【摘 要】
：
Toll-like receptors (TLR) act as early sensors of microbial pathogens, but accumulating evidence indicates that they also have an important role in autoimmunity.In particular, manipulation of TLRs in
【机 构】
：
The University of Melbourne Australia
【出 处】
：
MIT`s 1st Annual World Congress of Diabetes-2012(2012第一届糖尿病大
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Toll-like receptors (TLR) act as early sensors of microbial pathogens, but accumulating evidence indicates that they also have an important role in autoimmunity.In particular, manipulation of TLRs in the nonobese diabetic (NOD) mouse strain alters the onset of type 1 diabetes (T1D), an autoimmune disease in which lymphocytes mediate the destruction of insulin-producing beta cells.More than twenty-five loci (termed Idd) have been linked to T1D in NOD mice.To identify the underlying gene for the Idd11 locus on chromosome 4, we established a panel of congenic mouse strains that have different C57BL/6-derived intervals for chromosome 4 on the NOD genetic background.These congenic strains exhibited different levels of T1D incidence and localized Idd11 to sequence variation within a predicted gene of unknown function for which expression is upregulated by TLR activation.Additional analyses indicated that expression of this gene is lower in NOD mice compared to diabetes-resistant C57BL/6 and Idd11 congenic mice.Moreover, TLR activation of immune cells from NOD mice, compared to those from C57BL/6 and Idd11 congenic mice, led to enhanced cytokine production.We subsequently named the Idd11 candidate gene Trag for Toll-like Receptor Attenuator Gene.To confirm this proposed molecular function of Trag, we established a knockout C57BL/6 strain for this gene and discovered that Trag-deficient immune cells from these mice, similar to immune cells from NOD mice, exhibit enhanced cytokine production in response to TLR activation.These combined results suggest that genetic variation for Trag affects TLR-mediated immune responses, which contribute to T1D pathogenesis in NOD mice.
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