Figure 12.1 Genes encoded within the MHC involved in the immune system. Over the 7.6 Mb of DNA sequence comprising the extended MHC, 28% of genes are estimated to be involved in different immune functions including innate and adaptive immunity. A selection of genes are shown here with arrows to functional groupings. The majority are concerned with antigen presentation and processing. These include classical MHC class I and II molecules, together with antigen processing machinery needed for loading peptides onto class I molecules.
disequilibrium (Box 2.8), comparison between species of gene and sequence conservation, together with the finding of genes of common function to the MHC in flanking DNA such as the HFE gene (Section 12.6) and BTN family genes (encoding butyrophilin members) (Stephens et al. 1999). Allelic variation is greatest within the genes encoding class I and II molecules, with extremes of polymorphism observed in HLA-B and the HLA-DRB! region (Section 12.3.4) (Bergstrom et al. 1998). A further hypervariable region is found in the class III region in the complement locus with copy number variation at the RCCX module (Section 12.7) (Yang et al. 1999).
MHC class I molecules are present on nearly all nucleated cells and are vital to the cellular immune response (Box 12.1) (Cresswell et al. 2005). The transmembrane heavy chain (HC) encoded by MHC class I genes has two polymorphic domains, a1 and a2, responsible for binding peptides. Bound antigenic peptides are presented via the endogenous pathway to CD8+ cytotoxic T cells (Fig. 12.2). In contrast, MHC class II molecules are responsible for antigen presentation via the exogenous pathway (Box 12.2) (Watts 2004). Bacteria, parasites, and
Box 12.1 Class I molecules and antigen presentation via the endogenous pathway
Foreign (non-self) intracellular proteins such as those originating from viruses and some bacteria present in the cytosol of the cell are degraded by the proteasome into antigenic peptides (Fig 12.2). These are translocated into the endoplasmic reticulum (ER) by the transporter TAP (transporter associated with antigen processing). Here the unfolded MHC class I heavy chain associates with the molecular chaperone calnexin (CNX), initiating folding and disulphide bond formation. Following dissociation, the heavy chain binds P2 microglobulin and is incorporated into the peptide loading complex, which includes TAP, a glycoprotein molecule tapasin, cal-reticulin, and ERp57. Foreign peptides transported from the cytosol are trimmed to 8-10 amino acids if necessary by the ER associated aminopeptidase, ERAPP. Peptide binding to the HC/P2 microglobulin heterodimer initiates release from the peptide loading complex, allowing the fully assembled molecule bound with antigen to leave the ER and be delivered to the plasma membrane via the Golgi apparatus. Here the antigen is presented to CD8+ cytotoxic T cells via the T cell receptor. Cells presenting non-self peptides are destroyed, usually by cellular apoptosis.
T cell T cell receptor
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