Many of the genes identified as predisposing to autoimmunity can be classified as affecting autoantigen availability and clearance; apoptosis; signaling thresholds; cytokine expression or signaling; co-stimulatory molecules or their receptors; or regulatory T cells (see Figs. 15.32 and 15.33).
Genes that control antigen availability and clearance are important both centrally, in the thymus, and in the periphery. In the thymus, genes that control expression of self proteins influence tolerance in developing lymphocytes. In the periphery, hereditary deficiency of some proteins can predispose to autoimmunity—for example, deficiency of early components of the complement cascade is associated with the development of SLE (see Section 15-16). Genes that control apoptosis, such as FAS, are important in regulating the duration and vigor of immune responses. Failure to regulate immune responses properly causes excessive destruction of self tissues, releasing autoantigens. In addition, because clonal deletion and anergy are not absolute, immune responses can include some self-reactive cells. As long as their numbers are limited by apoptotic mechanisms, they may not necessarily cause autoimmune disease, but they could cause a problem if apoptosis is not properly regulated.
One of the largest categories of mutations associated with autoimmunity pertains to signals that control lymphocyte activation. These include mutations in co-stimulatory molecules, inhibitory Fc receptors, and inhibitory receptors containing ITIMs, such as PD-1 and CTLA-4 (see Section 15-19). Another subset contains mutations in proteins involved in signal transduction through the antigen receptor itself. Mutations that affect signaling intensity in either direction—making signaling more or less sensitive—can result in autoimmunity. A decrease in sensitivity in the thymus, for example, can lead to a failure of negative selection and thereby to autoreactivity in the periphery. In contrast, increasing receptor sensitivity in the periphery can lead to greater and prolonged activation, resulting in an exaggerated immune response with the side effect of autoimmunity. Additionally, mutations that affect the expression or signaling of cytokines and co-stimulatory molecules have been linked to autoimmunity. A final subset comprises mutations effecting Treg-cell development or function, such as FoxP3 mutations (see Section 15-21).
15-21 Monogenic defects of immune tolerance.
Predisposition to most of the common autoimmune diseases is due to the combined effects of multiple genes, but there are some monogenic autoimmune diseases (Fig. 15.36). Here, the mutant allele confers a very high risk of disease to the individual, but the overall impact on the population is minimal because these variants are rare. The existence of monogenic autoimmune disease was first observed in mutant mice in which the inheritance of an autoimmune syndrome followed a pattern consistent with a single-gene defect. Such alleles are usually recessive or X-linked. For example, the disease APECED is a recessive autoimmune disease caused by a defect in the gene AIRE (see Section 15-3).
Two monogenic autoimmune syndromes have been linked to defects in regulatory T cells. The X-linked recessive autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) is typically caused by missense mutations in the gene encoding the transcription factor FoxP3, which is key in the differentiation and function of some types of Treg cells (see Section 9-21). This disease is characterized by severe allergic inflammation, autoimmune polyendocrinopathy, secretory diarrhea, hemolytic anemia, and thrombocytopenia, and usually leads to early death. Despite mutation of the FOXP3 gene, the number of FoxP3+ Treg cells in the blood of individuals with IPEX is comparable to the number in healthy individuals; however, the