Susceptibility genes in thyroid autoimmunity

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci, putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both the diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely, these loci interact and their interactions may influence disease phenotype and severity.     

The Contribution of Immune Regulatory and Thyroid Specific Genes to the Etiology of Graves' and Hashimoto's Diseases

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely these loci interact and their interactions may influence disease phenotype and severity.     

The contribution of immune regulatory and thyroid specific genes to the etiology of Graves' and Hashimoto's diseases

The autoimmune thyroid diseases (AITD) are complex diseases which are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility in combination with external factors (e.g. dietary iodine) are believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been employed to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT) and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g. HLA, CTLA-4) and thyroid specific genes (e.g. TSHR, Tg). Most likely these loci interact and their interactions may influence disease phenotype and severity.     

Understanding inflammatory bowel disease via immunogenetics

The major inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are both debilitating disorders of the gastrointestinal tract, characterized by a dysregulated immune response to unknown environmental triggers. Both disorders have an important and overlapping genetic component, and much progress has been made in the last 20 years at elucidating some of the specific factors contributing to disease pathogenesis. Here we review our growing understanding of the immunogenetics of inflammatory bowel disease, from the twin studies that first implicated a role for the genome in disease susceptibility to the latest genome-wide association studies that have identified hundreds of associated loci. We consider the insight this offers into the biological mechanisms of the inflammatory bowel diseases, such as autophagy, barrier defence and T-cell differentiation signalling. We reflect on these findings in the context of other immune-related disorders, both common and rare. These observations include links both obvious, such as to pediatric colitis, and more surprising, such as to leprosy. As a changing picture of the underlying genetic architecture emerges, we turn to future directions for the study of complex human diseases such as these, including the use of next generation sequencing technologies for the identification of rarer risk alleles, and potential approaches for narrowing down associated loci to casual variants. We consider the implications of this work for translation into clinical practice, for example via early therapeutic hypotheses arising from our improved understanding of the biology of inflammatory bowel disease. Finally, we present potential opportunities to better understand environmental risk factors, such as the human microbiota in the context of immunogenetics.     

Asthma as a paradigm for autoimmune disease

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanisms in some cases, by looking at the key elements that regulate the immune response in both asthma and autoimmune conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of asthma and autoimmune conditions in the same patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in asthma, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic diseases suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T cell receptor loci have long been considered important candidates for a common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to successful treatment of asthma and autoimmune conditions.     

Selfie: Autoimmunity,boon or bane

The immune system provides protection to tissues damaged by infectious microrganisms or physical damage. In autoimmune diseases, the immune system recognizes and attacks its own tissues, i.e., self-destruction. Various agents such as genetic factors and environmental triggers are thought to play a major role in the development of autoimmune diseases. A common feature of all autoimmune diseases is the presence of autoantibodies and inflammation, including mononuclear phagocytes, autoreactive T lymphocytes, and autoantibody producing B cells (plasma cells). It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Autoimmune diseases can be classified as organ-specific or non-organ specific depending on whether the autoimmune response is directed against a particular tissue or against widespread antigens as in chronic inflammatory autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Both SLE and RA are characterized by the presence of autoantibodies which play a major role in their etiopathogenesis. SLE is characterized by circulating antibodies and immune complex deposition that can trigger an inflammatory damage in organs. RA is a progressive inflammatory disease in which T cells, B cells, and pro-inflammatory cytokines play a key role in its pathophysiology.     

