Presented antigen from damaged pancreatic β cells activates autoreactive T cells in virus-mediated autoimmune diabetes

Abstract

The induction of autoimmunity by viruses has been attributed to numerous mechanisms. In mice, coxsackievirus B4 (CB4) induces insulin-dependent diabetes mellitus (IDDM) resembling the final step of disease progression in humans. The immune response following the viral insult clearly precipitates IDDM. However, the molecular pathway between viral infection and the subsequent activation of T cells specific for islet antigen has not been elucidated. These T cells could become activated through exposure to sequestered antigens released by damaged β cells, or they could have responded to factors secreted by the inflammatory response itself. To distinguish between these possibilities, we treated mice harboring a diabetogenic T cell repertoire with either the islet-damaging agent streptozotocin (STZ) or poly I:C, which nonspecifically activates T cells. Significantly, only treatment of mice with STZ resulted in IDDM and mimicked the effects observed following CB4 infection. Furthermore, antigen-presenting cells from STZ-treated mice were shown to directly activate autoreactive T cells and induce diabetes. Therefore, the primary role of CB4 in the precipitation of IDDM is to damage tissue, causing release and presentation of sequestered islet antigen. These events stimulate autoreactive T cells and thereby initiate disease.

Prolonged Viral RNA Detection in Blood and Lymphoid Tissues from Coxsackievirus B4 E2 Orally‐Inoculated Swiss Mice

“…All samples, including those showing negative results for CVB4 E2 RNA, were positive for GAPDH mRNA, proving the RNA integrity and the absence of reaction inhibitors (results not shown). Our data show that a systemic spreading of CVB4 E2 following oral inoculation is possible and that outbred mice, in addition to inbred, diabetic, immuno-compromised or transgenic mice (4,8,9,11,18,21), can be infected with that viral strain. The natural expression in the mouse of a coxsackievirus and adenovirus receptor strongly homologous to the human one (19), made possible the use of these animals as models to study the infection with CVB4 E2.…”

IFNβ Accelerates Autoimmune Type 1 Diabetes in Nonobese Diabetic Mice and Breaks the Tolerance to β Cells in Nondiabetes-Prone Mice

“…Studies on identical twins showed a concordance rate of diabetes lower than 50%, suggesting an important role for the environmental factors, e.g., viral infections (5). Viruses might be involved in the pathogenesis of the disease through exposure to sequestered Ags released by damaged ␤ cells, by altering some mechanisms of peripheral tolerance, by molecular mimicry, or by a direct destruction of the insulin-producing cells (6,7).…”

Lessons from the mouse: potential contribution of bystander lymphocyte activation by viruses to human type 1 diabetes

“…For CVB4, this acceleration requires a threshold number of autoreactive T cells and therefore the presence of preexisting autoimmunity [92]. Based on mouse studies, CVB4 is thought to induce diabetes not by inducing beta cell death or molecular mimicry, but instead by evoking beta cell damage, release of sequestered antigens and presentation of these antigens by resident macrophages to autoreactive T cells [14,16,93]. Type I IFN expression within islets prevents CVB replication and CVB-induced diabetes acceleration [94].…”