From the earliest studies of autoimmune diseases in patients and experimental animals, it has been appreciated that these diseases have a genetic predisposition. For example, type 1 diabetes shows a concordance of 35% to 50% in monozygotic twins and 5% to 6% in dizygotic twins, and other autoimmune diseases show similar evidence of a genetic contribution. Linkage analyses in families, genome-wide association studies, and large-scale sequencing efforts have revealed some information about the genes that may play causal roles in the development of autoimmunity and chronic inflammatory disorders.
Most common autoimmune diseases are complex polygenic disorders in which affected individuals inherit multiple genetic polymorphisms that contribute to disease susceptibility, and these genes act with environmental factors to cause the diseases. Some of these polymorphisms are associated with several auto immune diseases, suggesting that the associated genes influence general mechanisms of immune regulation and self-tolerance. Other loci are associated with particular diseases, suggesting that they may affect organ damage or autoreactive lymphocytes of particular specificities. Each genetic polymorphism makes a small contribution to the development of particular autoimmune diseases and is also found in healthy individuals but at a lower frequency than in patients with the diseases. It is postulated that in individual patients, several such polymorphisms are coinherited and together contribute to development of the disease. Understanding the interplay of multiple genes with one another and with environmental factors is one of the continuing challenges in the field.
The best-characterized genes associated with autoimmune diseases and our current understanding of how they may con tribute to loss of self-tolerance are described here.
Association of MHC Alleles With Autoimmunity
Among the genes that are associated with autoimmunity, the strongest associations are with MHC genes. HLA typing of large groups of patients with various autoimmune diseases has shown that some HLA alleles occur at higher frequency in these patients than in the general population. From such studies, one can calculate the odds ratio for development of a disease in individuals who inherit various HLA alleles (often referred to as the relative risk) (Table 1). The strongest such association is between ankylosing spondylitis, an inflammatory and presumably autoimmune disease of vertebral joints, and the HLA class I allele B27. Individuals who are HLA-B27 positive are over 100 times more likely to develop ankylosing spondylitis than individuals who are B27-negative. Neither the pathogenesis of this disease nor the basis of its association with HLA-B27 is known. The association of HLA class II DR and DQ alleles with auto immune diseases has received great attention, mainly because MHC class II genes are more frequently associated with autoimmune diseases than are MHC class I genes. MHC class II molecules are involved in the selection and activation of CD4+ T cells, which are involved in most immune responses to protein antigens.
Table1. Association of Human Leukocyte Antigen Alleles With Autoimmune Disease
Several features of the association of HLA alleles with auto immune diseases are noteworthy.
• An HLA-disease association may be identified by serologic typing of one HLA locus, but the actual association may be with other alleles that are linked to the typed allele and inherited together. For example, individuals with a particular HLA-DR allele (hypothetically DR3) may show a higher probability of inheriting a particular HLA-DQ allele (hypo thetically DQ5) than the probability of inheriting these alleles separately and randomly (i.e., at equilibrium) in the population. Such inheritance is an example of linkage dis equilibrium. A disease may be found to be DR3-associated by HLA typing, but the causal association may actually be with the coinherited DQ5. This realization has emphasized the concept of extended HLA haplotypes, which refers to sets of linked genes, both classical HLA and adjacent non-HLA genes, that tend to be inherited together as a single unit.
• In many autoimmune diseases, the disease-associated nucleotide polymorphisms encode amino acids in the peptide binding clefts of the MHC molecules. This observation is not surprising because polymorphic residues of MHC molecules are located within and adjacent to the clefts, and the structure of the clefts is the key determinant of both functions of MHC molecules, namely, antigen presentation and recognition by T cells.
• Disease-associated HLA alleles are found in healthy individuals. In fact, if all individuals bearing a particular disease associated HLA allele are monitored prospectively, most will never develop the disease. Therefore, expression of a particular HLA gene is not by itself the cause or predictor of any autoimmune disease, but it may be one of several factors that contribute to autoimmunity.
• Inheritance of certain HLA alleles confers protection against developing some autoimmune diseases, such as type 1 diabetes and rheumatoid arthritis.
The mechanisms underlying the association of different HLA alleles with various autoimmune diseases are still not clear. In diseases in which particular MHC alleles increase the risk, the disease-associated MHC molecule may present a self peptide and activate pathogenic T cells, and this has been established in a few cases. But a key question that has not been answered in most cases is whether a disease-associated HLA molecule presents the relevant self antigen differently from HLA molecules that are not associated with the disease. When a particular allele is shown to be protective, it is hypothesized that this allele might induce negative selection of some potentially pathogenic T cells, or it might promote the development of Tregs, but there is no clear evidence in support of either hypothesis.
Polymorphisms in Non-HLA Genes Associated With Autoimmunity Linkage analyses and genome-wide association studies have led to the putative identification of nucleotide polymorphisms (variants) of several genes that are associated with autoimmune diseases, and this has been extended by more recent genome sequencing efforts. Before the genes that are most clearly vali dated are discussed, it is important to summarize some of the general features of these genes.
• As stated earlier, it is likely that combinations of multiple inherited genetic polymorphisms interacting with environ mental factors induce the immunologic abnormalities that lead to autoimmunity.
