AS, ankylosing spondylitis; CeD, celiac diseases; IBD, inflammatory bowel disease; MS, multiple sclerosis; PS, psoriasis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; T1D, type 1 diabetes.

Data from Zenewicz L, C Abraham, RA Flavell, and J Cho. Unraveling the genetics of autoimmunity. Cell 140:791-797, 2010, with permission of the publisher.

multiple cell types, including intestinal epithelial cells. It is thought that the disease-associated polymorphism reduces the function of NOD2, which cannot provide effective defense against 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 the hallmark of inflammatory bowel disease (see Chapter 13).

• 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 P cells and causing diabetes.

• CD25. Polymorphisms affecting expression of CD25, the a chain of the IL-2 receptor, are associated with multiple sclerosis, type 1 diabetes, and other autoimmune diseases. It is not clear if these changes in CD25 expression affect the maintenance of regulatory T cells or the IL-2-induced generation of effector and memory T cells; defects in regulation and excessive effector and memory responses may both contribute to autoimmunity.

• IL-23 receptor (IL-23R). Some polymorphisms in the receptor for IL-23 protect against the development of inflammatory bowel disease and the skin disease psoriasis. IL-23 is one of the cytokines involved in the development of TH17 cells that trigger inflammatory reactions (see Chapters 9 and 10). It may be that these polymorphisms in the IL-23R affect TH17 responses to microbes encountered in the intestinal tract and thus the development of intestinal and cutaneous inflammation.

• ATG16. Polymorphisms in this gene are also associated with inflammatory bowel disease. ATG16 is one of a family of proteins involved in autophagy, a cellular response to nutrient deprivation in which a starved cell "eats" its own organelles to provide substrates for energy generation and metabolism. The process of autophagy may play a role in the maintenance of intact intestinal epithelial cells or the destruction of microbes that have entered the cytoplasm, but how the ATG16 polymorphism contributes to inflammatory bowel disease is not known.

There has been a tremendous increase in the number of polymorphisms identified in inflammatory diseases, largely because of genome-wide association studies. However, these studies do not necessarily identify a causal gene but may point to a region where a putative causal gene is located. Genome-wide association studies are not suitable for the identification of rare variants that may be highly penetrant and may actually be the cause of the disease. The advent of whole genome sequencing is likely to reveal even more single nucleotide polymorphisms (SNPs) in various diseases, so the list is certain to grow. One of the great challenges in the field of genetics of complex diseases, including autoimmune and inflammatory diseases, is to correlate the genetic polymorphisms with phenotypic changes. Until this is done, it will be difficult to elucidate the roles of these genes in the pathogenesis of the diseases.

Single-Gene 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 14-5). Unlike the polymorphisms in complex diseases described before, 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. Many of these genes were mentioned earlier in the chapter, when we discussed the mechanisms of self-tolerance. Although these genes are associated with rare

TABLE 14-5 Examples of Single-Gene Mutations That Cause Autoimmune Diseases


Phenotype of Mutant or Knockout Mouse

Mechanism of Failure of Tolerance

Human Disease?

Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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