Type 1 diabetes mellitus (T1DM) is the result of immune-mediated destruction of insulin-secreting pancreatic beta cells. For more than 25 years researchers have searched for an environmental agent or event that triggers this autoimmune response. Past research has suggested that T cells that react to islet beta cells can contribute to the autoimmune response in diabetic patients and also play a part in self-tolerance in healthy individuals. The rarity of these cells and inadequate technology has impaired the examination of this paradigm. In the February 2 issue of the Journal of Clinical Investigation Mark Peakman and colleagues from King's College London suggest a mechanism for the specificity of this immune regulation that explains why the same peptides present on pancreatic b cells that activate T cells in patients with T1DM and normal individuals cause an autoimmune response in diabetic patients, but no such response in normal individuals.
The authors developed a novel assay to examine T cell responses to a panel of epitopes naturally expressed by islet cells and demonstrated that it is the pathways of T cell differentiation and maturation in reaction to these epitopes in T1DM patients (in whom autoimmunity develops) and normal individuals (in whom autoimmunity is arrested) that are different. Upon exposure to antigen, naïve T cells in normal individuals differentiate into T cells that produce IL-10, and possibly TGF- beta, subsequently inhibiting cells that would normally mediate an aggressive immune response. The results reported by Peakman and colleagues suggest that in patients with T1DM, there is instead induction of a predominant number of T cells that produce IFN-gamma and IL-2, which drives an autoaggressive immune response. Why these T cell activation pathways differ between normal and T1DM patients will require further characterization.
In an accompanying commentary, Kevan Herald from the Naomi Berrie Diabetes Center at Columbia University, New York, comments that "these new findings concerning the responses of normal individuals and patients with T1DM to autoantigens shed light on the differences in immune responses between these two groups and the mechanisms of pathogenesis of the disease. The findings suggest ways in which regulation of the autoimmune response occur and offer approaches to immune modulation and ultimately tolerance, the immunologist's "Holy Grail."
Materials provided by Journal Of Clinical Investigation. Note: Content may be edited for style and length.
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