Fig. 15.38 Population studies show association of susceptibility to type 1 diabetes with HLA genotype. The HLA genotypes (determined by serotyping) of patients with diabetes (lower panel) are not representative of those found in the general population (upper panel). Almost all patients with diabetes express HLA‑DR3 and/or HLA‑DR4, and HLA‑DR3/DR4 heterozygosity is greatly overrepresented in diabetics compared with controls. These alleles are linked tightly to HLA‑DQ alleles that confer susceptibility to type 1 diabetes. By contrast, HLA‑DR2 protects against the development of diabetes and is found only extremely rarely in patients with diabetes. The small letter x represents any allele other than DR2, DR3, or DR4.
Family studies of HLA haplotypes in type 1 diabetes
Fig. 15.39 Family studies show strong linkage of susceptibility to type 1 diabetes with HLA genotype. In families in which two or more siblings have type 1 diabetes, it is possible to compare the HLA genotypes of affected siblings. Affected siblings share two HLA haplotypes much more frequently than would be expected if the HLA genotype did not influence disease susceptibility.
effect: individuals carrying HLA-DR2, even in association with one of the susceptibility alleles, rarely develop diabetes. It has also been shown that two siblings affected with the same autoimmune disease are far more likely than expected to share the same MHC haplotypes (Fig. 15.39). As HLA genotyping has become more exact through DNA sequencing, disease associations originally discovered by serotyping have been defined more precisely. For example, the association between type 1 diabetes and the DR3 and DR4 alleles is now known to be due to their tight genetic linkage to DQβ alleles that confer susceptibility to the disease. Indeed, susceptibility is most closely associated with polymorphisms at a particular position in the DQβ amino acid sequence that affect the peptide-binding cleft of MHC class II (Fig. 15.40). The diabetes-prone NOD strain of mice also has a serine residue polymorphism at that same position in the homologous mouse MHC class II molecule, known as I-Ag7.
The association of MHC genotype with autoimmune disease is not surprising; associations can be explained by a simple model in which susceptibility to an autoimmune disease is determined by differences in the ability of different allelic variants of MHC molecules to present autoantigenic peptides to autoreactive T cells. This would be consistent with what we know of T-cell involvement in particular diseases. In diabetes, for example, there are associations with both MHC class I and MHC class II alleles, consistent with the finding that both CD8 and CD4 T cells mediate the autoimmune response. An alternative hypothesis emphasizes the role of MHC alleles in shaping the T-cell receptor repertoire (see Chapter 8). This hypothesis proposes that self peptides associated with certain MHC molecules may drive the positive selection of developing thymocytes that are specific for particular autoantigens. Such