic mice made with an expanded IRBP-specific TCR (P2.U2) of intermediate affinity exhibited strong but incomplete negative selection of thymocytes. This negative selection was absent in IRBP −/− mice and greatly defective in Aire GW/+ mice. Most P2.U2 +/− mice and all P2.U.2 +/− Aire GW/+ mice rapidly developed inflammation of the retina and adjacent uvea (uveitis). Aire-dependent IRBP expression in the thymus also promoted Treg differentiation, but the niche for this fate determination was small, suggesting differences in antigen presentation leading to negative selection vs. thymic Treg differentiation and a stronger role for negative selection in preventing autoimmune disease in the retina.

MAIT cells in immune‐mediated tissue injury and repair

Article

Full-text available

Oct 2023
EUR J IMMUNOL

Mucosal‐associated invariant T (MAIT) cells are T cells that express a semi‐invariant αβ T cell receptor (TCR), recognising non‐peptide antigens, such as microbial‐derived Vitamin B2 metabolites, presented by the non‐polymorphic MHC class I related‐1 molecule (MR1). Like NKT cells and γδT cells, MAIT cells belong to the group of innate‐like T cells that combine properties of the innate and adaptive immune systems. They account for up to 10% of the blood T‐cell population in humans and are particularly abundant at mucosal sites. Beyond the emerging role of MAIT cells in antibacterial and antiviral defences, increasing evidence suggests additional functions in non‐infectious settings, including immune‐mediated inflammatory diseases and tissue repair. Here, we discuss recent advances in the understanding of MAIT cell functions in sterile tissue inflammation, with a particular focus on autoimmunity, chronic inflammatory diseases, and tissue repair. This article is protected by copyright. All rights reserved

Post-transcriptional checkpoints in autoimmunity

Article

Jun 2023

Post-transcriptional regulation is a fundamental process in gene expression that has a role in diverse cellular processes, including immune responses. A core concept underlying post-transcriptional regulation is that protein abundance is not solely determined by transcript abundance. Indeed, transcription and translation are not directly coupled, and intervening steps occur between these processes, including the regulation of mRNA stability, localization and alternative splicing, which can impact protein abundance. These steps are controlled by various post-transcription factors such as RNA-binding proteins and non-coding RNAs, including microRNAs, and aberrant post-transcriptional regulation has been implicated in various pathological conditions. Indeed, studies on the pathogenesis of autoimmune and inflammatory diseases have identified various post-transcription factors as important regulators of immune cell-mediated and target effector cell-mediated pathological conditions. This Review summarizes current knowledge regarding the roles of post-transcriptional checkpoints in autoimmunity, as evidenced by studies in both haematopoietic and non-haematopoietic cells, and discusses the relevance of these findings for developing new anti-inflammatory therapies.

Addressing the key issue: Antigen-specific targeting of B cells in autoimmune diseases

Article

May 2023
IMMUNOL LETT

Autoimmune diseases are heterogeneous pathologies characterized by a breakdown of immunological tolerance to self, resulting in a chronic and aberrant immune response to self-antigens. The scope and extent of affected tissues can vary greatly per autoimmune disease and can involve multiple organs and tissue types. The pathogenesis of most autoimmune diseases remains unknown but it is widely accepted that a complex interplay between (autoreactive) B and T cells in the context of breached immunological tolerance drives autoimmune pathology. The importance of B cells in autoimmune disease is exemplified by the successful use of B cell targeting therapies in the clinic. For example, Rituximab, a depleting anti-CD20 antibody, has shown favorable results in reducing the signs and symptoms of multiple autoimmune diseases, including Rheumatoid Arthritis, Anti-Neutrophil Cytoplasmic Antibody associated vasculitis and Multiple Sclerosis. However, Rituximab depletes the entire B cell repertoire, leaving patients susceptible to (latent) infections. Therefore, multiple ways to target autoreactive cells in an antigen-specific manner are currently under investigation. In this review, we will lay out the current state of antigen-specific B cell inhibiting or depleting therapies in the context of autoimmune diseases.

Current view on the pathogenesis of immune-mediated inflammatory diseases associated with ocular manifestations

Article

Jan 2023
Vestn Oftalmol

This literature review discusses the new concept of pathogenesis of systemic immune-mediated inflammatory diseases (IMIDs), presents their classification and analyzes their association with ocular manifestations.

Magnetic resonance imaging in personalized medicine

Chapter

Jan 2023

Mahbuba Rahman

Involvement of trained immunity during autoimmune responses

Article

Dec 2022
J AUTOIMMUN

Recently, it has been described that innate immune cells such as monocytes, macrophages, and natural killer cells can develop a non-specific immune response induced by different stimuli, including lipopolysaccharides, Mycobacterium bovis Bacillus Calmette-Guérin, and oxidized low-density lipoprotein. This non-specific immune response has been named "trained immunity," whose mechanism is essential for host defense and vaccine response, promoting better infection control. However, limited information about trained immunity in other non-infectious diseases, such as autoimmune illness, has been reported. The complexity of autoimmune pathology arises from dysfunctions in the innate and adaptive immune systems, triggering different clinical outcomes depending on the disease. Nevertheless, T and B cell function dysregulation is the most common characteristic associated with autoimmunity by promoting the escape from central and peripheral tolerance. Despite the importance of adaptative immunity to autoimmune diseases, the innate immune system also plays a prominent and understudied role in these pathologies. Accordingly, epigenetic and metabolic changes associated with innate immune cells that undergo a trained process are possible new therapeutic targets for autoimmune diseases. Even so, trained immunity can be beneficial or harmful in autoimmune diseases depending on several factors associated with the stimuli. Here, we reviewed the role of trained immunity over the innate immune system and the possible role of these changes in common autoimmune diseases, including Systemic Lupus Erythematosus, Rheumatoid Arthritis, Multiple Sclerosis, and Type 1 Diabetes.

Autoimmune diseases

Chapter

Aug 2022

There are over 80 defined autoimmune diseases, characterized by the activation of the immune system and tissue damage in the absence of an external threat to the organism, which affect 5 percent-7 percent of the population. Diseases considered to be autoimmune in origin can be characterized by activation of the adaptive immune response with B and T lymphocytes responding to self-antigens in the absence of any detectable tumor invasion or microbial assault; or as those that display the activation of the innate immune system and an excess of inflammatory mediators, but no evidence of an antigen-specific immune response, the former constituting the vast majority of such disease entities. Here we will discuss the immune cells and immune responses involved in autoimmune reaction, initiation and facilitation of autoimmunity and then will elaborate on human multisystem autoimmune diseases and some more common system-specific autoimmune diseases.

Prospect of ULK1 modulators in targeting regulatory T cells

Article

Sep 2022
BIOORG CHEM

Regulatory T (Treg) cells play an instrumental role in coordinating immune homeostasis via potent inhibitory effects. Defects in Treg cells lead to autoimmunity, but an overwhelming proportion of Treg cells encourages cancer progression. Hence, targeting Treg cells has emerged as a promising approach for mitigating disease severity. Recent studies have revealed that kinases are a critical component for tuning the fate of Treg cells, but the entire network of Treg-modulating kinases is still unclear. Here, we propose that the autophagy-activating UNC-51-like kinase 1 (ULK1) is a candidate for Treg cell modulation. While accumulating evidence has highlighted the role of autophagy-related kinases in Treg cells, the ULK1-Treg cell axis is yet to be examined. In this review, we predicted the potential role of ULK1 in Treg cell modulation. Furthermore, we summarized current ULK1 activators and inhibitors that can be investigated as Treg-targeting strategies, which might have beneficial outcomes in autoimmunity and cancer.

