CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice

Moser, Katrin; Kalies, Kathrin; Szyska, Martin; Humrich, Jens Y; Amann, Kerstin; Manz, Rudolf A.

doi:10.1002/art.33424

Cited by 33 publications

(31 citation statements)

References 48 publications

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“…In contrast, CXCR3-deficient NZB/W mice had reduced IgG1 titers but did not show clinical improvement (45). This might be explained by the finding that infiltration of CD4, CD8 T cells and IgG, IgM PCs in the kidneys was not disturbed and suggest the presence of CXCR3-dependent and -independent pathways, pointing out the diversity in the pathogenesis of lupus nephritis.…”

Section: Autoreactive Pcsmentioning

confidence: 88%

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Winter

Dame

Jundt

et al. 2012

The Journal of Immunology

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Long-lived plasma cells survive in a protected microenvironment for years or even a lifetime and provide humoral memory by establishing persistent Ab titers. Long-lived autoreactive, malignant, and allergen-specific plasma cells are likewise protected in their survival niche and are refractory to immunosuppression, B cell depletion, and irradiation. Their elimination remains an essential therapeutic challenge. Recent data indicate that long-lived plasma cells reside in a multicomponent plasma cell niche with a stable mesenchymal and a dynamic hematopoietic component, both providing essential soluble and membrane-bound survival factors. Alternative niches with different hematopoietic cell components compensate fluctuations of single cell types but may also harbor distinct plasma cell subsets. In this Brief Review, we discuss conventional therapies in autoimmunity and multiple myeloma in comparison with novel drugs that target plasma cells and their niches. In the future, such strategies may enable the specific depletion of pathogenic plasma cells while leaving the protective humoral memory intact.

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Section: Autoreactive Pcsmentioning

confidence: 88%

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Winter

Dame

Jundt

et al. 2012

The Journal of Immunology

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“…Deletion of Xist in the hematopoietic cell lineage partially reactivates the Xi, resulting in increased expression of ∼86 X-linked genes in blood cells, some which are involved in hematopoiesis and cell cycle regulation (70). Interestingly, this list includes two immunity genes CXCR3 and TRL7 whose overexpression is associated with lupus (71)(72)(73), which suggests that immunity-related genes are somehow poised for reactivation in the blood lineage when Xist RNA is missing. Future work is required to determine the specificity of X-linked gene reactivation when Xist is deleted, and how partial reactivation of Xi changes depending on the cell type.…”

Section: Discussionmentioning

confidence: 99%

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X

Wang

Syrett

Kramer

et al. 2016

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

244

298

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Females have a greater immunological advantage than men, yet they are more prone to autoimmune disorders. The basis for this sex bias lies in the X chromosome, which contains many immunityrelated genes. Female mammals use X chromosome inactivation (XCI) to generate a transcriptionally silent inactive X chromosome (Xi) enriched with heterochromatic modifications and XIST/Xist RNA, which equalizes gene expression between the sexes. Here, we examine the maintenance of XCI in lymphocytes from females in mice and humans. Strikingly, we find that mature naïve T and B cells have dispersed patterns of XIST/Xist RNA, and they lack the typical heterochromatic modifications of the Xi. In vitro activation of lymphocytes triggers the return of XIST/Xist RNA transcripts and some chromatin marks (H3K27me3, ubiquitin-H2A) to the Xi. Single-cell RNA FISH analysis of female T cells revealed that the X-linked immunity genes CD40LG and CXCR3 are biallelically expressed in some cells. Using knockout and knockdown approaches, we find that Xist RNA-binding proteins, YY1 and hnRNPU, are critical for recruitment of XIST/Xist RNA back to the Xi. Furthermore, we examined B cells from patients with systemic lupus erythematosus, an autoimmune disorder with a strong female bias, and observed different XIST RNA localization patterns, evidence of biallelic expression of immunity-related genes, and increased transcription of these genes. We propose that the Xi in female lymphocytes is predisposed to become partially reactivated and to overexpress immunity-related genes, providing the first mechanistic evidence to our knowledge for the enhanced immunity of females and their increased susceptibility for autoimmunity.X chromosome inactivation | XIST RNA | epigenetics | female-biased autoimmunity

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“…These strains develop systemic autoimmune diseases characterized by increased serum autoantibody levels and vasculitis, as well as MPGN [13,14,15]. BXSB- Yaa carries a mutant gene located on the Y chromosome, designated as Y-linked autoimmune acceleration (Yaa) , and males show more severe MPGN than females [16].…”

Section: Introductionmentioning

confidence: 99%

Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

Kimura¹,

Ichii²,

Otsuka³

et al. 2013

Am J Nephrol

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Background: Membranous proliferative glomerulonephritis (MPGN) is a major primary cause of chronic kidney disease (CKD). Podocyte injury is crucial in the pathogenesis of glomerular disease with proteinuria, leading to CKD. To assess podocyte injuries in MPGN, the pathological features of spontaneous murine models were analyzed. Methods: The autoimmune-prone mice strains BXSB/MpJ-Yaa and B6.MRL-(D1Mit202-D1Mit403) were used as the MPGN models, and BXSB/MpJ-Yaa⁺ and C57BL/6 were used as the respective controls. In addition to clinical parameters and glomerular histopathology, the protein and mRNA levels of podocyte functional markers were evaluated as indices for podocyte injuries. The relation between MPGN pathology and podocyte injuries was analyzed by statistical correlation. Results: Both models developed MPGN with albuminuria and elevated serum anti-double-strand DNA (dsDNA) antibody levels. BXSB/MpJ-Yaa and B6.MRL showed severe proliferative lesions with T and B cell infiltrations and membranous lesions with T cell infiltrations, respectively. Foot process effacement and microvillus-like structure formation were observed ultrastructurally in the podocytes of both MPGN models. Furthermore, both MPGN models showed a decrease in immune-positive areas of nephrin, podocin and synaptopodin in the glomerulus, and in the mRNA expression of Nphs1, Nphs2, Synpo, Actn4, Cd2ap, and Podxl in the isolated glomerulus. Significant negative correlations were detected between serum anti-dsDNA antibody levels and glomerular Nphs1 expression, and between urinary albumin-to-creatinine ratio and glomerular expression of Nphs1, Synpo, Actn4, Cd2ap, or Podxl.Conclusion: MPGN models clearly developed podocyte injuries characterized by the decreased expression of podocyte functional markers with altered morphology. These data emphasized the importance of regulation of podocyte injuries in MPGN.

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CXCR3 promotes the production of IgG1 autoantibodies but is not essential for the development of lupus nephritis in NZB/NZW mice

Cited by 33 publications

References 48 publications

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Pathogenic Long-Lived Plasma Cells and Their Survival Niches in Autoimmunity, Malignancy, and Allergy

Unusual maintenance of X chromosome inactivation predisposes female lymphocytes for increased expression from the inactive X

Close Relations between Podocyte Injuries and Membranous Proliferative Glomerulonephritis in Autoimmune Murine Models

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