Abstract
Human type 1 diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic β cells by T cells. Antigen presenting cells including dendritic cells and macrophages are required to activate and suppress antigen-specific T cells. It has been suggested that antigen uptake from live cells by dendritic cells via scavenger receptor class A (SR-A) may be important. However, the role of SR-A in autoimmune disease is unknown. In this study, SR-A−/− nonobese diabetic (NOD) mice showed significant attenuation of insulitis, lower levels of insulin autoantibodies, and suppression of diabetes development compared with NOD mice. We also found that diabetes progression in SR-A−/− NOD mice treated with low-dose polyinosinic-polycytidylic acid (poly(I∶C)) was significantly accelerated compared with that in disease-resistant NOD mice treated with low-dose poly(I∶C). In addition, injection of high-dose poly(I∶C) to mimic an acute RNA virus infection significantly accelerated diabetes development in young SR-A−/− NOD mice compared with untreated SR-A−/− NOD mice. Pathogenic cells including CD4+CD25+ activated T cells were increased more in SR-A−/− NOD mice treated with poly(I∶C) than in untreated SR-A−/− NOD mice. These results suggested that viral infection might accelerate diabetes development even in diabetes-resistant subjects. In conclusion, our studies demonstrated that diabetes progression was suppressed in SR-A−/− NOD mice and that acceleration of diabetes development could be induced in young mice by poly(I∶C) treatment even in SR-A−/− NOD mice. These results suggest that SR-A on antigen presenting cells such as dendritic cells may play an unfavorable role in the steady state and a protective role in a mild infection. Our findings imply that SR-A may be an important target for improving therapeutic strategies for type 1 diabetes.
Highlights
Human type 1 diabetes (T1D) is an autoimmune disease that results from the autoreactive destruction of pancreatic b cells by T cells and the subsequent loss of insulin production [1]
We found that there were no significant differences in metabolic condition between SR-A2/2 Nonobese diabetic (NOD) mice and NOD mice
Our studies demonstrated that SR-A2/2 NOD mice showed significant suppression of diabetes development compared with NOD mice
Summary
Human type 1 diabetes (T1D) is an autoimmune disease that results from the autoreactive destruction of pancreatic b cells by T cells and the subsequent loss of insulin production [1]. Nonobese diabetic (NOD) mice serve as a spontaneous model system for studying the mechanisms involved in the initiation and propagation of the autoimmune response of human T1D [2]. In NOD mice, pancreatic b cells are destroyed by chronic autoimmune response mainly mediated by autoreactive CD4+ T cells and CD8+ T cells. The effector T cells are b cellreactive CD4+ T cells producing Th1 cytokines such as IFN-c and IFN-c-producing cytotoxic CD8+ T cells. In NOD mice, the balance between effector T cells and Treg shifts to effector T cells, and leads to disease onset [2,3]. Reversal of T1D is clinically more important, but the studies on reversal in mouse models are not successfully applied in humans yet
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