3 research outputs found

    Antigen-Specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy

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    Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies

    Dysfunction of hepatic regulatory T cells in experimental sclerosing cholangitis is related to IL-12 signaling

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    Background & Aims: Reduced numbers of regulatory T cells (Treg) have been reported in patients with primary sclerosing cholangitis (PSC); therefore, Treg expansion might serve as a therapeutic approach. Here, we explored whether treatment with IL-2/IL-2 monoclonal antibody complex (IL-2/IL-2Ab complex) could provide in vivo Treg expansion and treatment of experimental sclerosing cholangitis. Methods: Treg were expanded by repeated injection of IL-2/IL2Ab complex in mouse models of cholangitis (Mdr2(-/-), DDC) or colitis (dextran sulfate sodium [DSS]) as control. In vitro suppressive capacity and gene expression were analyzed in isolated hepatic and splenic Treg. Results: In vivo expansion resulted in a 5-fold increase in hepatic Treg, which localized within the inflamed portal tracts. However, although Treg expansion was associated with reduced proinflammatory IL-17 and increased anti-inflammatory IL-10 production by hepatic lymphocytes, the severity of cholangitis was not reduced. In contrast, DSS-induced colitis could be improved by Treg expansion, suggesting a selectively reduced functionality of intrahepatic Treg. Indeed, hepatic Treg manifested reduced Foxp3 expression and reduced suppressive capacity compared to splenic Treg. Hepatic Treg dysfunction could be linked to increased IL-12 signaling due to an upregulation of the IL-12 receptor. Accordingly, IL-12 receptor beta 2 knockout mice (IL12rb2(-/-)) were able to maintain hepatic Treg functionality. Conclusions: Hepatic Treg expanded in vivo failed to improve the course of cholangitis, which was related to the effects of hepatic IL-12 on Treg. Therefore, neutralization of IL-12 should be considered as part of treatment strategies targeting Treg in sclerosing cholangitis. Lay summary: Primary sclerosing cholangitis (PSC) is associated with a paucity of regulatory T cells (Treg) that have a particular ability to control immune responses; therefore, in vivo expansion of Treg might serve as a treatment of cholangitis. However, in a mouse model of PSC, we show that Treg enrichment in the liver was not sufficient to provide effective control of cholangitis, as the suppressive functionality of hepatic Treg was significantly limited by IL-12 signals. Thus, neutralization of IL-12 should be considered as part of treatment strategies to improve the efficacy of Treg-based treatments for liver diseases
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