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The MHC region on human chromosome 6p21 is a critical susceptibility locus for many human autoimmune diseases. Susceptibility to a number of these diseases, including rheumatoid arthritis, multiple sclerosis and type 1 diabetes, is associated with particular alleles of HLA-DR or HLA-DQ genes. Crystal structures of HLA-DR and HLA-DQ molecules with bound peptides from candidate autoantigens have demonstrated that critical polymorphic residues determine the shape and charge of key pockets of the peptide binding site and thus determine the interaction of these MHC molecules with peptides. These data provide strong support for the hypothesis that these diseases are peptide-antigen driven. In HLA-DR associated autoimmune diseases such as rheumatoid arthritis and pemphigus vulgaris, key polymorphic determinants are primarily localized to the P4 pocket of the binding site and determine whether the pocket has a positive or negative charge. Peptide binding studies have demonstrated that these changes in the P4 pocket have a significant impact on the repertoire of self-peptides that can be presented by these MHC class II molecules. In HLA-DQ associated diseases such as type 1 diabetes and celiac disease, the α57 polymorphism is critical for peptide presentation since it determines the charge of the P9 pocket of the binding site. The crystal structure of HLA-DQ8 demonstrated that the P9 pocket has a positive charge in HLA-DQ molecules associated with type 1 diabetes, due to the absence of a negative charge at P57. Striking structural similarities were identified between the human DQ8 and murine I-A molecules that confer susceptibility to type 1 diabetes, indicating that similar antigen presentation events may be relevant in humans and the NOD mouse model. Recent studies in the NOD mouse indicated that I- can promote expansion in the thymus of a CD4 T cell population which recognizes a peptide ligand that stimulates a panel of islet-specific T cell clones. MHC class II molecules that confer susceptibility to an autoimmune disease may thus promote positive selection of potentially pathogenic T cell population in the thymus and later induce the differentiation of these cells into effector populations by presentation of peptides derived from the target organ.

Genetic epidemiology is the study of the relationship between genomic and phenotypic variation with a goal to uncover the genetic basis of monogenic or complex disorders. A variety of study designs are available, and the importance of choosing an approach that is appropriate for the goals of the study cannot be over-emphasized. In addition to study design, important issues include selection of genetic marker type and number of markers to be tested, as well as the use of genotyping technology. In this chapter, we review these important features of genetic epidemiology studies with particular emphasis on applications to autoimmune conditions.

Type 1 diabetes (T1D) [MIM 222100] is the third most prevalent chronic disease of childhood, affecting up to 0.4% of individuals in some populations by age 30 years, with an overall lifetime risk of nearly 1%., T1D is caused by absolute insulin deficiency due to destruction of the pancreatic β-cells. The majority of T1D cases are believed to develop as a result of immune-mediated destruction of the β-cells, leaving a small proportion of idiopathic cases in which immune markers cannot be detected, which are caused by other pathogenetic mechanisms such as rare genetic syndromes, β-cell lytic virus infections, or environmental factors. T1D is associated with an increased risk of premature death due to acute complications and chronic disabling and life-threatening manifestations, including eye disease and blindness, renal failure, neuropathy and cardiovascular disease.

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 Hashimotos 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.

Immune diseases of the central and peripheral nervous system constitute an heterogeneous group of disorders which share a significative implication of the immune system in pathophysiology. Multiple sclerosis (MS), Guillain Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are considered of autoimmune origin, with an unidentified candidate auto-antigen. Many investigations have been performed to find genetic associations or linkage with genes encoding proteins involved in immune regulation. The only significant positive result is the HLA, especially class II molecules, whereas other genes like cytokines or chemokines did not give reproductive results. Myasthenia gravis (MG) is an antigen specific autoimmune disease (antibodies against acetyl choline receptors (AchR)), mainly mediated by the humoral immunity, but also associated with thymus changes, allowing a rough classification into different subsets of patients. In MG, it was possible to identify a genetic association to HLA and AchR genes, suggesting a direct participation of these molecules to disease initiation and development. Finally, narcolepsy is a disease of possible autoimmune origin, as suggested by its tight association with HLA alleles, although the primary antigenic target remains unknown.