AUTOIMMUNE THYROIDITIS SPREAD CHARACTERISTICS IN POPULATION OF ADJARA

Article

Sep 2022

Autoimmune diseases of the thyroid gland are among the most widespread diseases in the world. Autoimmune diseases of the thyroid gland include Hashimoto's thyroiditis and Bazedov's disease. The purpose of the research was to investigate the autoimmune thyroiditis’ spread characteristics in Georgia, particularly in Adjara. The patient's blood was used as the research material and immunoassay method was used as the general method. By the Researches was established the existence of some correlation in relation to gender and age. As a result of the conducted research, among the patients with autoimmune thyroiditis, there were more females than males. However, the disease was more often detected in the reproductive age. We researched patients from 18 to 70 years ages. In a total amount there were - 1104 patients investigated and the percentage of patients with autoimmune thyroiditis is 31%.

Diagnosis and Classification of Fistula from Inflammatory Bowel Disease and Inflammatory Bowel Disease-Related Surgery

Article

Sep 2022
Gastrointest Endosc Clin

Fistula in inflammatory bowel disease (IBD) is a well-known yet poorly understood phenotype. Pathophysiology is largely based on the activation of the epithelial-mesenchymal transition (EMT); however, interactions with the microbiome, genetics, mechanical stress and the presence of stricturing disease, and surgical complications play a role. Perianal penetrating disease represents a more severe phenotype in IBD. Pouch-associated fistula can arise as a result of an anastomotic leak, surgical complications, or Crohn's disease (CD) of the pouch. Classification is site-dependent, includes a range of severity, and informs management. It is important to determine associated symptoms and recognize the complex interplay of underlying etiologies to form the basis of appropriate care.

AGENTS INFECTIEUX & RUPTURE DE TOLÉRANCE LYMPHOCYTAIRE B: étude des processus de maturation d’affinité et de différenciation plasmocytaire au cours d’une infection bactérienne dans un nouveau modèle knock-in autoréactif

Thesis

Sep 2013

Sophie Jung

Les maladies auto-immunes, qui touchent plus de 5% de la population, sont induites par une perte de la tolérance aux antigènes du Soi. Ces pathologies, généralement multifactorielles, résultent de l’effet combiné de plusieurs allèles de susceptibilité et de différents facteurs environnementaux. Les agents infectieux ont été tout particulièrement incriminés, mais les mécanismes en jeu restent encore mal élucidés. Les lymphocytes B, qui jouent un rôle central dans la pathogénie de nombreuses maladies auto-immunes, sont susceptibles d’être activés selon différents mécanismes au cours d’un processus infectieux et cette activation peut englober des cellules autoréactives. On ne sait cependant pas si cette activation peut entraîner la production d’auto-anticorps pathogènes de forte affinité et d’isotype IgG à partir du pool de cellules productrices d’auto-anticorps naturels de faible affinité, qui sont présentes de façon constitutive dans le répertoire B de l’individu sain. Nous avons mis au point un nouveau modèle murin knock-in pour des lymphocytes B présentant une affinité intermédiaire pour leur auto-antigène, la protéine HEL2x mutée (Hen-Egg Lysozyme). Ce modèle autoréactif d’affinité intermédiaire SWHEL X HEL2x, élaboré sur un fond génétique non auto-immun, permet de suivre le processus de maturation d’affinité des cellules B anti-HEL en présence de leur auto-antigène HEL2x au cours de l’infection chronique par la bactérie Borrelia burgdorferi. L’infection induit au niveau ganglionnaire une prolifération ainsi qu’une activation lymphocytaire B incluant des cellules anergiques. Certains clones autoréactifs sont capables de gagner les centres germinatifs ganglionnaires, de commuter vers l’isotype IgG et présentent des mutations somatiques au niveau de la région variable de la chaîne lourde de leur immunoglobuline, dans la zone d’interaction avec HEL2x, indiquant un processus de sélection par l’auto-antigène. Malgré un taux augmenté d’auto-anticorps d’isotype IgM, ces animaux ne produisent pas de plasmocytes capables de sécréter des auto-anticorps d’isotype IgG. Nos observations suggèrent l’existence de mécanismes de tolérance périphérique intrinsèques mis en place en particulier au niveau du centre germinatif. Un premier point de contrôle va éliminer les lymphocytes B autoréactifs ayant commuté de classe et présentant des mutations somatiques leur conférant une affinité augmentée pour l’auto-antigène tandis qu’un second point de contrôle va empêcher la différenciation en plasmocytes IgG+. Chez l’individu non prédisposé génétiquement, des mécanismes pourraient ainsi permettre de prévenir le développement d’une auto-immunité pathogène au cours d’un épisode infectieux.

Transcriptome Profiling in Autoimmune Diseases

Chapter

Jan 2022

Autoimmune diseases are a group of different inflammatory disorders characterized by systemic or localized inflammation, affecting approximately 0.1–1% of the general population. Several studies suggest that genetic risk loci are shared between different autoimmune diseases and pathogenic mechanisms may also be shared. The strategy of performing differential gene expression profiles in autoimmune disorders has unveiled new transcripts that may be shared among these disorders. Microarray technology and bioinformatics offer the most comprehensive molecular evaluations and it is widely used to understand the changes in gene expression in specific organs or in peripheral blood cells. The major goal of transcriptome studies is the identification of specific biomarkers for different diseases. It is believed that such knowledge will contribute to the development of new drugs, new strategies for early diagnosis, avoiding tissue autoimmune destruction, or even preventing the development of autoimmune disease. In this review, we primarily focused on the transcription profiles of three typical autoimmune disorders, including type 1 diabetes mellitus (destruction of pancreatic islet beta cells), systemic lupus erythematosus (immune complex systemic disorder affecting several organs and tissues), and multiple sclerosis (inflammatory and demyelinating disease of the central nervous system).KeywordsAutoimmune diseasesDifferential gene expressionMicroarrayBioinformaticsBiomarkersType 1 diabetes mellitusSystemic lupus erythematosusMultiple sclerosisImmune systemImmunodeficiencySelf-antigensTolerance lossT cellsCell proliferationGenetic lociImmunological primingSex hormonesImmune responsesArbovirusCoronavirusZikaChikungunyaDengueRheumatological complicationsMultiple sclerosisNeuromyelitis opticaGuillain-Barré syndromeSARS-CoV2HLA haplotypesChromosomal locationLong noncoding RNA (lncRNA)B-cell insulin secretionmiRNAGlucose metabolismGender-related factorsBacterial infectionsUltra-violet radiationGenome-wide associationLinkageCytokine signaturesSusceptibility signatureNephritisInterferonPeripheral blood mononuclear cells (PBMC)Autoreactive T cellsMyelin-oligodendrocyte complexCNSMacrophage infiltrationDemyelinationGliosisAxonal lossGWAS studies

Gastrointestinal and hepatic manifestations of specific genetic disorders

Chapter

Feb 2022

Sonia S. Kupfer

This chapter aims to review the genetic basis for selected gastrointestinal and hepatic diseases. It puts genetics of gastrointestinal and hepatic disease into context. The spectrum of genetic associations from single‐gene Mendelian disorders to common complex, multigenic diseases is presented. Genome‐wide association studies involve typing common human genetic variation in large case–control cohorts; these studies have identified thousands of genetic associations, providing new insight into disease pathogenesis. Most human diseases have a genetic component to their pathogenesis, even infectious diseases typically regarded as diseases of environmental, and not genetic, causation. The extent to which genetic factors contribute to human disease can be considered to involve a continuum from pure Mendelian disorders (largely genetic causation) to infectious diseases where exposure to a given pathogen results, in most individuals, in similar disease manifestations (largely nongenetic causation).

