The Experts below are selected from a list of 10131 Experts worldwide ranked by ideXlab platform
Ola Winqvist - One of the best experts on this subject based on the ideXlab platform.
-
loss of the lupus autoantigen ro52 trim21 induces tissue inflammation and Systemic Autoimmunity by disregulating the il 23 th17 pathway
Journal of Experimental Medicine, 2009Co-Authors: Alexander Espinosa, Valerie Dardalhon, Susanna Brauner, Aurelie Ambrosi, Rowan Higgs, Fransisco J Quintana, Maria Sjostrand, Maijaleena Eloranta, Joan Ni Gabhann, Ola WinqvistAbstract:Ro52/Trim21 is targeted as an autoantigen in Systemic lupus erythematosus and Sjogren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of Systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52−/−), which appear phenotypically normal if left unmanipulated. However, Ro52−/− mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of Systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52−/− mice conferred protection from skin disease and Systemic Autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and Systemic Autoimmunity through the IL-23–Th17 pathway.
-
Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and Systemic Autoimmunity by disregulating the IL-23–Th17 pathway
The Journal of experimental medicine, 2009Co-Authors: Alexander Espinosa, Valerie Dardalhon, Susanna Brauner, Aurelie Ambrosi, Rowan Higgs, Fransisco J Quintana, Maria Sjostrand, Maijaleena Eloranta, Joan Ni Gabhann, Ola WinqvistAbstract:Ro52/Trim21 is targeted as an autoantigen in Systemic lupus erythematosus and Sjogren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of Systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of Systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and Systemic Autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and Systemic Autoimmunity through the IL-23-Th17 pathway.
Dwight H Kono - One of the best experts on this subject based on the ideXlab platform.
-
Interferon-γ and Systemic Autoimmunity
Discovery medicine, 2013Co-Authors: K. Michael Pollard, Christopher B. Toomey, David M Cauvi, Kevin V. Morris, Dwight H KonoAbstract:The term interferon describes a family of proteins consisting of three major types (I, II, III) which differ in their primary protein sequences, cognate receptors, genetic loci, and cell types responsible for their production. The interferons, especially types I and II, overlap significantly in the genes they control resulting in a shared spectrum of diverse biological effects which includes regulation of both the innate and adaptive immune responses. As such, the interferons are major effectors in the pathogenesis of Autoimmunity, especially Systemic Autoimmunity. The type I IFNs, because they are produced during the early stages of the innate immune response, are thought to play the foremost role in autoimmune responses. However, numerous studies have found that the single type II IFN, IFN-γ, plays an essential role in the development and severity of Systemic Autoimmunity, particularly Systemic lupus erythematosus. This is supported by animal studies where IFN-γ is uniformly required in both spontaneous and induced models of lupus. Although expression of IFN-γ in cells of the innate immune system is almost immediate after activation, expression in adaptive immunity requires a complex orchestration of cellular interactions, signaling events and epigenetic modifications. The multifaceted nature of IFN-γ in adaptive immunity identifies numerous possible therapeutic targets that, because of the essential contribution of IFN-γ to Systemic Autoimmunity, have the potential for producing significant benefits.
-
Definition of IFN-γ-related pathways critical for chemically-induced Systemic Autoimmunity
Journal of Autoimmunity, 2012Co-Authors: K. Michael Pollard, John C. Hamel, Christopher B. Toomey, Per Hultman, Hal M Hoffman, David M Cauvi, Dwight H KonoAbstract:Abstract IFN-γ is essential for idiopathic and murine mercury-induced Systemic Autoimmunity (mHgIA), and heterozygous IFN-γ +/− mice also exhibit reduced disease. This suggests that blocking specific IFN-γ-related pathways that may only partially inhibit IFN-γ production or function will also suppress Autoimmunity. To test this hypothesis, mice deficient in genes regulating IFN-γ 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-γ 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-γ expression in contrast to those that mediate later signaling events. These findings have implications for the therapeutic targeting of IFN-γ pathways in Systemic Autoimmunity.
-
Systemic Autoimmunity and Lymphoproliferation Are Associated with Excess IL-7 and Inhibited by IL-7Rα Blockade
PloS one, 2011Co-Authors: Rosana Gonzalez-quintial, Dwight H Kono, Joe Craft, Brian R. Lawson, John C. Scatizzi, Roberto Baccala, Argyrios N. TheofilopoulosAbstract:Lupus is characterized by disturbances in lymphocyte homeostasis, as demonstrated by the marked accumulation of activated/memory T cells. Here, we provide evidence that proliferation of the CD8+ precursors for the accumulating CD4–CD8– T cells in MRL-Faslpr lupus-predisposed mice is, in part, driven by commensal antigens. The ensuing lymphadenopathy is associated with increased production of IL-7 due to expansion of fibroblastic reticular cells, the primary source of this cytokine. The excess IL-7 is not, however, consumed by CD4–CD8– T cells due to permanent down-regulation of IL-7Rα (CD127), but instead supports proliferation of autoreactive T cells and progression of Autoimmunity. Accordingly, IL-7R blockade reduced T cell activation and autoimmune manifestations even when applied at advanced disease stage. These findings indicate that an imbalance favoring production over consumption of IL-7 may contribute to Systemic Autoimmunity, and correction of this imbalance may be a novel therapeutic approach in lymphoproliferative and autoimmune syndromes.
