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July 4, 2019

TLR9 signalling in HCV-associated atypical memory B cells triggers Th1 and rheumatoid factor autoantibody responses

Journal Of Hepatology - 2019



Cloé Comarmond, Valérie Lorin, Cindy Marques, Anna Maciejewski-Duval, Nizar Joher, Cyril Planchais, Maxime Touzot, Lucie Biard, Thierry Hieu, Valentin Quiniou, Anne-Claire Desbois, Michelle Rosenzwajg, David Klatzmann, Patrice Cacoub, Hugo Mouquet, David Saadoun.

  • puce

    Background & Aims: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinaemia vasculitis (CV). However, it remains unclear why only some individuals with HCV develop HCV-associated CV (HCV-CV). HCV-CV is characterized by the expansion of anergic CD19+CD27+CD21low/− atypical memory B cells (AtMs). Herein, we report the mechanisms by which AtMs participate in HCV-associated autoimmunity.

  • puce

    Methods: The phenotype and function of peripheral AtMs were studied by multicolour flow cytometry and co-culture assays with effector T cells and regulatory T cells in 20 patients with HCV-CV, 10 chronically HCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtMs stimulated or not by TLR9. Immunoglobulin gene repertoire and antibody reactivity profiles of AtM-expressing IgM antibodies were analysed following single B cell FACS sorting and expression-cloning of monoclonal antibodies.

  • puce

    Results: The Tbet+CD11c+CD27+CD21 AtM population is expanded in patients with HCV-CV compared to HCV controls without CV. TLR9 activation of AtMs induces a specific transcriptional signature centred on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in patients with HCV-CV. AtMs stimulated through TLR9 promote type 1 effector T cell activation and reduce the proliferation of CD4+CD25hiCD127−/lowFoxP3+ regulatory T cells. AtM expansions display intraclonal diversity with immunoglobulin features of antigen-driven maturation. AtM-derived IgM monoclonal antibodies do not react against ubiquitous autoantigens or HCV antigens including NS3 and E2 proteins. Rather, AtM-derived antibodies possess rheumatoid factor activity and target unique epitopes on the human IgG-Fc region.

  • puce

    Conclusions: Our data strongly suggest a central role for TLR9 activation of AtMs in driving HCV-CV autoimmunity through rheumatoid factor production and type 1 T cell responses.

  • puce

    lay summary: B cells are best known for their capacity to produce antibodies, which often play a deleterious role in the development of autoimmune diseases. During chronic hepatitis C, self-reactive B cells proliferate and can be responsible for autoimmune symptoms (arthritis, purpura, neuropathy, renal disease) and/or lymphoma. Direct-acting antiviral therapy clears the hepatitis C virus and eliminates deleterious B cells.

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