Autoimmune Models*

Cauvi, David M.; Pollard, K. Michael

doi:10.1016/b978-0-08-046884-6.00624-2

Cited by 1 publication

(1 citation statement)

References 272 publications

(259 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The characteristics of mercury-induced autoimmunity (HgIA) are similar to SLE and include lymphocyte proliferation, increased class II MHC expression, hypergammaglobulinemia, polyclonal Abs to self-antigens, notably anti-nuclear Abs (ANAs), and to some extent immune complex deposits in mice (47), as well as necrotizing vasculitis in rats (48–52). Furthermore, HgIA requires CD4 + T cells, B and T cell co-stimulatory molecules, IFN-γ, and susceptible MHC and background genes (25, 53–57), which strongly supports the possibility of related or identical pathogenic mechanisms as spontaneous lupus.…”

Section: Introductionmentioning

confidence: 99%

Induction of Systemic Autoimmunity by a Xenobiotic Requires Endosomal TLR Trafficking and Signaling from the Late Endosome and Endolysosome but Not Type I IFN

Pollard

Escalante

Huang

et al. 2017

The Journal of Immunology

View full text Add to dashboard Cite

Type I IFN and nucleic acid-sensing TLRs are both strongly implicated in the pathogenesis of lupus with most patients expressing IFN-induced genes in peripheral blood cells and with TLRs promoting type I IFNs and autoreactive B cells. About a third of SLE patients, however, lack the IFN signature suggesting the possibility of type I IFN-independent mechanisms. Here, we examined the role of type I IFN and TLR trafficking and signaling in a xenobiotic systemic autoimmunity induced by mercury (HgIA). Strikingly, autoAb production in HgIA was not dependent on the type I IFN receptor even in NZB mice that require type I IFN signaling for spontaneous disease, but was dependent on the endosomal TLR transporter UNC93B1 and the endosomal proton transporter, SLC15A4. HgIA also required the AP-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-κB pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IRF7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-κB proinflammatory signaling from the late endocytic pathway compartments in autoAb generation.

show abstract