Allergic disease and autoimmune effectors pathways

Allergy and autoimmunity result from dysregulation of the immune system. Until recently, it was generally accepted that the mechanisms that govern these disease processes are quite disparate; however, new discoveries suggest possible common pathogenetic effector pathways. This review illustrates the concomitant presentation of these conditions and the potential relationship or common mechanism in some cases, by looking at the key elements that regulate the immune response in both allergic and autoimmunite conditions: mast cells, antibodies, T cells, cytokines, and genetic determinants. The parallel appearance of allergic and autoimmune conditions in the some patients may reveal that such aberrations of the immune system have a common pathophysiologic mechanism. Mast cells, which play a key role in allergic reactions, and the wealth of inflammatory mediators they express, make it likely that they have profound effects on many autoimmune processes. Activation of protein kinases by inflammatory cytokines and environmental stresses may contribute to both allergic and autoimmune diseases. The presence of autoantibodies in some allergic conditions suggests an autoimmune basis for these conditions. Because of the central role T cells play in immune reactivity, the T-cell receptor (TCR) loci have long been considered important candidates for common disease susceptibility within the immune system such as asthma, atopy, and autoimmunity. Immunomodulation is the key to a successful treatment of allergic and autoimmune conditions.     

Impact of Microbes on Autoimmune Diseases

Autoimmune and autoinflammatory diseases arise as a consequence of complex interactions of environmental factors with genetic traits. Although specific allelic variations cluster in predisposed individuals and promote the generation and/or expansion of autoreactive T and B lymphocytes, autoimmunity appears in various disease phenotypes and localizes to diverging tissues. Furthermore, the discovery that allelic variations within genes encoding components of the innate immune system drive self-reactive immune responses as well, led to the distinction of immune responses against host tissues into autoimmune and autoinflammatory diseases. In both categories of disorders, different pathogenic mechanisms and/or subsequent orders of tissue assaults may underlie the target cell specificity of the respective autoimmune attack. Furthermore, the transition from the initial tissue assault to the development of full-blown disease is likely driven by several factors. Thus, the development of specific forms of autoimmunity and autoinflammation reflects a multi-factorial process. The delineation of the specific factors involved in the pathogenic process is hampered by the fact that certain symptoms are assembled under the umbrella of a specific disease, although they might originate from diverging pathogenic pathways. These multi-factorial triggers and pathogenic pathways may also explain the inter-individual divergent courses and outcomes of diseases among humans. Here, we will discuss the impact of different environmental factors in general and microbial pathogens in particular on the regulation/expression of genes encoded within susceptibility alleles, and its consequences on subsequent autoimmune and/or autoinflammatory tissue damage utilizing primarily the chronic cholestatic liver disease primary biliary cirrhosis as model.     

Rare autoimmune disorders with Mendelian inheritance

Autoimmune diseases represent a heterogeneous group of common disorders defined by complex trait genetics and environmental effects. The genetic variants usually align in immune and metabolic pathways that affect cell survival or apoptosis and modulate leukocyte function. Nevertheless, the exact triggers of disease development remain poorly understood and the current therapeutic interventions only modify the disease course. Both the prevention and the cure of autoimmune disorders are beyond our present medical capabilities. In contrast, a growing number of single gene autoimmune disorders have also been identified and characterized in the last few decades. Mutations and other gene alterations exert significant effects in these conditions, and often affect genes involved in central or peripheral immunologic tolerance induction. Even though a single genetic abnormality may be the disease trigger, it usually upsets a number of interactions among immune cells, and the biological developments of these monogenic disorders are also complex. Nevertheless, identification of the triggering molecular abnormalities greatly contributes to our understanding of the pathogenesis of autoimmunity and facilitates the development of newer and more effective treatment strategies.     

The common variants/multiple disease hypothesis of common complex genetic disorders

Unlike simple rare Mendelian disorders, the genetic basis for common disorders is unclear. A general model of the genetics of common complex disorders is proposed which emphasizes the shared nature of common alleles in related common disorders, such as schizophrenia and bipolar disorder, Type II diabetes and obesity, and among autoimmune diseases. This model, the common variants/multiple disease hypothesis, emphasizes that many disease genes may not be disease specific. Common deleterious alleles, found at a relatively high frequency in the population may play a role in related clinical phenotypes in the context of different genetic backgrounds and under different environmental conditions.     

