| 1. |
- Pollard, Kenneth M, et al.
(författare)
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beta 2-microglobulin is required for the full expression of xenobiotic-induced systemic autoimmunity
- 2011
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Ingår i: JOURNAL OF IMMUNOTOXICOLOGY. - : Informa Healthcare. - 1547-691X. ; 8:3, s. 228-237
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Tidskriftsartikel (refereegranskat)abstract
- ercury exposure in both humans and mice is associated with features of systemic autoimmunity. Murine HgCl(2)-induced autoimmunity (mHgIA) requires MHC Class II, CD4(+) T-cells, co-stimulatory molecules, and interferon-gamma (IFN-gamma), similar to spontaneous models of systemic lupus erythematosus (SLE). beta(2)-microglobulin (B2m) is required for functional MHC Class I molecules and the neonatal F(c) receptor (F(c)Rn). Deficiency of B2m in lupus-prone strains is consistently associated with reduced IgG levels, but with variable effects on other manifestations. Herein, we examined the role of B2m in mHgIA and show that in the absence of B2m, mercury-exposed mice failed to exhibit hypergammaglobulinemia, had reduced anti-nucleolar autoantibodies (ANoA), and had a lower incidence of immune complex deposits in splenic blood vessels, whereas IgG anti-chromatin autoantibodies and renal immune deposits were largely unaffected. Subclass analysis of the IgG anti-chromatin, however, revealed a significant reduction in the IgG(1) subtype. Examination of IFN gamma, IL-4, and IL-2 in exposed skin, draining lymph nodes, and spleen following mercury exposure showed reduced IL-4 in the spleen and skin in B2m-deficient mice, consistent with the lower IgG(1) anti-chromatin levels, and reduced IFN-gamma expression in the skin. These findings demonstrate how a single genetic alteration can partially but significantly modify the clinical manifestations of systemic autoimmunity induced by exposure to xenobiotics.
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| 2. |
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| 3. |
- Pollard, K. Michael, et al.
(författare)
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Mechanisms of Environment-Induced Autoimmunity
- 2021
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Ingår i: Annual Review of Pharmacology and Toxicology. - : ANNUAL REVIEWS. - 0362-1642 .- 1545-4304. - 9780824304614 ; 61, s. 135-157
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Forskningsöversikt (refereegranskat)abstract
- Although numerous environmental exposures have been suggested as triggers for preclinical autoimmunity, only a few have been confidently linked to autoimmune diseases. For disease-associated exposures, the lung is a common site where chronic exposure results in cellular toxicity, tissue damage, inflammation, and fibrosis. These features are exacerbated by exposures to particulate material, which hampers clearance and degradation, thus facilitating persistent inflammation. Coincident with exposure and resulting pathological processes is the posttranslational modification of self-antigens, which, in concert with the formation of tertiary lymphoid structures containing abundant B cells, is thought to promote the generation of autoantibodies that in some instances demonstrate major histocompatibility complex restriction. Under appropriate gene-environment interactions, these responses can have diagnostic specificity. Greater insight into the molecular and cellular requirements governing this process, especially those that distinguish preclinical autoimmunity from clinical autoimmune disease, may facilitate determination of the significance of environmental exposures in human autoimmune disease.
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| 4. |
- Pollard, Michael K, et al.
(författare)
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Definition of IFN-gamma-related pathways critical for chemically-induced systemic autoimmunity
- 2012
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 39:4, s. 323-331
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Tidskriftsartikel (refereegranskat)abstract
- IFN-gamma is essential for idiopathic and murine mercury-induced systemic autoimmunity (mHgIA), and heterozygous IFN-gamma(+/-) mice also exhibit reduced disease. This suggests that blocking specific IFN-gamma-related pathways that may only partially inhibit IFN-gamma production or function will also suppress autoimmunity. To test this hypothesis, mice deficient in genes regulating IFN-gamma expression (Casp1, Nlrp3, Il12a, Il12b, Stat4) or function (Ifngr1, Irf1) were examined for mHgIA susceptibility. Absence of either Ifngr1 or Irf1 resulted in a striking reduction of disease, while deficiency of genes promoting IFN-gamma expression had modest to no effect. Furthermore, both Irf1- and Ifng-deficiency only modestly reduced the expansion of CD44(hi) and CD44(hi)CD55(lo) CD4(+) T cells, indicating that they are not absolutely required for T cell activation. Thus, there is substantial redundancy in genes that regulate IFN-gamma expression in contrast to those that mediate later signaling events. These findings have implications for the therapeutic targeting of IFN-gamma pathways in systemic autoimmunity.
