title: Altered Toll-like receptor signaling pathways in human type 1 diabetes.
abstract: There is compelling evidence from animal models of type 1 diabetes (T1D) that the innate immune system plays a key role in early mechanisms triggering islet destruction. Very little is known, however, about innate immune subsets and pathways potentially involved in mechanisms leading to human T1D. The present study used a comprehensive approach to analyze innate immune functions in primary monocytes and dendritic cells (DCs) from newly diagnosed patients with T1D versus age-matched healthy individuals. We observed that incubation of PBMCs in the presence of the TLR7/8 agonist R848 led to increased proportion of plasmacytoid dendritic cells (pDCs) expressing IFN-α in patients versus healthy control subjects. We also found that TLR4 activation induced a higher frequency of IL-1β expressing monocytes and a reduction in the percentage of IL-6 expressing myeloid dendritic cells (mDCs). The altered TLR responsiveness was not due to aberrant proportions of peripheral DC subsets and monocytes in the blood and did not correlate with altered hemoglobin A1c and the expression of diabetes susceptibility genes but could potentially be associated with enhanced nuclear factor-kappa B signaling. Finally, we observed that levels of serum IFN-α2, IL-1β, IFN-γ, and CXCL-10 were elevated in new onset patients versus the control group. Taken together, our observations provide evidence that altered innate immunity exists in mDCs and pDCs from T1D and raise the possibility that these alterations may be associated with disease mechanisms.
authors: Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, 1775 Aurora Ct., Mail Stop B-140, Aurora, CO 80045, USA.
authors: Adam J
authors: AJ
authors: Meyers
authors: Roopali R
authors: RR
authors: Shah
authors: Peter A
authors: PA
authors: Gottlieb
authors: Danny
authors: D
authors: Zipris
mesh_terms: D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D018925:Chemokines / Q000097:blood; D002648:Child; D002675:Child, Preschool; D003713:Dendritic Cells / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology*; D015854:Up-Regulation; D055815:Young Adult
chemical_list: D018925:Chemokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D051193:Toll-Like Receptors