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. 2007 Nov;8(7):453-65.
doi: 10.2174/138920207783591690.

The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action

S C L Gough  1 , M J Simmonds
Affiliations

The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action

S C L Gough et al. Curr Genomics. 2007 Nov.

Abstract

The HLA region encodes several molecules that play key roles in the immune system. Strong association between the HLA region and autoimmune disease (AID) has been established for over fifty years. Association of components of the HLA class II encoded HLA-DRB1-DQA1-DQB1 haplotype has been detected with several AIDs, including rheumatoid arthritis, type 1 diabetes and Graves' disease. Molecules encoded by this region play a key role in exogenous antigen presentation to CD4+ Th cells, indicating the importance of this pathway in AID initiation and progression. Although other components of the HLA class I and III regions have also been investigated for association with AID, apart from the association of HLA-B*27 with ankylosing spondylitis, it has been difficult to determine additional susceptibility loci independent of the strong linkage disequilibrium (LD) with the HLA class II genes. Recent advances in the statistical analysis of LD and the recruitment of large AID datasets have allowed investigation of the HLA class I and III regions to be re-visited. Association of the HLA class I region, independent of known HLA class II effects, has now been detected for several AIDs, including strong association of HLA-B with type 1 diabetes and HLA-C with multiple sclerosis and Graves' disease. These results provide further evidence of a possible role for bacterial or viral infection and CD8+ T cells in AID onset. The advances being made in determining the primary associations within the HLA region and AIDs will not only increase our understanding of the mechanisms behind disease pathogenesis but may also aid in the development of novel therapeutic targets in the future.

Keywords: Genes; autoimmunity & HLA.

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Figures

Fig. (1)
Fig. (1)
a) Diagrammatic representation of the HLA region on chromosome 6p21, b) More detailed diagrams of common AID genes within the HLA class I and class II region c) Representation of endogenous antigen presentation by HLA class I classical molecules (including HLA-A, -B and –C). Endogenous antigen generated in the cytosol is degraded within the proteasomes and then transported into the rough endoplasmic reticulum (RER) through the TAP1/TAP2 complex. Antigen is then bound by HLA class I molecules in connection with β2M and then once bound the molecule is exported to the cell surface for recognition by CD8+ T cells and natural killer (NK) cells. Exogenous antigen presentation by HLA class II classical molecules (including HLA-DR and –DQ) is also represented. Exogenous antigen is imported into the cell and then enters the endosytic pathway (encompassing the early endosome, late endosome and lysosome) where the antigen is degraded. At the same time HLA class II molecules complexed with the invariant chain move from the RER where they are synthesised to the endocytic pathway. As the HLA class II/Invariant chain complex moves into the increasing more acidic compartment of the endocytic pathway the in-variant chain is digested, leaving only CLIP bound. The CLIP is then replaced with degraded antigen and then the HLA class II mole-cule/antigen complex is exported to the surface of the cell for presentation to CD4+ T helper (Th) cells. PSMB = Proteasome subunit B –type, TAP = Transporters associated with antigen presentation, β2M = β2 Microglobulin, CLIP = class II associated invariant chain.
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