| 1. |
- 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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| 2. |
- Haraldsson, M Katarina, et al.
(författare)
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The lupus-related Lmb3 locus contains a disease-suppressing Coronin-1A gene mutation.
- 2008
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613 .- 1097-4180. ; 28:1, s. 40-51
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Tidskriftsartikel (refereegranskat)abstract
- Here, we show that a lupus-suppressing locus is caused by a nonsense mutation of the filamentous actin-inhibiting Coronin-1A gene. This mutation was associated with developmental and functional alterations in T cells including reduced migration, survival, activation, and Ca2+ flux. T-dependent humoral responses were impaired, but no intrinsic B cell defects were detected. By transfer of T cells, it was shown that suppression of autoimmunity could be accounted for by the presence of the Coro1a(Lmb3) mutation in T cells. Our results demonstrate that Coronin-1A is required for the development of systemic lupus and identify actin-cytoskeleton regulatory proteins as potential targets for modulating autoimmune diseases.
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| 3. |
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| 4. |
- Pollard, K Michael, et al.
(författare)
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Costimulation requirements of induced murine systemic autoimmune disease
- 2004
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Ingår i: Journal of Immunology. - 0022-1767 .- 1550-6606. ; 173:9, s. 5880-5887
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Tidskriftsartikel (refereegranskat)abstract
- Costimulation between T cells and APC is required for productive immune responses. A number of receptor/ligand pairs have been shown to mediate costimulation, including CD28/B7 molecules (CD80 and CD86), CD40/CD40 ligaad (CD40L, CD154), and LFA-1 (CD18)/ICAM-1 (CD54). T-B cell Costimulation also plays a significant role in autoimmune diseases such as systemic lupus erythematosus. Murine HgCl2-induced autoimmunity (mHgIA) is a T cell-dependent systemic autoimmune disease that shares a number of common pathogenic mechanisms with idiopathic lupus. In this report, the significance of costimulation in mHgIA is examined by attempting to induce disease in mice deficient in either CD40L, CD28, or ICAM-1. Unlike absence of ICAM-1, homozygous deficiencies in either CD40L or CD28 significantly reduced the development of mHgIA. CD40L displayed a gene dosage effect as heterozygous mice also showed reduction of autoantibody responses and immunopathology. Markers of T cell activation such as CD44 and CTLA-4 were associated with disease expression in wild-type and ICAM-1-deficient mice but not in CD40L- or CD28-deficient mice. Absence of CTLA-4 expression in CD40L-/- mice suggests that signaling via both CD28 and CD40L is important for T cell activation and subsequent autoimmunity in mHgIA. Attempts to circumvent the absence of CD40L by increasing CD28 signaling via agonistic Ab failed to elicit CTLA-4 expression. These findings indicate that breaking of self-tolerance in mHgIA requires signaling via both the CD28/B7 and CD40/CD40L pathways.
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| 5. |
- Pollard, K Michael, et al.
(författare)
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Immunology and genetics of induced systemic autoimmunity
- 2005
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Ingår i: Autoimmunity Reviews. - : Elsevier BV. - 1568-9972 .- 1873-0183. ; 4:5, s. 282-288
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the role of specific genes in lupus, we have examined the effects of single gene deletions on mercury-induced autoimmunity. Deficiency of certain genes abrogated induction of autoimmunity, while absence of others had little effect. The most interesting observations were obtained with genes related to interferon-γ. Genes involved in upregulation of IFN-γ expression did not significantly influence autoimmunity whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody responses and immunopathology. Absence of IRF-1, a gene expressed in response to IFN-γ, resulted in selective retention of anti-chromatin autoantibodies demonstrating that specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction influence specific disease parameters. These studies show that single gene deletions can have various outcomes ranging from no effect, suppression of one or more features of disease, to suppression of all features of disease, and that all three outcomes can be observed in the IFN-γ pathway. IFN-γ influences the expression and function of other lupus relevant genes such as IL-6 and β2microglobulin, therefore the effects of these gene deletions on disease expression may also reflect responses downstream of IFN-γ function. © 2005 Elsevier B.V. All rights reserved.
