TLR9 Signaling in HCV-Associated Atypical Memory B Cells Triggers Th1 and Rheumatoid Factor Autoantibody Responses

Chloé COMARMOND¹, Valerie Lorin ², Cindy Marques ¹, Anna Maciejewski-Duval ¹, Nizar Joher ², Cyril Planchais ², Maxime Touzot ³, Thierry Hieu ², Valentin Quiniou ¹, Anne Desbois ⁴, Michelle Rosenzwajg ¹, David Klatzmann ¹, Patrice Cacoub ⁵, Hugo Mouquet ² and David Saadoun ⁵, ¹Assistance Publique des Hopitaux de Paris, PARIS, France, ²Institut Pasteur, PARIS, France, ³Institut Curie, Paris, France, ⁴GHPS, Paris, France, ⁵AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France, Paris, France

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: B cell memory and Hepatitis C, systemic vasculitides

Session Information

Date: Sunday, November 10, 2019

Title: 3S100: B Cell Biology & Targets in Autoimmune & Inflammatory Disease (880–885)

Session Type: ACR Abstract Session

Session Time: 4:30PM-6:00PM

Background/Purpose: Hepatitis C virus (HCV) infection contributes to the development of autoimmune disorders such as cryoglobulinemia vasculitis (CV). However, it remains unclear why only some HCV-infected individuals develop CV. HCV-CV is characterized by expansions of anergic CD19⁺CD27⁺CD21^low/- atypical memory B cells (AtM). Here, we report the mechanisms by which AtM participate to HCV-associated autoimmunity.

Methods: Phenotype and function of peripheral AtM were studied by multi-color flow cytometry and co-culture assays with effector T cells and regulatory T cells in twenty chronically HCV-CV patients, 10 chronically HCV-infected patients without CV and 8 healthy donors. We performed gene expression profile analysis of AtM stimulated or not by TLR9. Immunoglobulin gene repertoire of AtM were analyzed after single B cell FACS sorting and expression-cloning of antibodies. Antibody reactivities of AtM were studied by ELISA.

Results: We show Tbet⁺CD11c⁺CD27⁺CD21^– AtM B-cell expansions in HCV-CV patients as compared to HCV controls without CV. TLR9 activation of AtM induces a specific transcriptional signature centered on TNFα overexpression, and an enhanced secretion of TNFα and rheumatoid factor-type IgMs in HCV-CV patients. AtM stimulated through TLR9 promote type 1 effector T-cell activation and reduce the proliferation of CD4⁺CD25^hiCD127^-/lowFoxP3⁺ regulatory T cells. AtM expansions display intraclonal diversity with immunoglogulin 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 target unique epitopes on the human IgG Fc region and possess rheumatoid factor activity.

Conclusion: Our data strongly suggest a central role for TLR9 activation of AtM in driving HCV-CV autoimmunity through rheumatoid factors production and type 1 T-cell response.

Disclosure: C. COMARMOND, None; V. Lorin, None; C. Marques, None; A. Maciejewski-Duval, None; N. Joher, None; C. Planchais, None; M. Touzot, None; T. Hieu, None; V. Quiniou, None; A. Desbois, None; M. Rosenzwajg, None; D. Klatzmann, None; P. Cacoub, Abbvie, 5, AstraZeneca, 5, Bristol meyer squibb, 5, Gilead, 5, Glaxo Smith Kline, 5, Janssen, 5, Merck Sharp Dohme, 5, Roche, 5, Servier, 5, Vifor, 5; H. Mouquet, None; D. Saadoun, Abbvie, 5, AstraZeneca, 5, Bristol meyer squibb, 5, Gilead, 5, Glaxo Smith Kline, 5, Roche, 5, Servier, 5.

To cite this abstract in AMA style:

COMARMOND C, Lorin V, Marques C, Maciejewski-Duval A, Joher N, Planchais C, Touzot M, Hieu T, Quiniou V, Desbois A, Rosenzwajg M, Klatzmann D, Cacoub P, Mouquet H, Saadoun D. TLR9 Signaling in HCV-Associated Atypical Memory B Cells Triggers Th1 and Rheumatoid Factor Autoantibody Responses [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/tlr9-signaling-in-hcv-associated-atypical-memory-b-cells-triggers-th1-and-rheumatoid-factor-autoantibody-responses/. Accessed .

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