Human leukocyte antigen (HLA) molecules are glycoproteins that are expressed on almost all nucleated cells. The HLA region is located on the short arm of chromosome 6, at 6p21, referred to as the MHC. There are three classic loci at HLA class I: (1) HLA-A, (2) HLA-B, and (3) HLA-Cw, and five loci at class II: (1) HLA-DR, (2) HLA-DQ, (3) HLA-DP, (4) HLA-DM, and (5) HLA-DO. The HLA molecules are highly polymorphic, there being many alleles at each individual locus. Thus, allelic variation contributes to defining a unique “fingerprint” for each person's cells, which allows an individual's immune system to define what is foreign and what is self. The clinical significance of the HLA system is highlighted in human tissue transplantation, especially in kidney and bone marrow transplantation, where efforts are made to match at the HLA-A, -B, and -DR loci. MHC class I molecules, complexed to certain peptides, act as substrates for CD8+ T-cell activation, whereas MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells (see Chapter 10). Therefore, MHC molecules are central to effective adaptive immune responses. Conversely, however, genetic and epidemiologic data have implicated these molecules in the pathogenesis of various autoimmune and chronic inflammatory diseases. Several skin diseases, such as psoriasis (see Chapter 18), psoriatic arthropathy (central and peripheral), dermatitis herpetiformis, pemphigus, reactive arthritis syndrome (see Chapter 20), and Behçet disease (see Chapter 166), all show an association with inheritance of certain HLA haplotypes (i.e., there is a higher incidence of these conditions in individuals and families with particular HLA alleles). However, the molecular mechanisms by which polymorphisms in HLA molecules confer susceptibility to certain disorders are still unclear. This situation is further complicated by the fact that, for most diseases, it is unknown which autoantigens (presented by the disease-associated MHC molecules) are primarily involved. For many diseases, the MHC class association is the main genetic association. Nevertheless, for most of the MHC-associated diseases, it has been difficult to unequivocally determine the primary disease-risk gene(s), owing to the extended linkage disequilibrium in the MHC region. However, recent genetic and functional studies support the long-held assumption that common MHC class I and II alleles themselves are responsible for many disease associations, such as the HLA cw6 allele in psoriasis. Of practical clinical importance is the strong genetic association between certain HLA alleles and the risk of adverse drug reactions. For example, in Han Chinese and some other Asian populations, HLA-B*1502 confers a greatly increased risk of carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis. Therefore, screening for HLA-B*1502 before starting carbamazepine in patients from high-risk populations is recommended or required by regulatory agencies.42