Closing the circle between the bedside and the bench: Toll-like receptors in models of virally induced diabetes

Abstract

Animal models provide many strategies to unravel the complex interplay of genetic, immunologic, and environmental factors involved in the pathogenesis of type 1A (autoimmune) diabetes. Diabetes can be studied at multiple levels, and new technological advancements provide insights into the functioning of organelle and cellular structures. The role of innate immunity in the response to environmental pathogens has provided possible biochemical and molecular mechanisms which can explain certain clinical events in diabetes. These investigations may uncover new therapies and strategies to prevent type 1A diabetes.

Figure 1. The circle between the bedside and the bench

Clinical examination of patients at the bedside can be utilized to design experiments in animal models at the laboratory bench in order to further knowledge about T1D. In turn, information gained through scientific research at the bench can be used to develop therapeutics for treatment of T1D and its clinical symptoms. The study of diabetes in the “bedside to bench” model begins at the population level and continues to the molecular level of genomic research. In the future, answers to many challenging questions surrounding T1D pathogenesis may lie in the very atoms that comprise the molecules of the cell (adapted from Majno and Joris (2004)30).

Figure 2. A model of TLR signaling in dentritic cells during virus induced diabetes

Signaling via the endosomal localized TLR3 (poly I:C) or TLR9 (KRV) during diabetes induction (step 1) leads to downstream signaling events to the nucleus (step 2). These signals activate transcription factors, such as NFκB and IRF, which transcribe type 1 IFNs and other important cytokines (step 3) that have direct effects on the adaptive immune system and possibly on beta cells. Research data suggests that chloroquine inhibits TLR9 signaling and decreases KRV induced diabetes, thus making it a potential therapeutic candidate in the clinic. Other possible therapeutic candidates may exist, such as miRNAs, which are produced following TR3 ligation and capable of regulating inflammatory responses.