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This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901288v1 183/9/5728    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Alam, M.-u. Articles by Millar, D. G. PubMed PubMed Citation Articles by Alam, M.-u. Articles by Millar, D. G.

Transgenic Expression of Hsc70 in Pancreatic Islets Enhances Autoimmune Diabetes in Response to β Cell Damage¹

Masih-ul Alam,^* Julie A. Harken,^* Anna-Maria Knorn,^* Alisha R. Elford, Kip Wigmore, Pamela S. Ohashi,² and Douglas G. Millar^23*

^*Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and Campbell Family Institute for Breast Cancer Research, University Health Network, Toronto, Ontario, Canada

Inflammation following tissue damage promotes lymphocyte recruitment, tissue remodeling, and wound healing while maintaining self tolerance. Endogenous signals associated with tissue damage and cell death have been proposed to initiate and instruct immune responses following injury. In this study, we have examined the effects of elevated levels of a candidate endogenous danger signal, heat shock cognate protein 70 (hsc70), on stimulation of inflammation and autoimmunity following cell damage. We find that damage to pancreatic β cells expressing additional cytosolic hsc70 leads to an increased incidence of diabetes in a transgenic mouse model. Steady-state levels of activated APC and T cell populations in the draining lymph node were enhanced, which further increased following streptozotocin-induced β cell death. In addition, proinflammatory serum cytokines, and lymphocyte recruitment were increased in hsc70 transgenic mice. Islet Ag-specific T cells underwent a greater extent of proliferation in the lymph nodes of mice expressing hsc70 following β cell damage, suggesting elevated Ag presentation following release of Ag in the presence of hsc70. These findings suggest that an elevated content of hsc70 in cells undergoing necrotic or apoptotic cell death can increase the extent of sterile inflammation and increase the susceptibility to autoimmunity.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by an Medical Research Council (UK) New Investigator Award (to D.G.M.) and a Biotechnology and Biological Sciences Research Council (UK) research grant (to D.G.M.). P.S.O. is supported by Grant 17506 from the Canadian Cancer Society. P.S.O. holds a Canada Research Chair in Infection and Immunity.

² P.S.O. and D.G.M. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Douglas Millar, University of Manchester, Faculty of Life Science, AV Hill Building, Oxford Road, Manchester M13 9PT, U.K. E-mail address: douglas.millar{at}manchester.ac.uk

⁴ Abbreviations used in this paper: DAMP, damage associated molecular pattern; hsc, heat shock cognate protein; DC, dendritic cell; ILN, inguinal lymph node; PDLN, pancreatic draining lymph node; STZ, streptozotocin; MLD, multiple low dose; SID, single intermediate dose; LCMV-GP, lymphocytic choriomeningitis virus glycoprotein; RIP, rat insulin promoter; Tg, transgenic.