The autoimmune disease-associated PTPN22 variant promotes calpain-mediated Lyp/Pep degradation associated with lymphocyte and dendritic cell hyperresponsiveness

Article

Full-text available

Aug 2011
Nat Genet

A variant of the PTPN22-encoded Lyp phosphatase (Lyp620W) confers risk for autoimmune disease, but the mechanisms underlying this association remain unclear. We show here that mice expressing the Lyp variant homolog Pep619W manifest thymic and splenic enlargement accompanied by increases in T-cell number, activation and positive selection and in dendritic- and B-cell activation. Although Ptpn22 (Pep) transcript levels were comparable in Pep619W and wild-type Pep619R mice, Pep protein levels were dramatically reduced in the mutant mice, with Pep619W protein being more rapidly degraded and showing greater association with and in vitro cleavage by calpain 1 than Pep619R. Similarly, levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R. Thus, calpain-mediated degradation with consequently reduced Lyp/Pep expression and lymphocyte and dendritic cell hyperresponsiveness represents a mechanism whereby Lyp620W may increase risk for autoimmune disease.

The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans

Article

Full-text available

Aug 2011
J CLIN INVEST

Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene polymorphisms are associated with many autoimmune diseases. The major risk allele encodes an R620W amino acid change that alters B cell receptor (BCR) signaling involved in the regulation of central B cell tolerance. To assess whether this PTPN22 risk allele affects the removal of developing autoreactive B cells, we tested by ELISA the reactivity of recombinant antibodies isolated from single B cells from asymptomatic healthy individuals carrying one or two PTPN22 risk allele(s) encoding the PTPN22 R620W variant. We found that new emigrant/transitional and mature naive B cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non-carriers, revealing defective central and peripheral B cell tolerance checkpoints. Hence, a single PTPN22 risk allele has a dominant effect on altering autoreactive B cell counterselection before any onset of autoimmunity. In addition, gene array experiments analyzing mature naive B cells displaying PTPN22 risk allele(s) revealed that the association strength of PTPN22 for autoimmunity may be due not only to the impaired removal of autoreactive B cells but also to the upregulation of genes such as CD40, TRAF1, and IRF5, which encode proteins that promote B cell activation and have been identified as susceptibility genes associated with autoimmune diseases. These data demonstrate that early B cell tolerance defects in autoimmunity can result from specific polymorphisms and precede the onset of disease.

Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handling in the mechanism for HLA-B27 in disease susceptibility

Article

Full-text available

Jul 2011
Nat Genet

Ankylosing spondylitis is a common form of inflammatory arthritis predominantly affecting the spine and pelvis that occurs in approximately 5 out of 1,000 adults of European descent. Here we report the identification of three variants in the RUNX3, LTBR-TNFRSF1A and IL12B regions convincingly associated with ankylosing spondylitis (P < 5 × 10(-8) in the combined discovery and replication datasets) and a further four loci at PTGER4, TBKBP1, ANTXR2 and CARD9 that show strong association across all our datasets (P < 5 × 10(-6) overall, with support in each of the three datasets studied). We also show that polymorphisms of ERAP1, which encodes an endoplasmic reticulum aminopeptidase involved in peptide trimming before HLA class I presentation, only affect ankylosing spondylitis risk in HLA-B27-positive individuals. These findings provide strong evidence that HLA-B27 operates in ankylosing spondylitis through a mechanism involving aberrant processing of antigenic peptides.

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

Article

Full-text available

Mar 2011
Nat Genet

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P < 5 × 10⁻⁸) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

Meta-Analysis of Genome-Wide Association Studies in Celiac Disease and Rheumatoid Arthritis Identifies Fourteen Non-HLA Shared Loci

Article

Full-text available

Feb 2011
PLOS GENET

Epidemiology and candidate gene studies indicate a shared genetic basis for celiac disease (CD) and rheumatoid arthritis (RA), but the extent of this sharing has not been systematically explored. Previous studies demonstrate that 6 of the established non-HLA CD and RA risk loci (out of 26 loci for each disease) are shared between both diseases. We hypothesized that there are additional shared risk alleles and that combining genome-wide association study (GWAS) data from each disease would increase power to identify these shared risk alleles. We performed a meta-analysis of two published GWAS on CD (4,533 cases and 10,750 controls) and RA (5,539 cases and 17,231 controls). After genotyping the top associated SNPs in 2,169 CD cases and 2,255 controls, and 2,845 RA cases and 4,944 controls, 8 additional SNPs demonstrated P<5 × 10(-8) in a combined analysis of all 50,266 samples, including four SNPs that have not been previously confirmed in either disease: rs10892279 near the DDX6 gene (P(combined) = 1.2 × 10(-12)), rs864537 near CD247 (P(combined) = 2.2 × 10(-11)), rs2298428 near UBE2L3 (P(combined) = 2.5 × 10(-10)), and rs11203203 near UBASH3A (P(combined) = 1.1 × 10(-8)). We also confirmed that 4 gene loci previously established in either CD or RA are associated with the other autoimmune disease at combined P<5 × 10(-8) (SH2B3, 8q24, STAT4, and TRAF1-C5). From the 14 shared gene loci, 7 SNPs showed a genome-wide significant effect on expression of one or more transcripts in the linkage disequilibrium (LD) block around the SNP. These associations implicate antigen presentation and T-cell activation as a shared mechanism of disease pathogenesis and underscore the utility of cross-disease meta-analysis for identification of genetic risk factors with pleiotropic effects between two clinically distinct diseases.

Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47

Article

Full-text available

Feb 2011
Nat Genet

Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 × 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis.

Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci

Article

Full-text available

Dec 2010
Nat Genet

We undertook a meta-analysis of six Crohn's disease genome-wide association studies (GWAS) comprising 6,333 affected individuals (cases) and 15,056 controls and followed up the top association signals in 15,694 cases, 14,026 controls and 414 parent-offspring trios. We identified 30 new susceptibility loci meeting genome-wide significance (P < 5 × 10⁻⁸). A series of in silico analyses highlighted particular genes within these loci and, together with manual curation, implicated functionally interesting candidate genes including SMAD3, ERAP2, IL10, IL2RA, TYK2, FUT2, DNMT3A, DENND1B, BACH2 and TAGAP. Combined with previously confirmed loci, these results identify 71 distinct loci with genome-wide significant evidence for association with Crohn's disease.

A genome-wide asociation study identifies new psoriasis susceptibility loci and an interaction betwEn HLA-C and ERAP1

Article

Full-text available

Nov 2010
Nat Genet

To identify new susceptibility loci for psoriasis, we undertook a genome-wide association study of 594,224 SNPs in 2,622 individuals with psoriasis and 5,667 controls. We identified associations at eight previously unreported genomic loci. Seven loci harbored genes with recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2). These associations were replicated in 9,079 European samples (six loci with a combined P < 5 × 10⁻⁸ and two loci with a combined P < 5 × 10⁻⁷). We also report compelling evidence for an interaction between the HLA-C and ERAP1 loci (combined P = 6.95 × 10⁻⁶). ERAP1 plays an important role in MHC class I peptide processing. ERAP1 variants only influenced psoriasis susceptibility in individuals carrying the HLA-C risk allele. Our findings implicate pathways that integrate epidermal barrier dysfunction with innate and adaptive immune dysregulation in psoriasis pathogenesis.