Etiology of Crohn’s disease: many roads lead to autophagy

Crohn's disease is a complex multifactor diseases that occur in individuals with genetic predisposition in whom environmental and microbial triggers cause a deleterious chronic immune response. Susceptibility to Crohn's disease is influenced by common variants at many loci. Genetic studies have emphasized the role of host susceptibility in inflammatory bowel disease onset with the identification of about 100 risk loci, most of which encode proteins involved in immunity, host defense against microbes, and gut homeostasis. In this review, we focus on susceptibility genes related to autophagy in the etiology of Crohn's disease (CD) and their complex interplay with the gut microbiota, as illustrated by the relationship between immunity-related GTPase family M alleles, microRNA, and xenophagy in CD predisposition.     

Infection, vaccines and other environmental triggers of autoimmunity

The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression.Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic.Infections: bacterial, viral and parasitic infections are known to induce and exacerbate autoimmune diseases, mainly by the mechanism of molecular mimicry. This was studied for some syndromes as for the association between SLE and EBV infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and more. Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination.Occupational and other chemical exposures are considered as triggers for autoimmunity. A debate still exists about the role of silicone implants in induction of scleroderma like disease.Not only foreign chemicals and agents have been associated with induction of autoimmunity, but also an intrinsic hormonal exposure, such as estrogens. This might explain the sexual dimorphism in autoimmunity.Better understanding of these environmental risk factors will likely lead to explanation of the mechanisms of onset and progression of autoimmune diseases and may lead to effective preventive involvement in specific high-risk groups.So by diagnosing a new patient with autoimmune disease a wide anamnesis work should be done.     

Infection,vaccines and other environmental triggers of autoimmunity

The etiology of autoimmune diseases is still not clear but genetic, immunological, hormonal and environmental factors are considered to be important triggers. Most often autoimmunity is not followed by clinical symptoms unless an additional event such as an environmental factor favors an overt expression.

Many environmental factors are known to affect the immune system and may play a role as triggers of the autoimmune mosaic.

Infections: bacterial, viral and parasitic infections are known to induce and exacerbate autoimmune diseases, mainly by the mechanism of molecular mimicry. This was studied for some syndromes as for the association between SLE and EBV infection, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection and more. Vaccines, in several reports were found to be temporally followed by a new onset of autoimmune diseases. The same mechanisms that act in infectious invasion of the host, apply equally to the host response to vaccination. It has been accepted for diphtheria and tetanus toxoid, polio and measles vaccines and GBS. Also this theory has been accepted for MMR vaccination and development of autoimmune thrombocytopenia, MS has been associated with HBV vaccination.

Occupational and other chemical exposures are considered as triggers for autoimmunity. A debate still exists about the role of silicone implants in induction of scleroderma like disease.

Not only foreign chemicals and agents have been associated with induction of autoimmunity, but also an intrinsic hormonal exposure, such as estrogens. This might explain the sexual dimorphism in autoimmunity.

Better understanding of these environmental risk factors will likely lead to explanation of the mechanisms of onset and progression of autoimmune diseases and may lead to effective preventive involvement in specific high-risk groups.

So by diagnosing a new patient with autoimmune disease a wide anamnesis work should be done.     

Hepatitis C and interferon induced thyroiditis

Autoimmune thyroid diseases (AITDs) are complex diseases that develop as a result of interactions between genetic, epigenetic, and environmental factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. The major environmental triggers of AITD include iodine, smoking, medications, pregnancy, and possibly stress. In this review we will focus on two well-documented environmental triggers of AITD, hepatitis C virus (HCV) infection and interferon alpha (IFNa) therapy. Chronic HCV infection has been shown to be associated with increased incidence of clinical and subclinical autoimmune thyroiditis (i.e. the presence of thyroid antibodies in euthyroid subjects). Moreover, IFNa therapy of chronic HCV infection is associated with subclinical or clinical thyroiditis in up to 40% of cases which can be autoimmune, or non-autoimmune thyroiditis. In some cases interferon induced thyroiditis (IIT) in chronic HCV patients may result in severe symptomatology necessitating discontinuation of therapy. While the epidemiology and clinical presentation of HCV and interferon induced thyroiditis have been well characterized, the mechanisms causing these conditions are still poorly understood.     

