To better understand the association between HLA genes and autoimmune diabetes, and specifically the IDDM1 locus, it is important to realize that approximately 40% of the functional genes that have been identified in the class II section of the HLA locus encode for proteins that are involved in the immune response. The MHC is classified into three major sections termed class I, II, and III. Class I and II genes encode for an alpha (a) and beta (p) heterodimers that form the cleft or pocket on antigen-presenting cells (APC), where antigen is bound and presented to T lymphocytes. The amino acid sequences in these pockets are variable (polymorphic), especially for class II molecules, giving them the ability to bind to a wide variety of different peptide antigens. APCs such as macrophages, dendritic cells, activated T cells and B cells, use HLA class II molecules to bind peptides derived from extracellular proteins and specifically present them to T-helper lymphocytes (also termed CD4+ T cells, since CD4 is a molecule that is expressed on their surface) (42). When the presentation of MHC-bound antigen by the APC to the T-cell receptor (TCR) occurs in the presence of the appropriate coreceptors (i.e., CD4) and costimulatory molecules (i.e., CD80/86 with CD28; CD40 with CD154) (43), the T helper cells become activated and subsequently elicit an immune response through the release of inflammatory cytokines, the recruitment of cytotoxic killer cells (CD8+ T cells), and the production of antibody by activated B cells (also known as plasma cells). HLA class I molecules on the other hand are found on all nucleated cells of the body, bind intracellular peptides (such as small pieces of viral peptides from infected cells) and present them to cytotoxic T cells, also known as CD8+ T lymphocytes. Activated CD8+ T cells are capable of exerting direct cytotoxic effects on their target cells. T cells, whether they are T-helper (CD4+) or cytotoxic (CD8+) cells, are MHC-restricted, meaning that they can only be activated when antigen is presented to them specifically bound to either HLA class II (for CD4+ T cells) or HLA class I (for CD8+ T cells) molecules.
Disruption in the mechanisms of antigen presentation can result in either immune deficiency or autoimmunity, depending on the specific abnormalities present. For example, it has been observed that the amino acid at position 57 on the HLA-DQ beta chain is associated with either risk for or protection from autoimmune diabetes (44). Specifically, when aspartic acid (Asp57P) is present at position HLA-DQA1+0102/DQB1+0602 (DR2), then the risk of developing autoimmune disease is low. On the other hand, lack of aspartic acid at this position is observed for HLA DQB1 molecules associated with diabetes risk, such as HLA-DQB1+0201 (DR3-DQ2) and HLA-DQB1+0302 (DR4-DQ8). Variations in the MHC class II molecules have been linked not only to diabetes, but also to various other chronic autoimmune conditions, such as multiple sclerosis, celiac disease, rheumatoid arthritis, and narcolepsy. Although not entirely clear at this time, it appears that the polymorphisms encountered in the beta chain of HLA class II molecules expressed by APCs may influence presentation of autoantigens to T cells. Antigen presentation is not only important for the induction of a normal immune response, but it is also critical for the induction of immune tolerance, which is both centrally and peripherally mediated.
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