Editors' ChoiceDiabetes

A Warning Bell Tolls for Type 1 Diabetes

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Science Translational Medicine  17 Oct 2012:
Vol. 4, Issue 156, pp. 156ec189
DOI: 10.1126/scitranslmed.3004935

Type 1 diabetes (T1D) is a disorder in which the immune system mistakenly attacks and destroys the insulin-producing beta cells of the pancreas. The appearance of autoantibodies against islet antigens such as insulin, GAD65, and insulinoma-associated protein–2 is one of the initial signs of the autoimmune destruction of beta cells. However, despite knowing the identity of these antigens, the exact mechanisms that cause T1D are still not fully understood. Recent studies in animal models indicate that the innate immune system may play a critical role in development of this disease.

Toll-like receptors (TLRs) are a type of pattern recognition receptor, which recognize highly conserved molecules broadly shared by pathogens. Once TLRs sense pathogens, intercellular signaling cascades are initiated that lead to an innate immune response, including induction of inflammatory cytokines and chemokines. Alkanani et al. hypothesized that abnormalities in immune response at the onset of T1D may be caused in part by TLRs.

To investigate the responsiveness of the immune system in terms of T1D onset, the authors analyzed peripheral blood mononuclear cells (PBMCs) from autoantibody-positive and -negative individuals for TLR-induced inflammatory cytokine and chemokine production. All study participants were free of hyperglycemia. The number of monocytes and myeloid and plasmacytoid dendritic cells between seropositive and seronegative subjects were comparable. However, the responses of PBMCs from autoantibody-positive and -negative subjects to TLR agonists were distinct—that is, there was an increased population of interleukin-1β–expressing monocytes and myeloid dendritic cells in seropositive individuals. Conversely, numbers of TLR ligand-induced IL-6 positive cells were lower in seropositive subjects. These trends were even more pronounced in autoantibody-positive children.

This study shows that autoantibody-positive subjects who are at risk for T1D, particularly young children, have dysregulated TLR signaling. Because the pathogenic mechanism for T1D is still unclear, it is imperative that we develop assays to predict and prevent the development of this disease. If future studies provide further evidence that prediabetic individuals progressing to T1D have similar aspects of dysregulated TLR signal, and these alterations are involved in the early course of T1D, there may be a critical advancement in the development of therapeutic strategies for the prevention of T1D.

A. K. Alkanani et al., Dysregulated Toll-like receptor–induced interleukin-1β and interleukin-6 responses in subjects at risk for the development of type 1 diabetes. Diabetes 10, 2525–2533 (2012). [PubMed]

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