Charakterisierung der adaptiven Autoimmunantwort beim Pemphigus vulgaris
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Philipps-Universität Marburg
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Abstract
Pemphigus vulgaris (PV) is an antibody-mediated autoimmune disease leading to blisters and erosions of the skin and mucous membranes. IgG autoantibodies against the desmosomal cadherins desmoglein (Dsg)1 and 3 are main drivers for the development of PV by inducing a loss of adhesion of epidermal keratinocytes (acantholysis). Autoreactive CD4+ T cells are crucial for the activation and differentiation of autoreactive B cells and for the induction of autoantibody production. Still, the exact cellular and humoral mechanisms leading to the production of autoantibodies are yet not fully understood. The aim of this work was to investigate the adaptive autoimmune response in PV with regard to the relevant cytokines as well as T and B cell subpopulations involved in autoantibody induction. In a cross-sectional study plasma and immune cells from peripheral blood of a total of 24 PV patients were examined. The results revealed a role of interleukin (IL)-21, a pleiotropic cytokine that can induce the differentiation of B cells into antibody-secreting plasma cells, in the pathogenesis of PV. Elevated plasma levels of this cytokine were detected compared to healthy controls with IL-21 being predominantly produced by CD4+ T cells in PV patients during active disease. IL-21-producing T cells were partially characterized by coproduction of the cytokines IL-4 and IL-17 suggesting a partial involvement of Th2 and Th17 cells in IL-21 production. After in vitro Dsg3-stimulation of patients’ peripheral blood mononuclear cells with Dsg3, IL-21 production by autoreactive T cells could be detected for the first time using sensitive ELISPOT assay further underling the functional importance of this cytokine in disease pathogenesis. In addition, circulating T follicular helper (Tfh) cells (defined as CD4+CXCR5+ T cells), being essential for the induction of an antibody-mediated immune response, were found to be increased in peripheral blood of the patients. Regarding the functionally relevant costimulatory molecules programmed cell death protein 1 (PD-1) and inducible T cell costimulator (ICOS), Tfh cells of patients showed no differences as compared to healthy controls. Moreover, low-frequent autoreactive B cells were identified in peripheral blood of patients using an established flow cytometric test system by labelling recombinant Dsg3 with Alexa Fluor 647 (Dsg3-AF647) and Dsg3-specific B cell subpopulations immature/naïve (CD19+CD27-), memory B cells (CD19+CD27+) and plasmablasts (CD19+CD27++CD38++) were characterized. Of note, increased autoreactive memory B cells could be detected in PV patients indicating an altered peripheral immune tolerance at this point of B cell development with possible involvement of autoreactive Tfh cells. In a subgroup analysis of 5 PV patients that had been previously treated with the B cell-depleting anti-CD20 antibody rituximab elevated frequencies of Dsg3-specific memory B cells were particularly found in phases of clinical remission, whereas this could not be observed during clinical relapse. It was speculated that the activation of autoreactive memory B cells may be the starting point for the production of new autoantibodies. The results of the present study identify IL-21 and IL-21-producing T cells as important contributors to the pathogenesis of PV. Together with the in-depth characterization of Dsg3-specific B cell subpopulations these findings may enable the future development of new targeted therapies for the treatment of PV.
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Dates
Created: 2020Issued: 2020-09-21Updated: 2020-09-21
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
ZytokinetherapyHautkrankheitenSkin diseasecytokinesautoimmunityAutoimmunitätTherapie
DFG-subjects
T-ZellenRituximabDurchlusszytometrieInterleukin 21B-ZellenDesmoglein 3Pemphigus vulgarisELISpot
DDC-Numbers
610
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Pollmann, Robert (0000-0002-4596-516X): Charakterisierung der adaptiven Autoimmunantwort beim Pemphigus vulgaris. : Philipps-Universität Marburg 2020-09-21. DOI: https://doi.org/10.17192/z2020.0353.