Expert Reviews in Molecular Medicine: http://www.expertreviews.org/
DOI: 10.1017/S1462399405009981; 18 October 2005
Oliver Brand, Stephen Gough and Joanne Heward (2005) HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity?
Expert Rev. Mol. Med. Vol. 7, Issue 23, DOI: 10.1017/S1462399405009981

HLA, CTLA-4 and PTPN22: the shared genetic master-key to autoimmunity?

Oliver Brand, Stephen Gough and Joanne Heward

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Several genetic loci appear to be involved in susceptibility to autoimmune disease. Some loci are disease specific, whereas others appear to exert a general effect on the autoimmune disease process. Despite a large number of studies of many different diseases, consistent associations with multiple autoimmune disorders have been restricted to three gene regions: the human leukocyte antigen (HLA) class II region on chromosome 6p21, the gene encoding cytotoxic T lymphocyte-associated 4 (CTLA-4) on chromosome 2q33, and the PTPN22 gene encoding lymphoid tyrosine phosphatase (LYP) on chromosome 1p13. Each of these loci is likely to encode molecules that are crucial in the immune cascade and are actively involved in T-cell activation. Moreover, gene polymorphisms that affect function might contribute to the triggering of autoimmune disease by as-yet-unknown mechanisms. This review summarises recent developments and current understanding of the way in which molecules encoded by these susceptibility loci contribute to T-cell activation, and hypothesises how aberrant function of these molecules might trigger autoimmunity.

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Figure 1. A schematic diagram showing the major genes within the HLA class II region.
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Figure 2. Proposed mechanisms by which CTLA-4 inhibits T-cell activation.
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Figure 3. Proposed mechanisms by which LYP affects T-cell activation.
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Figure 4. Proposed mechanism by which CTLA-4 might use LYP/Grb2 to inhibit T-cell activation.
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Table 1. HLA class II haplotype associations with autoimmune disease.
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