Is FCRL3 a new general autoimmunity gene?

Autoimmunity is a multistep pathogenic process, which arises in genetically predisposing individuals as a result of the harmful influence of environmental factors causing the breakdown of immune tolerance and induction of self-reactive immune response. Recent findings resolved common pathogenic mechanisms shared between different autoimmune diseases and suggested for the existence of genetic loci that could be involved in general autoimmunity and hence contribute to susceptibility of several autoimmune diseases. To date, several loci responsible for general autoimmunity have been identified. The Fc receptor-like 3 (FCRL3) gene is one of those loci for which a significant association with a number of autoimmune diseases such as rheumatoid arthritis (RA), autoimmune thyroid disease, and systemic lupus erythematosus (SLE) has been recently shown in Japanese. However, studies in Caucasians failed to confirm a strong association of this gene with RA and SLE and therefore made questionable the putative role of FCRL3 in general autoimmunity. In this review, we discuss whether the FCRL3 gene is a newly discovered gene contributing to shared susceptibility between autoimmune diseases.     

Recent advances in the genetics of systemic lupus erythematosus

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.     

Mapping autoimmunity genes

Rat and mouse models for the major human autoimmune/inflammatory diseases are under intense genetic scrutiny. Genome-wide linkage studies reveal that each model is regulated by multiple genetic loci. Many of these loci colocalize to homologous genomic regions associated with several different autoimmune diseases of mice, rats and humans. Candidate genes are being identified. Polymorphic alleles associated with these chromosomal segments may represent predisposing genetic elements common to a number of human diseases with very different clinical presentations.     

Epistasis and immunity: the role of genetic interactions in autoimmune diseases

Autoimmune disorders are a complex and varied group of diseases that are caused by breakdown of self-tolerance. The aetiology of autoimmunity is multi-factorial, with both environmental triggers and genetically determined risk factors. In recent years, it has been increasingly recognized that genetic risk factors do not act in isolation, but rather the combination of individual additive effects, gene-gene interactions and gene-environment interactions determine overall risk of autoimmunity. The importance of gene-gene interactions, or epistasis, has been recently brought into focus, with research demonstrating that many autoimmune diseases, including rheumatic arthritis, autoimmune glomerulonephritis, systemic lupus erythematosus and multiple sclerosis, are influenced by epistatic interactions. This review sets out to examine the basic mechanisms of epistasis, how epistasis influences the immune system and the role of epistasis in two major autoimmune conditions, systemic lupus erythematosus and multiple sclerosis.     

Autoimmunity and inflammation due to a gain-of-function mutation in phospholipase C gamma 2 that specifically increases external Ca2+ entry

The identification of specific genetic loci that contribute to inflammatory and autoimmune diseases has proved difficult due to the contribution of multiple interacting genes, the inherent genetic heterogeneity present in human populations, and a lack of new mouse mutants. By using N-ethyl-N-nitrosourea (ENU) mutagenesis to discover new immune regulators, we identified a point mutation in the murine phospholipase Cg2 (Plcg2) gene that leads to severe spontaneous inflammation and autoimmunity. The disease is composed of an autoimmune component mediated by autoantibody immune complexes and B and T cell independent inflammation. The underlying mechanism is a gain-of-function mutation in Plcg2, which leads to hyperreactive external calcium entry in B cells and expansion of innate inflammatory cells. This mutant identifies Plcg2 as a key regulator in an autoimmune and inflammatory disease mediated by B cells and non-B, non-T haematopoietic cells and emphasizes that by distinct genetic modulation, a single point mutation can lead to a complex immunological phenotype.     

Novel insights into autoimmune liver diseases provided by genome-wide association studies

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.