An interesting case of a monogenic autoimmune disease is autoimmune lymphoproliferative syndrome (ALPS), a systemic autoimmune syndrome caused by mutations in the gene encoding Fas. Fas is normally present on the surface of activated T and B cells, and when ligated by Fas ligand, it signals the Fas-bearing cell to undergo apoptosis (see Section 11-16). In this way it functions to limit the extent of immune responses. Mutations that eliminate or inactivate Fas lead to a massive accumulation of lymphocytes, especially T cells, and in mice, to the production of large quantities of pathogenic autoantibodies and a disease that resembles SLE. A mutation leading to this autoimmune syndrome was first observed in the MRL mouse strain and named lpr, for lymphoproliferation; it was subsequently identified as a mutation in Fas. The study of human patients with the rare autoimmune lymphoproliferative syndrome, which is similar to the syndrome in the MRL/lpr mice, led to the identification of FAS as the mutant gene responsible for most of these cases (see Fig. 15.36).
Fig. 15.37 Associations of HLA and sex with susceptibility to autoimmune disease. The ‘relative risk’ for an HLA allele in an autoimmune disease is calculated by comparing the observed number of patients carrying the HLA allele with the number that would be expected, given the prevalence of the HLA allele in the general population. For type 1 insulin‑dependent diabetes mellitus, the association is in fact with the HLA‑DQ gene, which is tightly linked to the DR genes but is not detectable by serotyping. Some diseases show a significant bias in the sex ratio; this is taken to imply that sex hormones are involved in pathogenesis. Consistent with this, the difference in the sex ratio in these diseases is greatest between menarche and menopause, when levels of such hormones are highest.
Healthy controls Diabetes DR3/x (24%) DR4/x (17.5%) DR2/x (30.3%) DR3/4 (2.5%) (25.7%) DR4/x (27%) (4%) DR3/4 (39%) DR3/x (30%) DRx/x DRx/x
Autoimmune diseases caused by single genes are rare, but are of great interest, as the mutations causing them identify important pathways that normally prevent the development of autoimmune responses.
15-22 MHC genes have an important role in controlling susceptibility to autoimmune disease.
Among genetic loci that contribute to autoimmunity, susceptibility to autoimmune disease has so far been most consistently associated with MHC genotype (Fig. 15.37), particularly MHC class II alleles, thus implicating CD4 T cells in their etiology. The development of experimental diabetes or arthritis in transgenic mice expressing specific human HLA antigens strongly suggests that particular MHC alleles confer disease susceptibility.
As in genome-wide association studies (GWASs), association of MHC with disease is identified by comparing the frequencies of MHC alleles in patients with the disease with the frequencies in the normal population. For type 1 diabetes, this approach demonstrated an association with the HLA-DR3 and HLA-DR4 alleles, identified by serotyping (Fig. 15.38). Such studies also showed that the MHC class II allele HLA-DR2 has a dominant protective