Inherited risk for most autoimmune diseases is attributable to multiple gene loci, of which the largest contribution is made by MHC genes. If an autoimmune disease develops in one of two twins, the same disease is more likely to develop in the other twin than in an unrelated member of the general population. Furthermore, this increased incidence is greater among mono zygotic (identical) twins than among dizygotic twins. These findings prove the importance of genetics in the susceptibility to autoimmunity. Genome-wide association studies have revealed some of the common variations (polymorphisms) of genes that may contribute to different autoimmune diseases. Emerging results suggest that different polymorphisms are more frequent (predisposing) or less frequent (protective) in patients than in healthy controls. The likelihood of a particular autoimmune disease in people with versus without a particular HLA allele is expressed as the odds ratio or relative risk. The importance of these polymorphisms is reinforced by the finding that many of them affect genes involved in immune responses, and the same genetic polymorphism may be associated with more than one autoimmune disease. However, these polymorphisms are frequently present in healthy individuals, and the individual contribution of each of these genes to the development of autoimmunity is very small, so many risk alleles together are needed to cause the disease.

Many autoimmune diseases in humans and inbred animals are linked to particular MHC alleles (Fig. 1). The association between human leukocyte antigen (HLA) alleles and autoimmune diseases in humans was recognized many years ago and was one of the first indications that T cells played an important role in these disorders (because the only known function of MHC molecules is to present peptide antigens to T cells). The incidence of numerous autoimmune diseases is greater among individuals who inherit particular HLA allele(s) than in the general population. Most of these disease associations are with class II HLA alleles (HLA-DR and HLA-DQ), perhaps because class II MHC molecules control the action of CD4+ T cells, which are involved in both cell- mediated and humoral immune responses to proteins as well in regulating immune responses. It is important to point out that, although an HLA allele may increase the risk of developing a particular autoimmune disease, the HLA allele is not, by itself, the cause of the disease. In fact, the disease never develops in the vast majority of people who inherit an HLA allele that does confer increased risk of the disease. Despite the clear association of MHC alleles with several autoimmune diseases, how these alleles contribute to the development of the diseases remains unknown. Some hypotheses are that particular MHC alleles may be especially effective at presenting pathogenic self peptides to autoreactive T cells or that they are inefficient at displaying certain self antigens in the thymus, leading to defective negative selection of T cells.

Fig1. Association of autoimmune diseases with alleles of the major histocompatibility complex (MHC) locus. Family and linkage studies show a greater likelihood of developing certain autoimmune dis eases in persons who inherit particular human leukocyte antigen (HLA) alleles than in persons who lack these alleles (odds ratio or relative risk). Selected examples of HLA disease associations are listed. For instance, in people who have the HLA-B27 allele, the risk of development of ankylosing spondylitis, an autoimmune disease of the spine, is 90 to 100 times higher than in B27-negative people; other diseases show various degrees of association with other HLA alleles. The asterisks indicate HLA alleles identified by molecular (DNA-based) typing instead of the older serologic (antibody-based) methods.

Polymorphisms in non-HLA genes are associated with various autoimmune diseases and may contribute to failure of self-tolerance or abnormal activation of lymphocytes (Fig. 2A). Many such disease-associated genetic variants have been described:

• Polymorphisms in the gene encoding the tyrosine phosphatase PTPN22 (protein tyrosine phosphatase N22) may lead to uncontrolled activation of both B and T cells and are associated with numerous auto immune diseases, including rheumatoid arthritis, SLE, and type 1 diabetes mellitus.

• Variants of the innate immune cytoplasmic microbial sensor NOD-2 that cause reduced resistance to intestinal microbes are associated with Crohn disease, an inflammatory bowel disease, in some ethnic populations.

 • Other polymorphisms associated with multiple auto immune diseases include genes encoding the IL-2 receptor α chain (CD25), believed to influence the balance of effector and regulatory T cells; the receptor for the cytokine IL-23, which promotes the development of proinflammatory Th17 cells; and CTLA-4, a key inhibitory receptor in T cells discussed earlier. Surprisingly, many of these polymorphisms are in the regulatory regions of the genes (promoters and enhancers) and not in the coding sequences, suggesting that they influence expression of the genes.

Fig2. Roles of non–MHC genes in autoimmunity. A, Select examples of variants (polymorphisms) of genes that confer susceptibility to autoimmune diseases but individually have small or no effects. B, Examples of genes whose mutations result in autoimmunity. These are rare examples of autoimmune diseases with Mendelian inheritance. The pattern of inheritance varies in the different diseases. APS-1 is autosomal recessive, and in most patients, both alleles of the gene (AIRE) have to be abnormal to cause the disease. IPEX is X-linked, so mutation in one allele of the gene (FOXP3) is sufficient to cause a defect in boys. ALPS is autosomal dominant with highly variable penetrance, because FAS and FASL are trimeric proteins and mutations in one of the alleles of either gene result in reduced expression of intact trimers. The disease caused by CTLA4 mutations is also autosomal dominant, perhaps because mutation in one allele reduces the expression of the protein enough to impair its function. AS, Ankylosing spondylitis; IBD, inflammatory bowel disease; IL, interleukin; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.

Some rare autoimmune disorders are Mendelian in origin, caused by mutations in single genes that have high penetrance and lead to autoimmunity in most individuals who inherit these mutations, although the pattern of inheritance varies. These genes, alluded to earlier, include AIRE, FOXP3, FAS, and CTLA4 (see Fig. 2B). Mutations in these genes have been valuable for identifying key molecules and pathways involved in self-tolerance. However, these Mendelian forms of autoimmunity are exceedingly rare, and common autoimmune diseases are not caused by mutations in any of these known genes. 

مواضيع ذات صلة

Role of Infections and Other Environmental Influences in Autoimmunity

الحساسية الدوائية نحو العوامل المخصرة للوصل العَصَبِي العَضَلِي

آليات حساسية السلفوناميدات ومظاهرها

Antigen - Antibody Interaction: Specificity and Cross - Reactivity

ANTIBODY SYNTHESIS

Tolerance to Commensal Microbes and Fetal Antigens

B Lymphocyte Tolerance

Peripheral T Lymphocyte Tolerance

Immune Memory

B Cells

T Cells

إزالَةُ التَحسس نحو البنسلين Penicillin Desensitization