Abstract
Type 1 diabetes is characterized by autoimmune destruction of pancreatic beta cells. The role played by autoantibodies directed against beta cells antigens in the pathogenesis of the disease is still unclear. Coxsackievirus B infection has been linked to the onset of type 1 diabetes; however its precise role has not been elucidated yet. To clarify these issues, we screened a random peptide library with sera obtained from 58 patients with recent onset type 1 diabetes, before insulin therapy. We identified an immunodominant peptide recognized by the majority of individual patients’sera, that shares homology with Coxsackievirus B4 VP1 protein and with beta-cell specific autoantigens such as phogrin, phosphofructokinase and voltage-gated L-type calcium channels known to regulate beta cell apoptosis. Antibodies against the peptide affinity-purified from patients’ sera, recognized the viral protein and autoantigens; moreover, such antibodies induced apoptosis of the beta cells upon binding the L-type calcium channels expressed on the beta cell surface, suggesting a calcium dependent mechanism. Our results provide evidence that in autoimmune diabetes a subset of anti-Coxsackievirus antibodies are able to induce apoptosis of pancreatic beta cells which is considered the most critical and final step in the development of autoimmune diabetes without which clinical manifestations do not occur.
Highlights
IntroductionAs for other autoimmune diseases, it is triggered by the interaction between genetic and environmental factors
Type 1 diabetes is a chronic autoimmune disease characterized by progressive and selective destruction of pancreatic beta cells in genetically predisposed individuals during childhood or adolescence [1,2].As for other autoimmune diseases, it is triggered by the interaction between genetic and environmental factors
To define pathogenetically relevant autoantigens in type 1 diabetes, we screened a dodecamer random peptide library [19,20,21,22,23], with pooled immunoglobulins derived from 58 patients with recent onset type I diabetes before insulin therapy
Summary
As for other autoimmune diseases, it is triggered by the interaction between genetic and environmental factors. Recent findings have shown that genetic polymorphism of IFIH1 is associated to increased risk to develop type 1 diabetes. This gene encodes for an innate immune system receptor for enteroviruses suggesting one possible mechanism for the diabetogenic effect of enteroviruses. This is further emphasized by the observation that the innate immune system is activated in the pancreatic islets of type 1 diabetic patients [5]
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