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

Abstract

Inflammation following tissue damage promotes lymphocyte recruitment, tissue remodelling, 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. Here 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, pro-inflammatory serum cytokines, and lymphocyte recruitment were increased in Hsc70 transgenic mice. Islet-antigen-specific T cells underwent a greater extent of proliferation in the lymph nodes of mice expressing Hsc70 following β-cell damage, suggesting elevated antigen presentation following release of antigen 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.

An analysis of the phosphoproteome of immune cell lines exposed to the immunomodulatory mycotoxin deoxynivalenol

“…Studies conducted in lymphocytes isolated from human peripheral blood mononuclear cells reported that Hsc70 expression regulates the development of B lymphocytes and is a potential target of tyrosine kinase activity in T lymphocytes. It has been associated with increases in inflammation and susceptibility to autoimmunity as well as regulating the myocardial immune response [37][38][39][40].…”

Cytokine effects and cellular signaling pathways of grass carp HSP70 in head kidney leukocytes

“…Besides, HSP70 has been implicated in both innate and adaptive immunity [3]. For example, extracellular HSP70 can be recognized by macrophage and nature killer (NK) cells [4,5] and plays critical roles in antigen presentation, autoimmunity and tumor immunity [6,7]. Particularly, HSP70 up-regulates the gene expression of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-a, interleukin (IL)-1b, IL-6 and IL-12 in human monocytes [6,8,9].…”

Comparative studies on temperature threshold for heat shock protein 70 induction in young and adult Murrah buffaloes

“…HSP70 could serve as a prognostic marker in heatstroke (Dehbi et al., 2010). In addition to this function, HSPs exert an immune‐stimulatory effect, activate the host inflammatory response (Johnson and Fleshner, 2006), increase in the phagocytosis and maturation of phagosomes (Anand et al., 2010), in the modulation of the autoimmunity and tumour immunity (Alam et al., 2009). Not only that, HSP expression has also been detected in gametes and early‐stage embryos (Wilkerson and Sarge, 2009).…”