The autoimmune rheumatologic diseases discussed in this chapter include rheumatoid arthritis (RA), systemic sclerosis (SSc), also called scleroderma, and systemic lupus erythematosus (SLE). Historically the terms connective-tissue diseases or collagen-vascular diseases have sometimes been used in considering diseases such as RA, SSc and SLE, because fibrinoid degeneration especially in collagen and vascular tissues is often found and was thought to contribute to clinical manifestations of these disorders. The predominant current view is that autoimmunity underlies the pathogenesis of these disorders, with normal tissues, cells and proteins the target of self-directed immune reactivity. Genetic susceptibility to autoimmune rheumatologic diseases is clearly multifactorial involving combinations of many different genes. More than three decades of research, however, indicates HLA genes most often make the strongest genetic contribution. Although the mechanism(s) by which particular HLA genes increase or decrease risk of a disease are not known it is not difficult to appreciate a central role since the products of HLA genes, HLA molecules, are intimately involved in the process of presenting both foreign and self antigens to T cells. For some diseases very specific HLA sequences have been identified and for others extended stretches of genes within the greater major histocompatibility complex (MHC) are implicated. More recently candidate genes other than those in the MHC have been identified for RA, SSc and SLE. Some implicated genes are known to be involved in other aspects of immune regulation while for other candidate genes the functions are as yet unknown.

Celiac disease, autoimmune hepatitis (AIH), and the inflammatory bowel diseases (IBDs), Crohn’s disease and ulcerative colitis (UC), are chronic inflammatory diseases of unknown etiology. They are considered complex genetic diseases because both inherited and environmental influences appear to be important in determining risk Complex genetic diseases are more common than Mendelian diseases in the population. Prevalence ranges for AIH, IBD and celiac disease are given in Table 1. Generally, accepted average prevalences are 1 in 1,000 persons for Crohn’s disease and UC, and 3 in 1,000 for celiac disease. However, the prevalence rate of Crohn’s, UC and celiac disease are much lower in some populations (e.g., 1.25 in 100,000 for Crohn’s disease in Hong Kong). The average prevalence of AIH is 10-fold lower at 1 in 10,000.

Dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM) belong to the heterogeneous group of the inflammatory myopathies and are characterized by muscle cell infiltrations and specific alterations of the muscle fibers. In DM it is evident a perifascicular atrophy of muscle tissue due to the activation and deposition of complement on capillaries; in PM and IBM there is a prominent endomysial infiltration of donally expanded CD8 T lymphocytes that surround and eventually invade single nonnecrotic muscle fibers, positive for MHC class I molecules. Muscle fibers in PM/IBM die for the action of cytotoxic enzymes (perform and granzymes) released by the invading CD8 T lymphocytes. In IBM, beside the autoimmune attack, there is an abnormal accumulation of proteins in vacuoles within muscle fibers. Triggering factors of myositis as well as the processes by which the immunological attack induces muscle weakness are still unknown. Upregulation of adhesion molecules, cytokines, chemokines contribute to recruit cells of the immune system and to maintain a chronic inflamed area. In vivo and in vitro studies on muscle cells have assessed their functions as target cells or antigen presenting cells. Combined studies on gene profiles and cellular immunology of disease-associated muscle biopsies will be of great help in clarifying the pathogenetic mechanisms underlying these inflammatory myopathies.

Autoimmune destruction of circulating blood cells in autoimmune hemolytic anemia (AIHA) and immune thrombocytopenic purpura (ITP) is often seen in autoimmune diseases and lymhoid malignancies. Erythrocytes or platelets that are recognized by autoantibodies are rapidly phagocytosed by macrophages. Although much is known about the mechanisms behind macrophage-mediated destruction of sensitized blood cells, less is known about the genetics behind AIHA and ITP. We here review what is known about the ethiology of AIHA and ITP, with particular emphasis on the role of genetic factors behind autoantibody production, T cell activation and apoptosis, and Fcγ receptor polymorphisms. The importance of inhibitory regulation of macrophages through CD47/SIRPα interaction, and its significance for autoimmune hematological disease is also discussed.

Autoimmune heart diseases in humans are multifactorial and genetically complex. Fortunately a great deal has been learned from animal models. They have established that a variety of infectious or toxic insults can lead to autoimmune heart disease in genetically susceptible animals. These animal models suggest that autoimmune heart disease has multiple etiologies, with differing mechanisms but overlapping genetic determinants culminating in the same end stage inflammatory heart disease. In this review we will focus on autoimmune heart disease caused by two different infectious agents, and B3. Both pathogens are known to infect the heart and are largely cleared after a brief illness. In certain susceptible individuals, however, a chronic, putative autoimmune attack is initiated. We review the evidence that post infectious chronic myocarditis is indeed autoimmune in nature and discuss our recent findings about the common genetic elements that may predispose to autoimmunity and autoimmune disease.