ASociation analyses identify six new psoriasis susceptibility loci in the Chinese population

Article

Full-text available

Nov 2010
Nat Genet

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻⁸) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

CoMon variants at TRAF3IP2 are aSociated with susceptibility to psoriatic arthritis and psoriasis

Article

Full-text available

Nov 2010
Nat Genet

Psoriatic arthritis (PsA) is an inflammatory joint disease that is distinct from other chronic arthritides and which is frequently accompanied by psoriasis vulgaris (PsV) and seronegativity for rheumatoid factor. We conducted a genome-wide association study in 609 German individuals with PsA (cases) and 990 controls with replication in 6 European cohorts including a total of 5,488 individuals. We replicated PsA associations at HLA-C and IL12B and identified a new association at TRAF3IP2 (rs13190932, P = 8.56 × 10⁻¹⁷). TRAF3IP2 was also associated with PsV in a German cohort including 2,040 individuals (rs13190932, P = 1.95 × 10⁻³). Sequencing of the exons of TRAF3IP2 identified a coding variant (p.Asp10Asn, rs33980500) as the most significantly associated SNP (P = 1.13 × 10⁻²⁰, odds ratio = 1.95). Functional assays showed reduced binding of this TRAF3IP2 variant to TRAF6, suggesting altered modulation of immunoregulatory signals through altered TRAF interactions as a new and shared pathway for PsA and PsV.

Association of IFIH1 and other autoimmunity risk alleles with selective IgA deficiency

Article

Full-text available

Sep 2010
Nat Genet

To understand the genetic predisposition to selective immunoglobulin A deficiency (IgAD), we performed a genome-wide association study in 430 affected individuals (cases) from Sweden and Iceland and 1,090 ethnically matched controls, and we performed replication studies in two independent European cohorts. In addition to the known association of HLA with IgAD, we identified association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previously associated with type 1 diabetes and systemic lupus erythematosus. Variants in CLEC16A, another known autoimmunity locus, showed suggestive evidence for association (rs6498142C>G, P = 1.8 x 10(-7)), and 29 additional loci were identified with P < 5 x 10(-5). A survey in IgAD of 118 validated non-HLA autoimmunity loci indicated a significant enrichment for association with autoimmunity loci as compared to non-autoimmunity loci (P = 9.0 x 10(-4)) or random SNPs across the genome (P < 0.0001). These findings support the hypothesis that autoimmune mechanisms may contribute to the pathogenesis of IgAD.

Occupational and environmental exposures and risk of systemic lupus erythematosus: Silica, sunlight, solvents

Article

Full-text available

Nov 2010

We examined occupational and non-occupational exposures in relation to risk of SLE in a case-control study conducted through the Canadian Network for Improved Outcomes in SLE (CaNIOS). SLE cases (n = 258) were recruited from 11 rheumatology centres across Canada. Controls (without SLE, n = 263) were randomly selected from phone number listings and matched to cases by age, sex and area of residence. Data were collected using a structured telephone interview. An association was seen with outdoor work in the 12 months preceding diagnosis [odds ratio (OR) 2.0; 95% CI 1.1, 3.8]; effect modification by sun reaction was suggested, with the strongest effect among people who reported reacting to midday sun with a blistering sunburn or a rash (OR 7.9; 95% CI 0.97, 64.7). Relatively strong but imprecise associations were seen with work as an artist working with paints, dyes or developing film (OR 3.9; 95% CI 1.3, 12.3) and work that included applying nail polish or nail applications (OR 10.2; 95% CI 1.3, 81.5). Patients were more likely than controls to report participation in pottery or ceramics work as a leisure activity, with an increased risk among individuals with a total frequency of at least 26 days (OR 2.1; 95% CI 1.1, 3.9). Analyses of potential respirable silica exposures suggested an exposure-response gradient (OR 1.0, 1.4. and 2.1 for zero, one and two or more sources of exposure, respectively; trend test P < 0.01). This study supports the role of specific occupational and non-occupational exposures in the development of SLE.

Genome-wide meta-analyses identify three loci associated with primary biliary cirrhosis

Article

Full-text available

Aug 2010
Nat Genet

A genome-wide association screen for primary biliary cirrhosis risk alleles was performed in an Italian cohort. The results from the Italian cohort replicated IL12A and IL12RB associations, and a combined meta-analysis using a Canadian dataset identified newly associated loci at SPIB (P = 7.9 x 10(-11), odds ratio (OR) = 1.46), IRF5-TNPO3 (P = 2.8 x 10(-10), OR = 1.63) and 17q12-21 (P = 1.7 x 10(-10), OR = 1.38).

Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis

Article

Full-text available

Aug 2010
Nat Genet

We genotyped individuals with primary biliary cirrhosis and unaffected controls for suggestive risk loci (genome-wide association P < 1 x 10(-4)) identified in a previous genome-wide association study. Combined analysis of the genome-wide association and replication datasets identified IRF5-TNPO3 (combined P = 8.66 x 10(-13)), 17q12-21 (combined P = 3.50 x 10(-13)) and MMEL1 (combined P = 3.15 x 10(-8)) as new primary biliary cirrhosis susceptibility loci. Fine-mapping studies showed that a single variant accounts for the IRF5-TNPO3 association. As these loci are implicated in other autoimmune conditions, these findings confirm genetic overlap among such diseases.

Genome-wide association study in alopecia areata implicates both innate and adaptive immunity

Article

Full-text available

Jul 2010
NATURE

Alopecia areata (AA) is among the most highly prevalent human autoimmune diseases, leading to disfiguring hair loss due to the collapse of immune privilege of the hair follicle and subsequent autoimmune attack. The genetic basis of AA is largely unknown. We undertook a genome-wide association study (GWAS) in a sample of 1,054 cases and 3,278 controls and identified 139 single nucleotide polymorphisms that are significantly associated with AA (P <or= 5 x 10(-7)). Here we show an association with genomic regions containing several genes controlling the activation and proliferation of regulatory T cells (T(reg) cells), cytotoxic T lymphocyte-associated antigen 4 (CTLA4), interleukin (IL)-2/IL-21, IL-2 receptor A (IL-2RA; CD25) and Eos (also known as Ikaros family zinc finger 4; IKZF4), as well as the human leukocyte antigen (HLA) region. We also find association evidence for regions containing genes expressed in the hair follicle itself (PRDX5 and STX17). A region of strong association resides within the ULBP (cytomegalovirus UL16-binding protein) gene cluster on chromosome 6q25.1, encoding activating ligands of the natural killer cell receptor NKG2D that have not previously been implicated in an autoimmune disease. By probing the role of ULBP3 in disease pathogenesis, we also show that its expression in lesional scalp from patients with AA is markedly upregulated in the hair follicle dermal sheath during active disease. This study provides evidence for the involvement of both innate and acquired immunity in the pathogenesis of AA. We have defined the genetic underpinnings of AA, placing it within the context of shared pathways among autoimmune diseases, and implicating a novel disease mechanism, the upregulation of ULBP ligands, in triggering autoimmunity.