-
Deficiency of the Cyclin Kinase Inhibitor p21(WAF-1/CIP-1) Promotes Apoptosis of Activated/Memory T Cells and Inhibits Spontaneous Systemic Autoimmunity
The Journal of experimental medicine, 2004Co-Authors: Brian R. Lawson, Dwight H Kono, Roberto Baccala, Jianxun Song, Michael Croft, Argyrios N. TheofilopoulosAbstract:A characteristic feature of Systemic lupus erythematosus is the accumulation of activated/memory T and B cells. These G0/G1-arrested cells express high levels of cyclin-dependent kinase inhibitors such as p21, are resistant to proliferation and apoptosis, and produce large amounts of proinflammatory cytokines. Herein, we show that ablation of p21 in lupus-prone mice allows these cells to reenter the cell cycle and undergo apoptosis, leading to autoimmune disease reduction. Absence of p21 resulted in enhanced Fas/FasL-mediated activation-induced T cell death, increased activation of procaspases 8 and 3, and loss of mitochondrial transmembrane potential. Increased apoptosis was also associated with p53 up-regulation and a modest shift in the ratio of Bax/Bcl-2 toward the proapoptotic Bax. Proliferation and apoptosis of B cells were also increased in p21-/- lupus mice. Thus, modulation of the cell cycle pathway may be a novel approach to reduce apoptosis-resistant pathogenic lymphocytes and to ameliorate Systemic Autoimmunity.
-
Deletion of p21 (WAF-1/Cip1) Does Not Induce Systemic Autoimmunity in Female BXSB Mice
Journal of immunology (Baltimore Md. : 1950), 2002Co-Authors: Brian R. Lawson, Dwight H Kono, Argyrios N. TheofilopoulosAbstract:Cell cycle, apoptosis, and replicative senescence are all influenced by the cyclin-dependent kinase inhibitor, p21. It was previously reported that deletion of p21 in 129/Sv × C57BL/6 mixed genetic background mice induced a severe lupus-like disease, almost exclusively in females. However, we did not confirm this finding in an independently derived stock of 129/Sv × C57BL/6 p21 −/− mice. To further address this discrepancy, we examined the effects of p21 deletion in BXSB female mice that develop late-life, mild lupus-like disease. Survival, polyclonal Igs, anti-chromatin Abs, and kidney histopathology in these mice were unremarkable and identical to wild-type littermates for up to 14 mo of age. We conclude that p21 deficiency does not promote Autoimmunity even in females of a predisposed strain. The findings indicate that the use of mixed background 129/Sv × C57BL/6 mice to study effects of gene deletions in Systemic Autoimmunity may be confounded by the genetic heterogeneity of this cross. We suggest that studies addressing gene deletion effects in Systemic Autoimmunity should use sufficiently backcrossed mice to attain genetic homogeneity, include wild-type littermate controls, and preferentially use congenic inbred strains with late-life lupus predisposition to emulate the polygenic nature of this disease.
Mohammed Bellahcene - One of the best experts on this subject based on the ideXlab platform.
-
Systemic Autoimmunity induced by the TLR7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease.
Disease models & mechanisms, 2017Co-Authors: Muneer G. Hasham, Nicoleta Baxan, Daniel J. Stuckey, Jane Branca, Bryant Perkins, Oliver Dent, Ted Duffy, Tolani S. Hameed, Sarah E. Stella, Mohammed BellahceneAbstract:Systemic autoimmune diseases such as Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to Systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to Systemic Autoimmunity lacks inducible rodent models. Here, we characterise immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the Toll-like receptor 7/8 (TLR7/8) agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during Autoimmunity.
-
Systemic Autoimmunity induced by the tlr7 8 agonist resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease
Disease Models & Mechanisms, 2017Co-Authors: Muneer G. Hasham, Nicoleta Baxan, Daniel J. Stuckey, Jane Branca, Bryant Perkins, Oliver Dent, Ted Duffy, Tolani S. Hameed, Sarah E. Stella, Mohammed BellahceneAbstract:Systemic autoimmune diseases such as Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to Systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to Systemic Autoimmunity lacks inducible rodent models. Here, we characterise immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the Toll-like receptor 7/8 (TLR7/8) agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during Autoimmunity.
Alexander Espinosa - One of the best experts on this subject based on the ideXlab platform.
-
loss of the lupus autoantigen ro52 trim21 induces tissue inflammation and Systemic Autoimmunity by disregulating the il 23 th17 pathway
Journal of Experimental Medicine, 2009Co-Authors: Alexander Espinosa, Valerie Dardalhon, Susanna Brauner, Aurelie Ambrosi, Rowan Higgs, Fransisco J Quintana, Maria Sjostrand, Maijaleena Eloranta, Joan Ni Gabhann, Ola WinqvistAbstract:Ro52/Trim21 is targeted as an autoantigen in Systemic lupus erythematosus and Sjogren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of Systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52−/−), which appear phenotypically normal if left unmanipulated. However, Ro52−/− mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of Systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52−/− mice conferred protection from skin disease and Systemic Autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and Systemic Autoimmunity through the IL-23–Th17 pathway.
