The Major Histocompatibility Complex

The major histocompatibility complex (MHC) comprises three classes of genes located on the short arm of chromosome 6 that encode the antigen-recognition components of the immune system.

Class I (MIC): Transmembrane glycoproteins expressed by most normal body cells that present endogenous proteins at the cell surface, identifing cells as "self." When invaded, they present antigenic protein fragments from invading pathogens, resulting in recognition of the cell as "nonself" and attack by cytotoxic (killer) T lymphocytes (CTLs).

Celiac intestinal epithelial cells display a very high density of the MICA variant, a faulty molecule that marks these cells as nonself, targeting them for destruction by CTLs (Figure 2, step 10).

Class II: Highly variable transmembrane glycoproteins known as major histocompatibility molecules (MHMs). MHMs present phagocytosed antigens from exogenous sources on the surface of dendritic cells, B cells and other antigen-presenting cells (APCs). Helper T cells recognize the APCs and release cytokines—inducing a general inflammatory response—and lymphokines, stimulating the production of antigen-targeting B cells. B cells release immunoglobulins that attack and destroy the APCs and invading pathogens.

MHMs assembled with the a subunit encoded by the DQ2 MHM allele present gliadin and gliadin-tTG complexes at the dendritic cell surface. They are recognized by helper T cells and B cells, setting off the cascade of events (Figure 2) responsible for destruction of the villi and lamina propria, characteristic of the flattened intestinal mucosa found in celiac patients (Figure 1b).

Class III: A class of molecules that includes tumor necrosis factor a (TNFa) and components of the complement system (blood-soluble cytolytic proteins).

TNFa stimulates the release of cytokines causing inflammation of the lamina propria, and attracts metalloproteinase-secreting fibroblasts that destroy it.