Functionally defective germline variants of sialic acid acetylesterase in autoimmunity

Article

Full-text available

Jul 2010
NATURE

Sialic acid acetylesterase (SIAE) is an enzyme that negatively regulates B lymphocyte antigen receptor signalling and is required for the maintenance of immunological tolerance in mice. Heterozygous loss-of-function germline rare variants and a homozygous defective polymorphic variant of SIAE were identified in 24/923 subjects of European origin with relatively common autoimmune disorders and in 2/648 controls of European origin. All heterozygous loss-of-function SIAE mutations tested were capable of functioning in a dominant negative manner. A homozygous secretion-defective polymorphic variant of SIAE was catalytically active, lacked the ability to function in a dominant negative manner, and was seen in eight autoimmune subjects but in no control subjects. The odds ratio for inheriting defective SIAE alleles was 8.6 in all autoimmune subjects, 8.3 in subjects with rheumatoid arthritis, and 7.9 in subjects with type I diabetes. Functionally defective SIAE rare and polymorphic variants represent a strong genetic link to susceptibility in relatively common human autoimmune disorders.

Common variants in FOXP1 are associated with generalized vitiligo

Article

Full-text available

Jul 2010
Nat Genet

In a recent genome-wide association study of generalized vitiligo, we identified ten confirmed susceptibility loci. By testing additional loci that showed suggestive association in the genome-wide study, using two replication cohorts of European descent, we observed replicated association of generalized vitiligo with variants at 3p13 encompassing FOXP1 (rs17008723, combined P=1.04x10(-8)) and with variants at 6q27 encompassing CCR6 (rs6902119, combined P=3.94x10(-7)).

Viewpoint: Missing heritability and strategies for finding the underlying causes of complex disease

Article

Full-text available

Jun 2010
NAT REV GENET

Although recent genome-wide studies have provided valuable insights into the genetic basis of human disease, they have explained relatively little of the heritability of most complex traits, and the variants identified through these studies have small effect sizes. This has led to the important and hotly debated issue of where the 'missing heritability' of complex diseases might be found. Here, seven leading geneticists offer their opinion about where this heritability is likely to lie, what this could tell us about the underlying genetic architecture of common diseases and how this could inform research strategies for uncovering genetic risk factors.

Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci

Article

Full-text available

Jun 2010
Nat Genet

To identify new genetic risk factors for rheumatoid arthritis, we conducted a genome-wide association study meta-analysis of 5,539 autoantibody-positive individuals with rheumatoid arthritis (cases) and 20,169 controls of European descent, followed by replication in an independent set of 6,768 rheumatoid arthritis cases and 8,806 controls. Of 34 SNPs selected for replication, 7 new rheumatoid arthritis risk alleles were identified at genome-wide significance (P < 5 x 10(-8)) in an analysis of all 41,282 samples. The associated SNPs are near genes of known immune function, including IL6ST, SPRED2, RBPJ, CCR6, IRF5 and PXK. We also refined associations at two established rheumatoid arthritis risk loci (IL2RA and CCL21) and confirmed the association at AFF3. These new associations bring the total number of confirmed rheumatoid arthritis risk loci to 31 among individuals of European ancestry. An additional 11 SNPs replicated at P < 0.05, many of which are validated autoimmune risk alleles, suggesting that most represent genuine rheumatoid arthritis risk alleles.

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

Article

Full-text available

Aug 2009
Nat Genet

To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Variant of TYR and Autoimmunity Susceptibility Loci in Generalized Vitiligo

Article

Full-text available

May 2010
NEW ENGL J MED

Generalized vitiligo is an autoimmune disease characterized by melanocyte loss, which results in patchy depigmentation of skin and hair, and is associated with an elevated risk of other autoimmune diseases. To identify generalized vitiligo susceptibility loci, we conducted a genomewide association study. We genotyped 579,146 single-nucleotide polymorphisms (SNPs) in 1514 patients with generalized vitiligo who were of European-derived white (CEU) ancestry and compared the genotypes with publicly available control genotypes from 2813 CEU persons. We then tested 50 SNPs in two replication sets, one comprising 677 independent CEU patients and 1106 CEU controls and the other comprising 183 CEU simplex trios with generalized vitiligo and 332 CEU multiplex families. We detected significant associations between generalized vitiligo and SNPs at several loci previously associated with other autoimmune diseases. These included genes encoding major-histocompatibility-complex class I molecules (P=9.05x10(-23)) and class II molecules (P=4.50x10(-34)), PTPN22 (P=1.31x10(-7)), LPP (P=1.01x10(-11)), IL2RA (P=2.78x10(-9)), UBASH3A (P=1.26x10(-9)), and C1QTNF6 (P=2.21x10(-16)). We also detected associations between generalized vitiligo and SNPs in two additional immune-related loci, RERE (P=7.07x10(-15)) and GZMB (P=3.44x10(-8)), and in a locus containing TYR (P=1.60x10(-18)), encoding tyrosinase. We observed associations between generalized vitiligo and markers implicating multiple genes, some associated with other autoimmune diseases and one (TYR) that may mediate target-cell specificity and indicate a mutually exclusive relationship between susceptibility to vitiligo and susceptibility to melanoma.

Corrigendum: Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus

Article

Full-text available

Apr 2010
Nat Genet

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs that leads to profound disability and premature death. To identify new SSc susceptibility loci, we conducted the first genome-wide association study in a population of European ancestry including a total of 2,296 individuals with SSc and 5,171 controls. Analysis of 279,621 autosomal SNPs followed by replication testing in an independent case-control set of European ancestry (2,753 individuals with SSc (cases) and 4,569 controls) identified a new susceptibility locus for systemic sclerosis at CD247 (1q22-23, rs2056626, P = 2.09 x 10(-7) in the discovery samples, P = 3.39 x 10(-9) in the combined analysis). Additionally, we confirm and firmly establish the role of the MHC (P = 2.31 x 10(-18)), IRF5 (P = 1.86 x 10(-13)) and STAT4 (P = 3.37 x 10(-9)) gene regions as SSc genetic risk factors.

Comparison of Ustekinumab and Etanercept for Moderate-to-Severe Psoriasis

Article

Full-text available

Jan 2010
NEW ENGL J MED

Biologic agents offer a range of new therapeutic options for patients with psoriasis; however, the relative benefit-risk profiles of such therapies are not well known. We compared two biologic agents, ustekinumab (an interleukin-12 and interleukin-23 blocker) and etanercept (an inhibitor of tumor necrosis factor alpha), for the treatment of psoriasis. We randomly assigned 903 patients with moderate-to-severe psoriasis to receive subcutaneous injections of either 45 or 90 mg of ustekinumab (at weeks 0 and 4) or high-dose etanercept (50 mg twice weekly for 12 weeks). The primary end point was the proportion of patients with at least 75% improvement in the psoriasis area-and-severity index (PASI) at week 12; a secondary end point was the proportion with cleared or minimal disease on the basis of the physician's global assessment. Assessors were unaware of the treatment assignments. The efficacy and safety of a crossover from etanercept to ustekinumab were evaluated after week 12. There was at least 75% improvement in the PASI at week 12 in 67.5% of patients who received 45 mg of ustekinumab and 73.8% of patients who received 90 mg, as compared with 56.8% of those who received etanercept (P=0.01 and P<0.001, respectively). Similarly, 65.1% of patients who received 45 mg of ustekinumab and 70.6% of patients who received 90 mg of ustekinumab had cleared or minimal disease according to the physician's global assessment, as compared with 49.0% of those who received etanercept (P<0.001 for both comparisons). Among patients who did not have a response to etanercept, 48.9% had at least 75% improvement in the PASI within 12 weeks after crossover to ustekinumab. One or more adverse events occurred through week 12 in 66.0% of patients who received 45 mg of ustekinumab and 69.2% of patients who received 90 mg of ustekinumab and in 70.0% who received etanercept; 1.9%, 1.2%, and 1.2%, respectively, had serious adverse events. Safety patterns were similar before and after crossover from etanercept to ustekinumab. The efficacy of ustekinumab at a dose of 45 or 90 mg was superior to that of high-dose etanercept over a 12-week period in patients with psoriasis. (ClinicalTrials.gov number, NCT00454584.)

Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci

Article

Full-text available

Feb 2010
Nat Genet

To identify susceptibility loci for ankylosing spondylitis, we undertook a genome-wide association study in 2,053 unrelated ankylosing spondylitis cases among people of European descent and 5,140 ethnically matched controls, with replication in an independent cohort of 898 ankylosing spondylitis cases and 1,518 controls. Cases were genotyped with Illumina HumHap370 genotyping chips. In addition to strong association with the major histocompatibility complex (MHC; P < 10(-800)), we found association with SNPs in two gene deserts at 2p15 (rs10865331; combined P = 1.9 x 10(-19)) and 21q22 (rs2242944; P = 8.3 x 10(-20)), as well as in the genes ANTXR2 (rs4333130; P = 9.3 x 10(-8)) and IL1R2 (rs2310173; P = 4.8 x 10(-7)). We also replicated previously reported associations at IL23R (rs11209026; P = 9.1 x 10(-14)) and ERAP1 (rs27434; P = 5.3 x 10(-12)). This study reports four genetic loci associated with ankylosing spondylitis risk and identifies a major role for the interleukin (IL)-23 and IL-1 cytokine pathways in disease susceptibility.

Type I interferons: Crucial participants in disease amplification in autoimmunity

Article

Full-text available

Jan 2010
NAT REV RHEUMATOL

A significant body of data implicates the type I interferon (IFN) pathway in the pathogenesis of autoimmune rheumatic diseases. In these disorders, a self-reinforcing cycle of IFN production can contribute to immunopathology through multiple mechanisms. Type I IFN cytokines are pleiotropic in their effects, mediating antiviral and antitumor activities, and possess numerous immunomodulatory functions for both the innate and adaptive immune responses. A key principle of the type I IFN system is rapid induction and amplification of the signaling pathway, which generates a feed-forward loop of IFN production, ensuring that a vigorous antiviral immune response is mounted. Although such feed-forward pathways are highly adaptive when it comes to rapid and effective virus eradication, this amplification can be maladaptive in immune responses directed against host tissues. Such feed-forward loops, however, create special opportunities for therapy.

Checkpoints in lymphocyte development and autoimmune disease

Article

Full-text available

Jan 2010
NAT IMMUNOL

Antigen receptor-controlled checkpoints in B lymphocyte development are crucial for the prevention of autoimmune diseases such as systemic lupus erythematosus. Checkpoints at the stage of pre-B cell receptor (pre-BCR) and BCR expression can eliminate certain autoreactive BCRs either by deletion of or anergy induction in cells expressing autoreactive BCRs or by receptor editing. For T cells, the picture is more complex because there are regulatory T (T(reg)) cells that mediate dominant tolerance, which differs from the recessive tolerance mediated by deletion and anergy. Negative selection of thymocytes may be as essential as T(reg) cell generation in preventing autoimmune diseases such as type 1 diabetes, but supporting evidence is scarce. Here we discuss several scenarios in which failures at developmental checkpoints result in autoimmunity.

Regulatory T cells exert checks and balances on self tolerance and autoimmunity

Article

Full-text available

Jan 2010
NAT IMMUNOL

Immunological self tolerance is maintained at least in part by regulatory T (T(reg)) cells that actively and dominantly control potentially hazardous self-reactive T cells in the periphery. Antigens that stimulate self-reactive T cells may also activate natural T(reg) cells, thereby maintaining dominant self tolerance. Conversely, genetic anomalies or environmental agents that specifically or predominantly affect T(reg) cells cause or predispose to autoimmunity. With recent advances in our understanding of T(reg) cell development in the thymus and periphery and the molecular mechanism of T(reg) cell-mediated suppression, new ways of treating immunological diseases by targeting T(reg) cells at the cellular and molecular levels are envisaged.

A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus

Article

Full-text available

Nov 2009
Nat Genet

Genome-wide association studies have recently identified at least 15 susceptibility loci for systemic lupus erythematosus (SLE). To confirm additional risk loci, we selected SNPs from 2,466 regions that showed nominal evidence of association to SLE (P < 0.05) in a genome-wide study and genotyped them in an independent sample of 1,963 cases and 4,329 controls. This replication effort identified five new SLE susceptibility loci (P < 5 x 10(-8)): TNIP1 (odds ratio (OR) = 1.27), PRDM1 (OR = 1.20), JAZF1 (OR = 1.20), UHRF1BP1 (OR = 1.17) and IL10 (OR = 1.19). We identified 21 additional candidate loci with P< or = 1 x 10(-5). A candidate screen of alleles previously associated with other autoimmune diseases suggested five loci (P < 1 x 10(-3)) that may contribute to SLE: IFIH1, CFB, CLEC16A, IL12B and SH2B3. These results expand the number of confirmed and candidate SLE susceptibility loci and implicate several key immunologic pathways in SLE pathogenesis.

Genome-wide association study in a Chinese Han population identifies nine new susceptibility loci for systemic lupus erythematosus

Article

Full-text available

Nov 2009
Nat Genet

We performed a genome-wide association study (GWAS) of systemic lupus erythematosus (SLE) in a Chinese Han population by genotyping 1,047 cases and 1,205 controls using Illumina Human610-Quad BeadChips and replicating 78 SNPs in two additional cohorts (3,152 cases and 7,050 controls). We identified nine new susceptibility loci (ETS1, IKZF1, RASGRP3, SLC15A4, TNIP1, 7q11.23, 10q11.22, 11q23.3 and 16p11.2; 1.77 x 10(-25) < or = P(combined) < or = 2.77 x 10(-8)) and confirmed seven previously reported loci (BLK, IRF5, STAT4, TNFAIP3, TNFSF4, 6q21 and 22q11.21; 5.17 x 10(-42) < or = P(combined) < or = 5.18 x 10(-12)). Comparison with previous GWAS findings highlighted the genetic heterogeneity of SLE susceptibility between Chinese Han and European populations. This study not only advances our understanding of the genetic basis of SLE but also highlights the value of performing GWAS in diverse ancestral populations.

Finding the missing heritability of complex diseases

Article

Full-text available

Oct 2009
NATURE

Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.

Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource

Article

Full-text available

Oct 2009
Nat Genet

Genome-wide association studies (GWAS) have identified over 300 regions associated with more than 70 common diseases. However, identifying causal genes within an associated region remains a major challenge. One approach to resolving causal genes is through the dissection of gene-phenotype correlations. Here we use polychromatic flow cytometry to show that differences in surface expression of the human interleukin-2 (IL-2) receptor alpha (IL2RA, or CD25) protein are restricted to particular immune cell types and correlate with several haplotypes in the IL2RA region that have previously been associated with two autoimmune diseases, type 1 diabetes (T1D) and multiple sclerosis. We confirm our strongest gene-phenotype correlation at the RNA level by allele-specific expression (ASE). We also define key parameters for the design and implementation of post-GWAS gene-phenotype investigations and demonstrate the usefulness of a large bioresource of genotype-selectable normal donors from whom fresh, primary cells can be analyzed.

Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci

Article

Full-text available

Aug 2009
Nat Genet

We report the results of a meta-analysis of genome-wide association scans for multiple sclerosis (MS) susceptibility that includes 2,624 subjects with MS and 7,220 control subjects. Replication in an independent set of 2,215 subjects with MS and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 x 10(-11)), IRF8 (P = 3.73 x 10(-9)) and CD6 (P = 3.79 x 10(-9)). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is associated with higher mRNA expression of interferon-response pathway genes in subjects with MS.

Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

Article

Full-text available

May 2009
Nat Genet

Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10(-6)). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10(-8)) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

Genetics of Type 1A Diabetes

Article

Full-text available

May 2009
NEW ENGL J MED

Genetic contributions to the cause of type 1 diabetes have been studied for more than 30 years, but only recently, with modern genetic tools, has the importance of seemingly minor contributors been appreciated. This article reviews recent advances in knowledge of the genetics of type 1 diabetes and shows how this information could find clinical applications of considerable consequence.

The Major Histocompatibility Complex

Article

Jul 2011

Peter K. Gregersen

Autoantibodies before the clinical onset of systemic lupus erythematosus - The authors reply

Article

Jan 2004

A new model for an etiology of rheumatoid arthritis: Smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination

Article

Jan 2006
ARTHRIT RHEUM-ARTHR

Objective To investigate whether smoking and HLA–DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline-modified proteins.Methods In a case–control study involving patients with recent-onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk factor (smoking), major susceptibility genes included in the SE of HLA–DR, and the presence of the most specific autoimmunity known for RA (i.e., antibodies to proteins modified by citrullination). Immunostaining for citrullinated proteins in cells from bronchoalveolar lavage fluid was used to investigate whether smoking is associated with citrullination in the lungs.ResultsPrevious smoking was dose-dependently associated with occurrence of anticitrulline antibodies in RA patients. The presence of SE genes was a risk factor only for anticitrulline-positive RA, and not for anticitrulline-negative RA. A major gene–environment interaction between smoking and HLA–DR SE genes was evident for anticitrulline-positive RA, but not for anticitrulline-negative RA, and the combination of smoking history and the presence of double copies of HLA–DR SE genes increased the risk for RA 21-fold compared with the risk among nonsmokers carrying no SE genes. Positive immunostaining for citrullinated proteins was recorded in bronchoalveolar lavage cells from smokers but not in those from nonsmokers.Conclusion We identified an environmental factor, smoking, that in the context of HLA–DR SE genes may trigger RA-specific immune reactions to citrullinated proteins. These data thus suggest an etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity, all restricted to a distinct subset of RA.

Macrophages from IBD patients exhibit defective tumour necrosis factor-alpha secretion but otherwise normal or augmented pro-inflammatory responses to infection

Article

Aug 2011

Defects in macrophage function have been implicated in the establishment of Crohn's disease (CD). However, the response of macrophages from CD patients to live bacteria, particularly Mycobacterium avium subsp. paratuberculosis (MAP), has not been addressed. Considering MAP has long been associated to CD, our objective was to assess whether macrophages from CD patients showed impaired inflammatory response to infection by MAP comparing to M. avium subsp. avium (MA) and other live intestinal commensal bacteria. Human peripheral blood monocyte-derived macrophages were obtained from CD patients, ulcerative colitis (UC) patients and controls. Following in vitro infection with MAP, MA, Escherichia coli or Enterococcus faecalis, cytokine levels and cell surface receptor expression were evaluated at different time points. Macrophages from CD patients showed impaired TNF-α secretion in response to bacterial challenge, but augmented IL-23 secretion and preserved IL-12 secretion and CD-40 expression. In addition, CD macrophages showed low IL-10 secretion. Macrophages from IBD patients showed increased expression of TLR-2 and -4, unaffected by infection. Differences in cytokine secretion observed after bacterial challenge were not MAP-specific, as other bacteria (E. coli and MA) showed similar effects. Macrophages from UC patients showed a less compromised TNF-α synthesis in response to mycobacterial infection than CD macrophages, with increased constitutive IL-12 secretion, and preserved IL-10 secretion. The increased IL-23 levels in response to infection and decreased IL-10 production observed in macrophages from CD patients may contribute to the inflammatory exacerbation observed in those patients.

Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC

Article

Jul 2010
Nat Genet

We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined=1.48x10(-48), OR=1.90; rs9468925, Pcombined=2.21x10(-33), OR=0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined=9.72x10(-17), OR=1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.

A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility

Article

Jun 2010

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here, through a genome-wide association study of rheumatoid arthritis, we identified a polymorphism in CCR6, the gene encoding chemokine (C-C motif) receptor 6 (a surface marker for Th17 cells) at 6q27, that was associated with rheumatoid arthritis susceptibility and was validated in two independent replication cohorts from Japan (rs3093024, a total of 7,069 individuals with rheumatoid arthritis (cases) and 20,727 controls, overall odds ratio = 1.19, P = 7.7 x 10(-19)). We identified a triallelic dinucleotide polymorphism of CCR6 (CCR6DNP) in strong linkage disequilibrium with rs3093024 that showed effects on gene transcription. The CCR6DNP genotype was correlated with the expression level of CCR6 and was associated with the presence of interleukin-17 (IL-17) in the sera of subjects with rheumatoid arthritis. Moreover, CCR6DNP was associated with susceptibility to Graves' and Crohn's diseases. These results suggest that CCR6 is critically involved in IL-17-driven autoimmunity in human diseases.

Recent advances in the genetics of systemic lupus erythematosus

Article

May 2010
Expet Rev Clin Immunol

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of antinuclear autoantibodies and the inflammatory infiltration of many organ systems. SLE is a complex disorder in which multiple genetic variants, together with environmental and hormonal factors, contribute to disease risk. In this article, we summarize our current understanding of the genetic contribution to SLE in light of recent genome-wide association studies, which have brought the total number of confirmed SLE susceptibility loci to 29. In the second section, we explore the functional implications of these risk loci and, in particular, highlight the role that many of these genes play in the Toll-like receptor and type I interferon signaling pathways. Finally, we discuss the genetic overlap between SLE and other autoimmune and inflammatory conditions as several risk loci are shared among multiple disorders, suggesting common underlying pathogenic mechanisms.

Kinase inhibitors attract attention as oral rheumatoid arthritis drugs

Article

Apr 2010
NAT REV DRUG DISCOV

Alisa Opar

Biologics currently dominate the market for disease-modifying drugs for rheumatoid arthritis, but companies are betting that there is room for next-generation oral drugs that target protein kinases.

