Chromogranin A is an Autoantigen in Type 1 Diabetes

Overview

Journal Nat Immunol

Date 2010 Feb 9

PMID 20139986

Citations 205

Authors

Brian D Stadinski

Thomas Delong

Nichole Reisdorph

Richard Reisdorph

Roger L Powell

Michael Armstrong

Jon D Piganelli

Gene Barbour

Brenda Bradley

Frances Crawford

Philippa Marrack

Sushil K Mahata

John W Kappler

Kathryn Haskins

Affiliations

Soon will be listed here.

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-A(g7) in an atypical manner, occupying only the carboxy-terminal half of the I-A(g7) 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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References

Portela-Gomes G, Gayen J, Grimelius L, Stridsberg M, Mahata S . The importance of chromogranin A in the development and function of endocrine pancreas. Regul Pept. 2008; 151(1-3):19-25. DOI: 10.1016/j.regpep.2008.07.005. View

Mahapatra N, OConnor D, Vaingankar S, Hikim A, Mahata M, Ray S . Hypertension from targeted ablation of chromogranin A can be rescued by the human ortholog. J Clin Invest. 2005; 115(7):1942-52. PMC: 1159140. DOI: 10.1172/JCI24354. View

Arnold P, La Gruta N, Miller T, Vignali K, Scott Adams P, Woodland D . The majority of immunogenic epitopes generate CD4+ T cells that are dependent on MHC class II-bound peptide-flanking residues. J Immunol. 2002; 169(2):739-49. DOI: 10.4049/jimmunol.169.2.739. View

Crawford F, Kozono H, White J, Marrack P, Kappler J . Detection of antigen-specific T cells with multivalent soluble class II MHC covalent peptide complexes. Immunity. 1998; 8(6):675-82. DOI: 10.1016/s1074-7613(00)80572-5. View

Yoshida K, Martin T, Yamamoto K, Dobbs C, Munz C, Kamikawaji N . Evidence for shared recognition of a peptide ligand by a diverse panel of non-obese diabetic mice-derived, islet-specific, diabetogenic T cell clones. Int Immunol. 2002; 14(12):1439-47. DOI: 10.1093/intimm/dxf106. View

Haskins K, McDuffie M . Acceleration of diabetes in young NOD mice with a CD4+ islet-specific T cell clone. Science. 1990; 249(4975):1433-6. DOI: 10.1126/science.2205920. View

Curry W, Barkatullah S, Johansson A, Quinn J, Norlen P, Connolly C . WE-14, a chromogranin a-derived neuropeptide. Ann N Y Acad Sci. 2002; 971:311-6. DOI: 10.1111/j.1749-6632.2002.tb04485.x. View

Kappler J, White J, Kozono H, Clements J, Marrack P . Binding of a soluble alpha beta T-cell receptor to superantigen/major histocompatibility complex ligands. Proc Natl Acad Sci U S A. 1994; 91(18):8462-6. PMC: 44626. DOI: 10.1073/pnas.91.18.8462. View

Latek R, Suri A, Petzold S, Nelson C, Kanagawa O, UNANUE E . Structural basis of peptide binding and presentation by the type I diabetes-associated MHC class II molecule of NOD mice. Immunity. 2000; 12(6):699-710. DOI: 10.1016/s1074-7613(00)80220-4. View

10.

Crawford F, Huseby E, White J, Marrack P, Kappler J . Mimotopes for alloreactive and conventional T cells in a peptide-MHC display library. PLoS Biol. 2004; 2(4):E90. PMC: 387264. DOI: 10.1371/journal.pbio.0020090. View

11.

Tollefsen S, Arentz-Hansen H, Fleckenstein B, Molberg O, Raki M, Kwok W . HLA-DQ2 and -DQ8 signatures of gluten T cell epitopes in celiac disease. J Clin Invest. 2006; 116(8):2226-36. PMC: 1518792. DOI: 10.1172/JCI27620. View

12.

Kozono H, White J, Clements J, Marrack P, Kappler J . Production of soluble MHC class II proteins with covalently bound single peptides. Nature. 1994; 369(6476):151-4. DOI: 10.1038/369151a0. View

13.

Walker E, Warner N, Chesnut R, Kappler J, Marrack P . Antigen-specific. I region-restricted interactions in vitro between tumor cell lines and T cell hybridomas. J Immunol. 1982; 128(5):2164-9. View

14.

Katz J, Wang B, Haskins K, Benoist C, Mathis D . Following a diabetogenic T cell from genesis through pathogenesis. Cell. 1993; 74(6):1089-100. DOI: 10.1016/0092-8674(93)90730-e. View

15.

Hill J, Southwood S, Sette A, Jevnikar A, Bell D, Cairns E . Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLA-DRB1*0401 MHC class II molecule. J Immunol. 2003; 171(2):538-41. DOI: 10.4049/jimmunol.171.2.538. View

16.

Prochazka M, Leiter E, Serreze D, Coleman D . Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice. Science. 1987; 237(4812):286-9. DOI: 10.1126/science.2885918. View

17.

Daniel D, Gill R, Schloot N, Wegmann D . Epitope specificity, cytokine production profile and diabetogenic activity of insulin-specific T cell clones isolated from NOD mice. Eur J Immunol. 1995; 25(4):1056-62. DOI: 10.1002/eji.1830250430. View

18.

Maynard J, Petersson K, Wilson D, Adams E, Blondelle S, Boulanger M . Structure of an autoimmune T cell receptor complexed with class II peptide-MHC: insights into MHC bias and antigen specificity. Immunity. 2005; 22(1):81-92. DOI: 10.1016/j.immuni.2004.11.015. View

19.

Corper A, Stratmann T, Apostolopoulos V, Scott C, Garcia K, Kang A . A structural framework for deciphering the link between I-Ag7 and autoimmune diabetes. Science. 2000; 288(5465):505-11. DOI: 10.1126/science.288.5465.505. View

20.

Ientile R, Caccamo D, Griffin M . Tissue transglutaminase and the stress response. Amino Acids. 2007; 33(2):385-94. DOI: 10.1007/s00726-007-0517-0. View