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| 5. |
- Cauvi, David M, et al.
(författare)
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A tandem repeat in decay accelerating factor 1 is associated with severity of murine mercury-induced autoimmunity
- 2014
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Ingår i: Autoimmune Diseases. - : Hindawi Publishing Corporation. - 2090-0422 .- 2090-0430. ; 2014:260613
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Tidskriftsartikel (refereegranskat)abstract
- Decay accelerating factor (DAF), a complement-regulatory protein, protects cells from bystander complement-mediated lysis and negatively regulates T cells. Reduced expression of DAF occurs in several systemic autoimmune diseases including systemic lupus erythematosus, and DAF deficiency exacerbates disease in several autoimmune models, including murine mercury-induced autoimmunity (mHgIA). Daf1, located within Hmr1, a chromosome 1 locus associated in DBA/2 mice with resistance to mHgIA, could be a candidate. Here we show that reduced Daf1 transcription in lupus-prone mice was not associated with a reduction in the Daf1 transcription factor SP1. Studies of NZB mice congenic for the mHgIA-resistant DBA/2 Hmr1 locus suggested that Daf1 expression was controlled by the host genome and not the Hmr1 locus. A unique pentanucleotide repeat variant in the second intron of Daf1 in DBA/2 mice was identified and shown in F2 intercrosses to be associated with less severe disease; however, analysis of Hmr1 congenics indicated that this most likely reflected the presence of autoimmunity-predisposing genetic variants within the Hmr1 locus or that Daf1 expression is mediated by the tandem repeat in epistasis with other genetic variants present in autoimmune-prone mice. These studies argue that the effect of DAF on autoimmunity is complex and may require multiple genetic elements.
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| 6. |
- Pollard, K. Michael, et al.
(författare)
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Mercury-induced inflammation and autoimmunity
- 2019
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Ingår i: Biochimica et Biophysica Acta - General Subjects. - : ELSEVIER. - 0304-4165 .- 1872-8006. ; 1863:12
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Forskningsöversikt (refereegranskat)abstract
- Background: Human exposure to mercury leads to a variety of pathologies involving numerous organ systems including the immune system. A paucity of epidemiological studies and suitable diagnostic criteria, however, has hampered collection of sufficient data to support a causative role for mercury in autoimmune diseases. Nevertheless, there is evidence that mercury exposure in humans is linked to markers of inflammation and autoimmunity. This is supported by experimental animal model studies, which convincingly demonstrate the biological plausibility of mercury as a factor in the pathogenesis of autoimmune disease. Scope of the review: In this review, we focus on ability of mercury to elicit inflammatory and autoimmune responses in both humans and experimental animal models. Major conclusions: Although subtle differences exist, the inflammatory and autoimmune responses elicited by mercury exposure in humans and experimental animal models show many similarities. Proinflammatory cytokine expression, lymphoproliferation, autoantibody production, and nephropathy are common outcomes. Animal studies have revealed significant strain dependent differences in inflammation and autoimmunity suggesting genetic regulation. This has been confirmed by the requirement for individual genes as well as genome wide association studies. Importantly, many of the genes required for mercury-induced inflammation and autoimmunity are also required for idiopathic systemic autoimmunity. A notable difference is that mercury-induced autoimmunity does not require type I IFN. This observation suggests that mercury-induced autoimmunity may arise by both common and specific pathways, thereby raising the possibility of devising criteria for environmentally associated autoimmunity. General significance: Mercury exposure likely contributes to the pathogenesis of autoimmunity.
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