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Revealing what pathogenic T cells see in type 1 diabetes
S.I. Mannering, J.S. Morris, D.J. Thearle, K.P. Jensen, L.C. Harrison in collaboration with N.A. Williamson, A.W. Purcell, Department of Biochemistry and Molecular Biology and ImmunoID, The University of Melbourne; J. Rossjohn, The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, Monash University; B.A. Falk, G.T. Nepom, Benaroya Research Institute, Seattle, WA, USA
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Type 1 diabetes (T1D) is an autoimmune disease caused by T-cell mediated destruction of the pancreatic insulin-producing beta cells. People who have the immune system genes HLA-DR3 and HLA-DR4 are at increased risk of T1D. HLA molecules bind antigenic peptides and the complex is recognised by T-cell receptors. There is increasing evidence that insulin and its precursor proinsulin are autoantigens that play a major role in driving beta-cell destruction. Insights into the specificity of the T cells in autoimmune diseases have been hampered by technical difficulties in identifying and isolating human autoantigen-specific T cells. We developed a method that allows us to identify and isolate rare, autoantigen-specific, T cells from human blood (1, 2). Using T cells isolated this way we identified a peptide sequence (epitope) in the A chain of human insulin that, in association with HLA-DR4, activates T cells from subjects with and at risk of T1D. Biochemical analysis revealed that two of the amino acids in this epitope are chemically modified in a manner not found in the native insulin. Importantly, we found that recognition of this epitope by T cells depends upon this modification. Such modifications, known as post-translational modifications, have been shown to create antigenic peptides in rheumatoid arthritis and coeliac disease. This is the first description of a post-translational modification creating a T-cell epitope implicated in the pathogenesis of T1D.
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Figure 1: Molecular model of modified and unmodified insulin epitope bound to HLA DR4. The unmodified (A) and modified (B) forms of the insulin epitope bound in the cleft of HLA DR4. For clarity a cut-away, side-on-view of the peptide is shown. The post-translational modification is indicated by the arrow
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- Mannering SI, Morris JS, Jensen KP, Purcell AW, Honeyman MC, Van Endert PM, Harrison LC (2004). A sensitive method for detecting proliferation of rare autoantigen-specific T cells. J Immunol Meth 283:173-183.
- Mannering SI, Dromey JA, Morris JS, Thearle DJ, Jensen KP, Harrison LC (2005). An efficient method for cloning human autoantigen-specific T cells. J Immunol Meth 298:83-92.
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