Definition of IFN-γ-related pathways critical for chemically-induced systemic autoimmunity

Pollard, K. Michael; Hultman, Per; Toomey, Christopher B.; Cauvi, David M.; Hoffman, Hal M.; Hamel, John C.; Kono, Dwight H.

doi:10.1016/j.jaut.2012.04.003

Cited by 34 publications

(31 citation statements)

References 72 publications

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“…Sections of kidney and spleen were stained for direct immunofluorescence as previously described (26). Briefly, 4 μm sections were fixed with ethanol, then incubated with serial dilutions of FITC-conjugated goat anti-mouse IgG Abs (Southern Biotechnology, Birmingham, AL).…”

Section: Methodsmentioning

confidence: 99%

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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

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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.

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Section: Methodsmentioning

confidence: 99%

“…The exception is the MRL strain, for which Ifnar1 -deficiency and IFN-β treatment have the opposite effects on disease (19, 20). IFN-γ (type II IFN) is also important for the development of lupus and required in all spontaneous and induced mouse models examined so far (21–26). …”

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

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“…ANAs were detected on Hep2 slides (MBL Bion, Des Plains, IL) at 1/100 diluted sera and 1/200 diluted Alexa Fluor 488-conjugated anti-mouse IgG secondary antibody (Invitrogen) as described in [35]. …”

Section: Methodsmentioning

confidence: 99%

The effect of the autoimmunity-associated gene, PTPN22, on a BXSB-derived model of lupus

Maine¹,

Marquardt²,

Scatizzi³

et al. 2015

Clinical Immunology

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A single nucleotide polymorphism in PTPN22 is linked to increased disease susceptibility in a range of autoimmune diseases including systemic lupus erythematosus (SLE). PTPN22 encodes the Lyp phosphatase that dampens TCR signaling and is necessary for signaling downstream of toll-like receptors in myeloid cells. To understand these dual functions in disease, we examined the impact of deficiency in PTPN22 on a spontaneous murine model of SLE. Male PTPN22 KO mice carrying BXSB chromosome 1 and the Yaa disease accelerating factor, developed disease at a similar rate and severity as PTPN22 WT. In contrast, although female BXSB mice showed no differences in survival in the absence of PTPN22, autoantibody production was significantly increased and splenic populations associated with pathogenesis in this model were expanded in the PTPN22 KO group. These findings support the notion that when coupled with other predisposing autoimmunity genes, PTPN22 deficiency contributes to a predisposition to lupus pathogenesis.

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“…To varying extents, environmental factors also contribute to the development of autoimmunity. However, although idiopathic and environmentally induced systemic autoimmunity share common requirements [6,7], it is becoming clear that differences exist [8]. In this review we compare and contrast the innate immune system requirements for idiopathic systemic autoimmunity with systemic autoimmunity induced by exposure to mercury and pristane.…”

Section: Reviewmentioning

confidence: 99%

“…The adaptive immune responses required for murine mercury-induced autoimmunity (mHgIA) share common requirements with idiopathic lupus including certain cytokines [114,115], co-stimulation factors [116,117] and transcription factors [8,118]. However, whereas type I IFN signaling pathways predominate in idiopathic and pristane-induced autoimmune disease, our recent studies indicate that mHgIA is independent of type I IFN.…”

Section: Reviewmentioning

confidence: 99%

Requirements for innate immune pathways in environmentally induced autoimmunity

Pollard

Kono

2013

BMC Med

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There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Although the specific environmental agents and how they promote autoimmunity remain largely unknown, in part because of diverse etiologies, environmentally induced autoimmune models can provide insights into potential mechanisms. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. By contrast, although the innate immune system is indispensable for autoimmunity, there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases, suggesting distinct autoimmune-promoting pathways. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Accordingly, idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity, although dependent on nucleic acid-binding toll-like receptors, does not require type I interferon but needs proinflammatory cytokines. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity.

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Definition of IFN-γ-related pathways critical for chemically-induced systemic autoimmunity

Cited by 34 publications

References 72 publications

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

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

The effect of the autoimmunity-associated gene, PTPN22, on a BXSB-derived model of lupus

Requirements for innate immune pathways in environmentally induced autoimmunity

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