ß2 microglobulin Heavy chain

Figure 12.2 MHC class I molecules and antigen presentation.

Box 12.2 Class II molecules and antigen presentation via the exogenous pathway

Exogenous proteins are degraded by denaturation and proteases present in the acidic endosome and lysosomal compartments producing peptide lig-ands (Fig 12.3). The MHC class II molecules are heterodimers, comprising an a and a P chain. They are assembled in the ER with a molecular chaperone protein, Invariant chain (Ii), the cytoplasmic tail of which targets the complex to the endosomal pathway and prevents premature association of anti-genic peptide. Within the endosome, Ii undergoes stepwise degradation by proteases leaving a small fragment, CLIP (class II invariant chain peptide), lodged in the peptide binding groove. The removal of CLIP is catalysed by DM, a protein encoded by HLA-DM within the MHC, which also stabilizes the molecule and assists antigenic peptide selection. Following antigen binding, MHC class II molecules are delivered to the cell surface where they present the antigen to CD4+ helper T cells, triggering an immune response.

other extracellular pathogens are endocytosed into antigen presenting cells such as macrophages, B cells, and dendritic cells (Fig. 12.3). Class II molecules present antigen to CD4+ T helper cells and are integral to successful maintenance of self tolerance by the immune system and the adaptive immune response to invading pathogens.

12.2.2 Biological complexity among the many genes found in the human MHC

Currently there are 252 known expressed genes encoded by the MHC with a large proportion involved in the immune response (summarized in Fig. 12.1). In addition to classical class I and II genes, other genes in the MHC are involved in antigen presentation and processing, notably a cluster of genes within the class II region containing TAP1, TAP2, PSMB8, and PSMB9. TAP1 and TAP2 encode the transporter associated with antigen processing proteins 1 and 2, respectively, encoding the two subunits of TAP that are responsible for binding peptides in the cell cytoplasm and transporting them to the ER (Box 12.1). PSMB8 (previously known as LMP2) and PSMB9 (LMP2) encode protein components of the immuno-proteasome involved in degradation of ubiquitin tagged proteins for presentation by MHC class I molecules. In the extended class II region, TABP encodes tapasin - the TAP binding protein involved in the peptide loading complex (Box 12.1).

Elsewhere in the MHC are genes encoding mediators of inflammation and the immune response. These include members of the tumour necrosis factor (TNF) superfamily, immunoglobulins, the complement cascade (Section 12.7), molecular chaperones such as heat shock proteins, and lymphocyte antigen genes. The TNF superfamily is a cluster of genes within the MHC class III region which comprises TNF (encoding TNF), LTA (lymphotoxin alpha), and LTB (lymphotoxin beta), whose protein products have key roles in immunity and inflammation. Genetic variation in the TNF locus has been associated with susceptibility to a number of autoimmune and infectious diseases (Section 2.4.4). The class III region also includes five genes (LY6G5B, LY6G5C, LY6G6D, LY6G6E, and LY6G6C) encoding cell surface proteins which are part of the lymphocyte antigen superfamily and involved in the immune response (Mallya et al. 2006). The heat shock cluster of genes HSPA1A, HSPA1B, and HSPA1L is also found in the MHC class III region and encodes members of the heat shock protein 70 family, molecular chaperone proteins involved in the stress response (Milner and Campbell 1990).

Further examples of immune-related genes are found in the MHC, such as the MHC class I-related chain A and B genes (MICA and MICB) that encode proteins expressed on the cell surface in response to stress. These are ligands for the NKG2D receptor found on natural killer cells, CD8+ cytotoxic T cells, and gamma delta T cells (Bauer et al. 1999). Other functional groupings of MHC genes include large clusters of genes encoding histones and transfer RNA, pheromone and olfactory receptors, and zinc finger proteins such as enzymes and transcription factors (Horton et al. 2004).

The reported genetic linkage and association studies implicating genetic variation in the MHC and disease are typically highly significant but have proved hard to localize to specific variants. Almost all autoimmune diseases have been linked to the MHC, many showing their strongest association of any genomic region (Lechler and Warrens 2000). Susceptibility to many infectious diseases has also been linked to the MHC, notably malaria (Section 13.2.6), leprosy, hepatitis B, and human immunodeficiency virus 1 (HIV-1) infection (Section 14.4). In some cases causal relationships have been established between variants and disease, as exemplified by the iron storage disorder haemo-chromatosis and the HFE gene (Section 12.6) (Feder et al. 1996). For the majority of diseases, specific haplo-types or individual alleles have been associated with protection or susceptibility to disease. A proportion of the many reported disease associations of the MHC are summarized in Fig. 12.4.

12.2.3 Genetic diversity in the MHC and disease: insights from rheumatoid arthritis

The number of disease associations and the complexity of dissecting their genetic basis within the MHC are illustrated by many different examples through the course of this chapter. One disease that demonstrates the role of diversity in the MHC in disease susceptibility and the difficulties of defining causative variants is rheumatoid arthritis (Newton et al. 2004b, Coenen and Gregersen 2009). Rheumatoid arthritis is a chronic systemic disease of unknown cause which primarily affects the joints where it is associated with inflammatory and destructive processes. There is a strong body of evidence from twin and family studies that genetic factors are important in determining susceptibility - estimated at between 40% and 60% of the risk. Polymorphism of the MHC is the most important genomic locus identified, contributing about half of that genetic risk with a number of other non-MHC loci reported (Box 12.3). Within the MHC, polymorphic


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