Amelioration of immunoglobulin A vasculitis by suppression of the pathological expansion of T follicular helper 17 cells

Abstract

The main pathogenic features of immunoglobulin A vasculitis (IgAV) are overactive B cells and elevated production of IgA, which requires help from T follicular helper 17 (Tfh17) cells. To evaluate the pathological role of Tfh17 cells in IgAV, we investigated the mechanism responsible for Tfh17 differentiation and explored how to ameliorate IgAV by modulating Tfh17 generation. Peripheral blood mononuclear cells from IgAV patients were analyzed by flow cytometry. In vitro culture was performed to assess the modulation of cytokine-induced phenotypes. IgAV rats were used to explore the therapeutic effects of IL-6 blockade and the regulatory functions of IL-6 in Tfh17 cells. Serum cytokine and IgA levels were measured by ELISA while histopathological changes were evaluated by H&E,PAS or immunofluorescence staining. Frequency of CD4⁺CXCR5⁺CCR6⁺ Tfh17 cells were increased in IgAV patients and associated with disease severity. There was also a significant infiltration of Tfh17 cells in the kidney of human IgAV nephritis patients. IL-6 promoted the dendritic cell production of TGF-β and Tfh17 differentiation. In IgAV rats, the in vivo blockade of IL-6 signaling inhibited Tfh17 differentiation, resulting in reduction of the germinal center and IgA production. Suppression of Tfh17 cells using IL-6 blockade greatly ameliorated clinical symptoms such as hemorrhagic rash and bloody stool and decreased IgA deposition and mesangial proliferation in the kidney in IgAV rats. Our findings suggest that suppression of Tfh17 differentiation can alleviate IgA-mediated vasculitis and may permit the development of tailored medicines for treating IgAV.

Keywords: Immunoglobulin A vasculitis; Interleukin-6; T follicular helper 17 cell; Tocilizumab.