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Chromogranin A is an autoantigen in type 1 diabetes

Abstract

Autoreactive CD4+ T cells are involved in the pathogenesis of many autoimmune diseases, but the antigens that stimulate their responses have been difficult to identify and in most cases are not well defined. In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have identified the peptide WE14 from chromogranin A (ChgA) as the antigen for highly diabetogenic CD4+ T cell clones. Peptide truncation and extension analysis shows that WE14 bound to the NOD mouse major histocompatibility complex class II molecule I-Ag7 in an atypical manner, occupying only the carboxy-terminal half of the I-Ag7 peptide-binding groove. This finding extends the list of T cell antigens in type 1 diabetes and supports the idea that autoreactive T cells respond to unusually presented self peptides.

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Figure 1: Purification of the antigen for the T cell clone BDC-2.5.
Figure 2: Mass spectrometry of IEX fractions.
Figure 3: Absence of the T cell antigen in islets from Chga−/− mice.
Figure 4: Mimotope peptide antigens for the BDC T cells suggest the region of ChgA that contains the epitope for the BDC T cells.
Figure 5: The ChgA-derived peptide WE14 activates all three BDC T cells.
Figure 6: Precise processing of the WE14 peptide is required for optimal presentation by I-Ag7.

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Acknowledgements

We thank P. Pratt for technical assistance. Supported by the National Institutes of Health (RO1 DK50561 to K.H.; T32 AI007405 to T.D.; BioResources Core of DERC P30 DK057516 to K.H.; 5 U19-AI050864 to B.D.S. and J.W.K.; and RO1 AI17134 and RO1 AI18785 to B.D.S., P.M. and J.W.K.), the National Center for Research Resources (S10RR023703 to N.R.) and the Juvenile Diabetes Research Foundation (1-2008-132 to K.H. and N.R.).

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Contributions

B.D.S., T.D., N.R., R.R., J.W.K. and K.H. designed the experiments; B.D.S., T.D., R.L.P. and M.A. did most of the experiments, assisted by G.B., B.B. and F.C.; J.D.P. initially suggested ChgA as a candidate autoantigen; S.K.M. provided the Chga−/− and Chga+/+ mice; B.D.S., T.D., N.R., R.R., P.M., J.W.K. and K.H. analyzed and interpreted the data; B.D.S., T.D., J.W.K. and K.H. wrote the manuscript and prepared the figures; and N.R., R.R. and P.M. helped edit the manuscript.

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Correspondence to Kathryn Haskins.

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Stadinski, B., Delong, T., Reisdorph, N. et al. Chromogranin A is an autoantigen in type 1 diabetes. Nat Immunol 11, 225–231 (2010). https://doi.org/10.1038/ni.1844

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