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| 6. |
- Pollard, K. Michael, et al.
(författare)
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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
- 2017
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Ingår i: Journal of Immunology. - : AMER ASSOC IMMUNOLOGISTS. - 0022-1767 .- 1550-6606. ; 199:11, s. 3739-3747
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Tidskriftsartikel (refereegranskat)abstract
- 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 systemic lupus erythematosus patients, however, lack the IFN signature, suggesting the possibility of type I IFN-independent mechanisms. In this study, we examined the role of type I IFN and TLR trafficking and signaling in xenobiotic systemic mercury-induced autoimmunity (HgIA). Strikingly, autoantibody 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, solute carrier family 15, member 4. HgIA also required the adaptor protein-3 complex, which transports TLRs from the early endosome to the late endolysosomal compartments. Examination of TLR signaling pathways implicated the canonical NF-kappa B pathway and the proinflammatory cytokine IL-6 in autoantibody production, but not IFN regulatory factor 7. These findings identify HgIA as a novel type I IFN-independent model of systemic autoimmunity and implicate TLR-mediated NF-kappa B proinflammatory signaling from the late endocytic pathway compartments in autoantibody generation.
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| 7. |
- 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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| 8. |
- 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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| 9. |
- Pollard, K Michael, et al.
(författare)
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Toxicology of Autoimmune Diseases
- 2010
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Ingår i: CHEMICAL RESEARCH IN TOXICOLOGY. - : American Chemical Society (ACS). - 0893-228X .- 1520-5010. ; 23:3, s. 455-466
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Tidskriftsartikel (refereegranskat)abstract
- Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely, drugs and chemicals, can promote the development of autoimmunity, focusing oil a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity, some similarities do exist, and a working model is proposed.
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| 10. |
- Pollard, K Michael, et al.
(författare)
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Using single-gene deletions to identify checkpoints in the progression of systemic autoimmunity
- 2003
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Ingår i: Annals of the New York Academy of Sciences. - : Wiley. - 0077-8923 .- 1749-6632. ; 987, s. 236-239
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus is a multigenic disorder of unknown etiology. To investigate the roles that specific genes play in lupus, we have examined the disease profiles in mice with single-gene deletions. In total, some 17 genes have been studied. Absence of certain genes, such as CD40L, CD28, or Igh6, abrogated induction of autoimmunity. Other genes, such as Igh5, IL-4, or ICAM-1, had little effect on the development of disease. Intermediate effects were observed in IL-6-deficient mice, while absence of β2-microglobulin resulted in loss of hypergammaglobulinemia and IgG1 autoantibodies, but produced little change in anti-chromatin antibodies or glomerular deposits. The most interesting observations were obtained with genes related to the expression or function of interferon-γ (IFN-γ). Reductions in IFN-γ levels in murine lupus are associated with reductions in both autoantibody levels and immune-complex- mediated pathology. Genes involved in up-regulation of IFN-γ expression, such as IL-12, STAT-4, or ICE, did not significantly influence autoimmunity, whereas absence of IFN-γ or IFN-γ receptor led to greatly reduced autoantibody response and immunopathology. Absence of IRF-1, a gene ex-pressed in response to IFN-γ, resulted in selective retention of anti-chromatin antibodies but little glomerular pathology. These studies suggest that the presence of a baseline level of IFN-γ, rather than increased expression, is important for autoimmunity. Furthermore, as the IRF-1 knockout demonstrates, specific defects in signaling pathways and gene expression subsequent to IFN-γ/IFN-γ receptor interaction may influence only certain disease parameters. It has not escaped our attention that IFN-γ influences the expression and function of other immunologically relevant genes, such as IL-4, IL-6, and β2-microglobulin. Thus, these genes may be part of the downstream events following IFN-γ/IFN-γ receptor interaction that promote the development of autoimmunity.
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