Rheumatoid Arthritis Risk Allele PTPRC Is Also Associated With Response to Anti-Tumor Necrosis Factor alpha Therapy

Article

Mar 2010
ARTHRIT RHEUM-ARTHR

Anti-tumor necrosis factor alpha (anti-TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). The aim of the present study was to test established RA genetic risk factors to determine whether the same alleles also influence the response to anti-TNF therapy. A total of 1,283 RA patients receiving etanercept, infliximab, or adalimumab therapy were studied from among an international collaborative consortium of 9 different RA cohorts. The primary end point compared RA patients with a good treatment response according to the European League Against Rheumatism (EULAR) response criteria (n = 505) with RA patients considered to be nonresponders (n = 316). The secondary end point was the change from baseline in the level of disease activity according to the Disease Activity Score in 28 joints (triangle upDAS28). Clinical factors such as age, sex, and concomitant medications were tested as possible correlates of treatment response. Thirty-one single-nucleotide polymorphisms (SNPs) associated with the risk of RA were genotyped and tested for any association with treatment response, using univariate and multivariate logistic regression models. Of the 31 RA-associated risk alleles, a SNP at the PTPRC (also known as CD45) gene locus (rs10919563) was associated with the primary end point, a EULAR good response versus no response (odds ratio [OR] 0.55, P = 0.0001 in the multivariate model). Similar results were obtained using the secondary end point, the triangle upDAS28 (P = 0.0002). There was suggestive evidence of a stronger association in autoantibody-positive patients with RA (OR 0.55, 95% confidence interval [95% CI] 0.39-0.76) as compared with autoantibody-negative patients (OR 0.90, 95% CI 0.41-1.99). Statistically significant associations were observed between the response to anti-TNF therapy and an RA risk allele at the PTPRC gene locus. Additional studies will be required to replicate this finding in additional patient collections.

Inflammatory Bowel Disease

Article

Nov 2009
NEW ENGL J MED

Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis

Article

Nov 2009
Nat Genet

Gene-environment associations are important in rheumatoid arthritis (RA) susceptibility, with an association existing between smoking, HLA- DRB1 'shared epitope' alleles, PTPN22 and antibodies to cyclic citrullinated peptides (CCP). Here, we test the hypothesis that a subset of the anti-CCP response, with specific autoimmunity to citrullinated alpha-enolase, accounts for an important portion of these associations. In 1,497 individuals from three RA cohorts, antibodies to the immunodominant citrullinated alpha-enolase CEP-1 epitope were detected in 43-63% of the anti-CCP-positive individuals, and this subset was preferentially linked to HLA-DRB1*04. In a case-control analysis of 1,000 affected individuals and 872 controls, the combined effect of shared epitope, PTPN22 and smoking showed the strongest association with the anti-CEP-1-positive subset (odds ratio (OR) of 37, compared to an OR of 2 for the corresponding anti-CEP-1-negative, anti-CCP-positive subset). We conclude that citrullinated alpha-enolase is a specific citrullinated autoantigen that links smoking to genetic risk factors in the development of RA.

Emerging new pathways of pathogenesis and targets for treatment in systemic lupus erythematosus and Sjogren's syndrome

Article

Aug 2009
CURR OPIN RHEUMATOL

Andras Perl

Systemic lupus erythematosus (SLE) and Sjogren's syndrome are chronic inflammatory diseases characterized by the dysfunction of T cells, B cells, and dendritic cells and the production of antinuclear autoantibodies. Here, we evaluate newly discovered molecular and cellular targets for the treatment of SLE and Sjogren's syndrome. The mammalian target of rapamycin in T and B cells has been successfully targeted for treatment of SLE with rapamycin or sirolimus both in patients and animal models. Inhibition of oxidative stress, nitric oxide production, interferon alpha, toll-like receptors 7 and 9, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, and the nuclear factor kappa B pathway showed efficacy in animal models of lupus. B-cell depletion and blockade of anti-DNA antibodies and T-B cell interaction have shown success in animal models, whereas human studies have so far failed to accomplish clinical endpoints, possibly due to inadequacies in study design. Discovery of novel genes and signaling pathways in lupus pathogenesis offers novel biomarker-targeted approaches for treatment of SLE and Sjogren's syndrome.

Association of PTPN22 gene functional variants with development of pulmonary tuberculosis in Moroccan population

Article

Jul 2009
TISSUE ANTIGENS

Mycobacterium tuberculosis, the causal agent of pulmonary tuberculosis (TB), remains a major health problem throughout the world causing high mortality in humans. Previous studies showed that several genes may play crucial roles in susceptibility to TB. The PTPN22 gene encodes the lymphoid tyrosine phosphatase that has an important regulatory effect on T- and B-cell activation in immune response. The purpose of this study was to investigate the role of two functional missense single nucleotide polymorphisms (SNPs) of the PTPN22 gene region (R620W and R263Q) in the susceptibility to TB in the Moroccan population. A case-control association study was performed including 123 pulmonary TB patients and 155 healthy controls. All subjects were genotyped by TaqMan SNP genotyping assays. Regarding the PTPN22 R620W (C1858T) SNP, we observed a statistically significant difference in the distribution of the PTPN22 1885T allele between pulmonary TB patients and healthy controls (0.41% vs 3.2%, P = 0.01, odds ratio (OR) = 0.14, 95% confidence interval (CI) = 0.01-0.93). With respect to the PTPN22 R263Q (G788A), we observed an increase of 788A allele frequencies in TB patients compared with those in healthy controls (3.65% vs 0.65%, P = 0.01, OR = 5.85, 95% CI = 1.17-39.55). These results suggest that PTPN22 gene variants may affect susceptibility to TB in the Moroccan population.

What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases

Article

Jun 2009
ARTHRITIS RES THER

This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.

Targeting the Human Microbiome With Antibiotics, Probiotics, and Prebiotics: Gastroenterology Enters the Metagenomics Era

Article

Jun 2009

Studies of metagenomics and the human microbiome will tremendously expand our knowledge of the composition of microbial communities in the human body. As our understanding of microbial variation and corresponding genetic parameters is refined, this information can be applied to rational remodeling or "tailoring" of human-associated microbial communities and their associated functions. Physiologic features such as the development of innate and adaptive immunity, relative susceptibilities to infections, immune tolerance, bioavailability of nutrients, and intestinal barrier function may be modified by changing the composition and functions of the microbial communities. The specialty of gastroenterology will be affected profoundly by the ability to modify the gastrointestinal microbiota through the rational deployment of antibiotics, probiotics, and prebiotics. Antibiotics might be used to remove or suppress undesirable components of the human microbiome. Probiotics can introduce missing microbial components with known beneficial functions for the human host. Prebiotics can enhance the proliferation of beneficial microbes or probiotics, to maximize sustainable changes in the human microbiome. Combinations of these approaches might provide synergistic and effective therapies for specific disorders. The human microbiome could be manipulated by such "smart" strategies to prevent and treat acute gastroenteritis, antibiotic-associated diarrhea and colitis, inflammatory bowel disease, irritable bowel syndrome, necrotizing enterocolitis, and a variety of other disorders.

Clearing the AIRE: On the Pathophysiological Basis of the Autoimmune Polyendocrinopathy Syndrome Type-1

Article

Jul 2009

Autoimmune polyendocrine syndrome type-1 clinically manifests as the triad of hypoparathyroidism, primary adrenocortical insufficiency, and chronic mucocutaneous candidiasis. Mutations in the gene that encodes the autoimmune regulator protein, AIRE, have been identified as the cause of the autoimmune polyendocrine syndrome type-1. The loss of immunologic tolerance to tissue-restricted antigens consequent to an absence of AIRE expression in the thymus results in the thymic export of autoreactive T cells that initiate autoimmunity. In this article, we discuss the role of AIRE in autoimmune polyendocrine syndrome type-1 and identify issues that still need to be addressed to fully understand the molecular pathophysiology of this complex syndrome.

Genomics and the Multifactorial Nature of Human Autoimmune Disease

Abstract

No full-text available

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