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

Abstract

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.

Analysis of HLA class II genes in Hashimoto's thyroiditis reveals differences compared to Graves’ disease

“…The strong association of DR4 and only borderline association of DR3 in this study is in marked contrast to that seen in our previous HLA class II studies in GD where DR3 is the strongest association. 6,7 The data suggest, therefore, that although GD and HT fall collectively under the more general term of AITD and even though there are a number of shared genetic determinants between the AITDs 3,4 and the AIDs in general, 22 significant differences exist within the HLA class II region.…”

Evaluation of CTLA-4, CD28 and CD86 Genes Polymorphisms in Acute Renal Allograft Rejection among Tunisian Patients

“…CTLA-4 could prevent constitutive expression of downstream signaling pathways by interacting with the protein tyrosine kinases (PTKs) Lck, Fyn and ZAP-70 through SHP1 phosphatase; now these PTKs play a key role in the TCR signaling. CTLA-4 might also directly interact with the TCR-CD3 complex at the immunological synapse to disrupt T-cell activation by binding and blocking the immunoreceptor tyrosine-based activation motif (ITAM) which serves as substrate to the PTKs, and, when its tyrosine residue is phosphorylated, induces the activation of ZAP-70 (Brand, 2005;Chuang et al, 1999) (Figure 3). -4 (Sharp, 2002).…”

“…3. Proposed mechanisms by which CTLA-4 inhibits T-cell activation (Brand, 2005) Such down-regulation of T lymphocytes proliferation may induce immune tolerance, which is fundamental for allograft acceptance. Thus, the outcome of an immune response involves a balance between CD28-mediated T cell activation and CTLA-4-mediated inhibition.…”

Mapping candidate non-MHC susceptibility regions to multiple sclerosis

“…Although new to MS, chromosome 1p13 has been established as a general susceptibility region to many other human autoimmune diseases. 41 As concluded by all previous studies, the current study excludes the presence of a major non-MHC susceptibility locus to MS. The combined MS genomic map contains at least 17 top predicted candidate regions.…”