IL-17-producing T cells in lupus nephritis

Apostolidis, S.A.; Crispín, JC; Gc, Tsokos

doi:10.1177/0961203310389100

Cited by 115 publications

(82 citation statements)

References 46 publications

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“…Increased IL-10 expression in SLE patients correlates with disease activity and antibody production, and IL-10 blockade corrected dysregulated cytokine responses (12) and mediated clinical improvement in a subset of SLE patients (13). Given the immune-regulatory effects of IL-10 on T cells, enhanced IL-10 expression in SLE is seemingly conflicting with the well-established overexpression of IL-6 and IL-17A in SLE (14)(15)(16). Recently, however, this contradiction has been at least partially resolved.…”

Section: Discussionmentioning

confidence: 79%

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

154

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The immune-regulatory cytokine IL-10 plays a central role during innate and adaptive immune responses. IL-10 is elevated in the serum and tissues of patients with systemic lupus erythematosus (SLE), an autoimmune disorder characterized by autoantibody production, immune-complex formation, and altered cytokine expression. Because of its B cell-promoting effects, IL-10 may contribute to autoantibody production and tissue damage in SLE. We aimed to determine molecular events governing T cell-derived IL-10 expression in health and disease. We link reduced DNA methylation of the IL10 gene with increased recruitment of Stat family transcription factors. Stat3 and Stat5 recruitment to the IL10 promoter and an intronic enhancer regulate gene expression. Both Stat3 and Stat5 mediate trans-activation and epigenetic remodeling of IL10 through their interaction with the histone acetyltransferase p300. In T cells from SLE patients, activation of Stat3 is increased, resulting in enhanced recruitment to regulatory regions and competitive replacement of Stat5, subsequently promoting IL-10 expression. A complete understanding of the molecular events governing cytokine expression will provide new treatment options in autoimmune disorders, including SLE. The observation that altered activation of Stat3 influences IL-10 expression in T cells from SLE patients offers molecular targets in the search for novel target-directed treatment options.

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Section: Discussionmentioning

confidence: 79%

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Hedrich

Rauen

Apostolidis

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

154

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“…Systemic lupus erythematosus (SLE) is an autoimmune disease in which the body's immune system produces autoantibodies against normal healthy tissue or cellular components to form immune complexes that are deposited in various tissues, inducing inflammation leading to tissue damage [1]. Autoantibodies are produced by activated autoreactive B cells through antibody class-switching and somatic hypermutation, with help from activated autoreactive T cells [2].…”

Section: Introductionmentioning

confidence: 99%

Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

Ren

Liao

Vieson

et al. 2017

Clinical and Experimental Immunology

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SUMMARYWe have demonstrated previously that histone deacetylase (HDAC6) expression is increased in animal models of systemic lupus erythematosus (SLE) and that inhibition of HDAC6 decreased disease. In our current studies, we tested if an orally active selective HDAC6 inhibitor would decrease disease pathogenesis in a lupus mouse model with established early disease. Additionally, we sought to delineate the cellular and molecular mechanism(s) of action of a selective HDAC6 inhibitor in SLE. We treated 20-week-old (early-disease) New Zealand Black (NZB)/White F 1 female mice with two different doses of the selective HDAC6 inhibitor (ACY-738) for 5 weeks. As the mice aged, we determined autoantibody production and cytokine levels by enzyme-linked immunosorbent assay (ELISA) and renal function by measuring proteinuria. At the termination of the study, we performed a comprehensive analysis on B cells, T cells and innate immune cells using flow cytometry and examined renal tissue for immune-mediated pathogenesis using immunohistochemistry and immunofluorescence. Our results showed a reduced germinal centre B cell response, decreased T follicular helper cells and diminished interferon (IFN)-g production from T helper cells in splenic tissue. Additionally, we found the IFN-a-producing ability of plasmacytoid dendritic cells was decreased along with immunoglobulin isotype switching and the generation of pathogenic autoantibodies. Renal tissue showed decreased immunoglobulin deposition and reduced inflammation as judged by glomerular and interstitial inflammation. Taken together, these studies show selective HDAC6 inhibition decreased several parameters of disease pathogenesis in lupusprone mice. The decrease was due in part to inhibition of B cell development and response.

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“…74,75 T cell infiltrates also contribute to immunopathology in LN, particularly IL-17 producing CD3 + /CD4 + or CD3 + CD4/8 2/2 T cells. 76 Macrophages also contribute to renal damage, particularly F4/80(hi)/ CD11c(int)Gr1(lo)/Ly6C(lo)/VLA4(lo)/ MHCII(hi)/CD43(lo)/CD62L(lo) macrophages. 77,78 Maladaptive Tissue Repair Contributes to CKD Progression Damage to renal parenchymal cells triggers healing responses that contribute to renal pathology.…”

Section: Intrarenal Pathogenic Mechanisms Of Lnmentioning

confidence: 99%

The Pathogenesis of Lupus Nephritis

Lech¹,

Anders

2013

Journal of the American Society of Nephrology

396

295

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Lupus nephritis is an immune complex GN that develops as a frequent complication of SLE. The pathogenesis of lupus nephritis involves a variety of pathogenic mechanisms. The extrarenal etiology of systemic lupus is based on multiple combinations of genetic variants that compromise those mechanisms normally assuring immune tolerance to nuclear autoantigens. This loss of tolerance becomes clinically detectable by the presence of antinuclear antibodies. In addition, nucleic acids released from netting or apoptotic neutrophils activate innate and adaptive immunity via viral nucleic acid-specific Toll-like receptors. Therefore, many clinical manifestations of systemic lupus resemble those of viral infection. In lupus, endogenous nuclear particles trigger IFN-a signaling just like viral particles during viral infection. As such, dendritic cells, T helper cells, B cells, and plasma cells all contribute to the aberrant polyclonal autoimmunity. The intrarenal etiology of lupus nephritis involves antibody binding to multiple intrarenal autoantigens rather than the deposition of circulating immune complexes. Tertiary lymphoid tissue formation and local antibody production add to intrarenal complement activation as renal immunopathology progresses. Here we provide an update on the pathogenic mechanisms that lead to lupus nephritis and provide the rationale for the latest and novel treatment strategies.

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IL-17-producing T cells in lupus nephritis

Cited by 115 publications

References 46 publications

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Stat3 promotes IL-10 expression in lupus T cells through trans- activation and chromatin remodeling

Selective HDAC6 inhibition decreases early stage of lupus nephritis by down-regulating both innate and adaptive immune responses

The Pathogenesis of Lupus Nephritis

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