Transgenic expression of Hsc70 in pancreatic islets enhances autoimmune diabetes in response to beta cell damage

J Immunol. 2009 Nov 1;183(9):5728-37. doi: 10.4049/jimmunol.0901288. Epub 2009 Oct 7.

Abstract

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 beta 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 beta 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 beta 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / epidemiology
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / pathology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / pathology
  • Cattle
  • Cell Death / genetics
  • Cell Death / immunology
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cytosol / immunology
  • Cytosol / metabolism
  • Diabetes Mellitus, Experimental / epidemiology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology*
  • Diabetes Mellitus, Experimental / pathology*
  • Disease Models, Animal
  • HSC70 Heat-Shock Proteins / biosynthesis*
  • HSC70 Heat-Shock Proteins / genetics*
  • Incidence
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology*
  • Lymphocyte Activation / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Transgenic
  • Rats

Substances

  • HSC70 Heat-Shock Proteins