MHC molecules (HLA)

The major histocompatibility complex is a cluster of genes on the short arm of chromosome 6 (6p21.3), called the human leukocyte antigen (HLA) system in humans. Its classical genes are the most polymorphic in the human genome, with thousands of alleles, and are codominantly expressed; they are inherited as linked blocks (haplotypes), one from each parent, so any sibling has a 25% chance of being an HLA-identical match. Polymorphism is concentrated in the peptide-binding groove, so different alleles present different peptide repertoires — protecting the population from pathogens that might escape presentation, but making transplantation between unrelated people difficult.

Class I molecules (HLA-A, -B, -C) consist of a polymorphic transmembrane α (heavy) chain with three domains, non-covalently associated with β2-microglobulin (encoded on chromosome 15). The α1 and α2 domains form a groove closed at both ends, binding peptides of ≈ 8–10 amino acids derived mainly from cytosolic (endogenous) proteins; the α3 domain binds CD8. Class I is expressed on all nucleated cells (and platelets, but not mature red cells) and is also the ligand for NK-cell inhibitory receptors.

Class II molecules (HLA-DP, -DQ, -DR) consist of two transmembrane chains, α and β; the α1 and β1 domains form a groove open at both ends that holds longer peptides (≈ 13–25 amino acids) from endocytosed (exogenous) proteins; the β2 domain binds CD4. Class II is expressed constitutively by professional antigen-presenting cells — dendritic cells, macrophages and B cells — and by thymic epithelium, and can be induced on other cells by IFN-γ. The class III region between them encodes non-presenting immune proteins such as complement C2, C4 and factor B, and TNF.