-
Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and Systemic Autoimmunity by disregulating the IL-23–Th17 pathway
The Journal of experimental medicine, 2009Co-Authors: Alexander Espinosa, Valerie Dardalhon, Susanna Brauner, Aurelie Ambrosi, Rowan Higgs, Fransisco J Quintana, Maria Sjostrand, Maijaleena Eloranta, Joan Ni Gabhann, Ola WinqvistAbstract:Ro52/Trim21 is targeted as an autoantigen in Systemic lupus erythematosus and Sjogren's syndrome. Polymorphisms in the Ro52 gene have been linked to these autoimmune conditions, but the molecular mechanism by which Ro52 may promote development of Systemic autoimmune diseases has not been explored. To address this issue, we generated Ro52-null mice (Ro52(-/-)), which appear phenotypically normal if left unmanipulated. However, Ro52(-/-) mice develop severe dermatitis extending from the site of tissue injury induced by ear tags. The affected mice further develop several signs of Systemic lupus with hypergammaglobulinemia, autoantibodies to DNA, proteinuria, and kidney pathology. Ro52, which was recently identified as an E3 ligase, mediates ubiquitination of several members of the interferon regulatory factor (IRF) family, and the Ro52-deficient mice have an enhanced production of proinflammatory cytokines that are regulated by the IRF transcription factors, including cytokines involved in the Th17 pathway (interleukin [IL] 6, IL-12/IL-23p40, and IL-17). Loss of IL-23/IL-17 by genetic deletion of IL-23/p19 in the Ro52(-/-) mice conferred protection from skin disease and Systemic Autoimmunity. These data reveal that the lupus-associated Ro52 protein is an important negative regulator of proinflammatory cytokine production, and they provide a mechanism by which a defective Ro52 function can lead to tissue inflammation and Systemic Autoimmunity through the IL-23-Th17 pathway.
Shaun W. Jackson - One of the best experts on this subject based on the ideXlab platform.
-
b cell derived il 6 initiates spontaneous germinal center formation during Systemic Autoimmunity
Journal of Experimental Medicine, 2017Co-Authors: Tanvi Arkatkar, Shaun W. Jackson, Jane H. Buckner, Holly M. Jacobs, Elizabeth M. Dam, Baidong Hou, David J. RawlingsAbstract:Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in Systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral Autoimmunity, whether B cell-derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell-derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from Systemic Autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-γ, consistent with the critical roles for B cell-intrinsic IFN-γ receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive Autoimmunity via local IL-6 production required for TFH differentiation and autoimmune GC formation.
-
B cell–derived IL-6 initiates spontaneous germinal center formation during Systemic Autoimmunity
The Journal of experimental medicine, 2017Co-Authors: Tanvi Arkatkar, Jane H. Buckner, Holly M. Jacobs, Elizabeth M. Dam, Baidong Hou, David J. Rawlings, Shaun W. JacksonAbstract:Abstract Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in Systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral Autoimmunity, whether B cell-derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell-derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from Systemic Autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-γ, consistent with the critical roles for B cell-intrinsic IFN-γ receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive Autoimmunity via local IL-6 production required for TFH differentiation and autoimmune GC formation.
-
A disease-associated PTPN22 variant promotes Systemic Autoimmunity in murine models
The Journal of clinical investigation, 2013Co-Authors: Xuezhi Dai, Richard G. James, Tania Habib, Swati Singh, Shaun W. Jackson, Socheath Khim, Randall T. Moon, Denny Liggitt, Alejandro Wolf-yadlin, Jane H. BucknerAbstract:Multiple autoimmune diseases, including type 1 diabetes, rheumatoid arthritis, Graves disease, and Systemic lupus erythematosus, are associated with an allelic variant of protein tyrosine phosphatase nonreceptor 22 (PTPN22), which encodes the protein LYP. To model the human disease-linked variant LYP-R620W, we generated knockin mice expressing the analogous mutation, R619W, in the murine ortholog PEST domain phosphatase (PEP). In contrast with a previous report, we found that this variant exhibits normal protein stability, but significantly alters lymphocyte function. Aged knockin mice exhibited effector T cell expansion and transitional, germinal center, and age-related B cell expansion as well as the development of autoantibodies and Systemic Autoimmunity. Further, PEP-R619W affected B cell selection and B lineage–restricted variant expression and was sufficient to promote Autoimmunity. Consistent with these features, PEP-R619W lymphocytes were hyperresponsive to antigen-receptor engagement with a distinct profile of tyrosine-phosphorylated substrates. Thus, PEP-R619W uniquely modulates T and B cell homeostasis, leading to a loss in tolerance and Autoimmunity.