• Many of the polymorphisms associated with various autoimmune diseases are in genes that influence the development and regulation of immune responses. Although this conclusion appears predictable, it has reinforced the usefulness of the approaches being used to identify autoimmunity-associated genes.
• Different polymorphisms may protect against disease development or increase the incidence of the disease. The statistical methods used for genome-wide association studies have revealed both types of associations.
• Most disease-associated polymorphisms are located in noncoding regions of genes. This suggests that many of the polymorphisms may affect the expression of the encoded proteins.
Some of the many genes associated with human autoimmune diseases are listed in Table 2, and a few are briefly described next.
• PTPN22. A variant of the protein tyrosine phosphatase PTPN22, in which arginine at position 620 is replaced with a tryptophan, is associated with rheumatoid arthritis, type 1 diabetes, autoimmune thyroiditis, and other autoimmune diseases. The disease-associated variant is thought to reduce the signaling threshold of T cells, thus allowing activation even by poorly immunogenic self antigens. Precisely how these changes lead to autoimmunity is not known.
• NOD2. Polymorphisms in this gene are associated with Crohn’s disease, one type of IBD. NOD2 is a cytoplasmic sensor of bacterial peptidoglycans and is expressed in multiple cell types, including intestinal epithelial cells. It is postulated that the disease-associated polymorphism reduces the function of NOD2, so it cannot provide effective defense against certain intestinal microbes. As a result, these microbes are able to traverse the epithelium and initiate a chronic inflammatory reaction in the intestinal wall, which is a hallmark of IBD. Thus, Crohn’s disease may be an unregulated response to commensal microbes that has features of autoimmune diseases.
• Complement proteins. Genetic deficiencies of several complement proteins, including C1q, C2, and C4, are associated with SLE. The postulated mechanism of this association is that complement activation promotes the clearance of circulating immune complexes and apoptotic cell bodies, and in the absence of complement proteins, these complexes accumulate in the blood and are deposited in tissues and the antigens of dead cells persist. The ability of complement activation to enhance B cell signaling may, in some circumstances, promote B cell tolerance, but how or even if the complement system is activated by self antigens is unclear.
• IL-23 receptor (IL-23R). Some polymorphisms in the receptor for IL-23 are associated with increased susceptibility to IBD and the skin disease psoriasis, whereas other poly morphisms protect against development of these diseases. IL-23 is one of the cytokines involved in the development of Th17 cells, which stimulate inflammatory reactions.
• CD25 (IL-2Rα). Polymorphisms affecting the expression or function of CD25, the α chain of the IL-2 receptor, are associated with MS, type 1 diabetes, and other autoimmune diseases. These changes in CD25 likely affect the generation or function of Tregs.
• FcγRIIB. A polymorphism altering an isoleucine to a threonine in the transmembrane domain of this inhibitory Fc receptor impairs inhibitory signaling and is associated with SLE. Genetic deletion of this receptor in mice also results in a lupus-like autoimmune disease. The likely mechanism underlying the association is defective antibody-mediated feedback inhibition of B cells.
• ATG16L1. A loss-of-function polymorphism in this gene, which replaces a threonine in position 300 with an alanine, is associated with Crohn’s disease. ATG16L1 is one of a family of proteins involved in autophagy, a cellular response to infection, nutrient deprivation, and other forms of stress. How this polymorphism contributes to IBD is not known.
• Insulin. Polymorphisms in the insulin gene that encode variable numbers of repeat sequences are associated with type 1 diabetes. These polymorphisms may affect the thymic expression of insulin. It is postulated that if the protein is expressed at low levels in the thymus because of a genetic polymorphism, developing T cells specific for insulin may not be negatively selected. These cells survive in the mature immune repertoire and are capable of attacking insulin-producing islet β cells and causing diabetes.
Table2. Selected Non–Human Leukocyte Antigen Genes Associated With Autoimmune Diseases
Although many other genetic associations with autoimmune diseases have been reported, a continuing challenge is to correlate the genetic polymorphisms with the pathogenesis of the diseases.
Inherited Single-Gene (Mendelian) Abnormalities That Cause Autoimmunity
Studies with mouse models and patients have identified several genes that strongly influence the maintenance of tolerance to self antigens (Table 3). Unlike the complex polymorphisms described previously, these single-gene defects are examples of Mendelian disorders in which the mutation is rare but has a high penetrance, so that most individuals carrying the mutation are affected. We mentioned many of these genes earlier in the chapter when we discussed the mechanisms of self-tolerance. Although these genes are associated with rare autoimmune dis eases, their identification has provided valuable information about the importance of various mechanisms in the maintenance of self-tolerance. The proteins encoded by these genes contribute to central tolerance (AIRE), generation and function of Tregs (FOXP3, IL-2, IL-2R, CTLA-4), peripheral deletion of T and B lymphocytes (FAS, FAS-L), and regulation of pathogenic T cells in mucosal tissues (IL-10, IL10R). None of these mutations is seen in common autoimmune diseases.
Table3. Examples of Single-Gene Mutations That Cause Autoimmune Diseases
