LAUSR

Background IgG4-related disease (IgG4-RD) is a fibro-inflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing (1-3). Objectives In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in IgG4-RD. Methods Total circulating CD19+ B-lymphocytes, naïve B cells, memory B cells, or plasmablasts from IgG4-RD patients were cultivated with human fibroblasts. Pro-fibrotic soluble factors and collagen production in the co-cultures were assessed by ELISA and Luminex assays. RNA-sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as the induction of pro-fibrotic pathways in B cell subsets. Relevant pro-fibrotic and inflammatory molecules were confirmed in vitro by functional experiments and on IgG4-RD tissue sections by multi-color immunofluorescence studies. Results B cells from IgG4-RD patients (i) produced the pro-fibrotic molecule PDGF-B and stimulated collagen production by fibroblasts; (ii) expressed enzymes implicated in extracellular matrix remodeling such as LOXL2; (iii) produced the chemotactic factors CCL-4, CCL-5, and CCL-11; and (iv) induced the production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation, and therefore represent cells with intrinsic pro-fibrotic properties Conclusion We have demonstrated that B cells, contribute directly to tissue fibrosis in IgG4-RD. These unanticipated pro-fibrotic properties of B lymphocytes, particularly of plasmablasts, might be relevant for fibrogenesis in other fibro-inflammatory disorders and for wound healing processes in physiological conditions. References [1] Della-Torre E, Lanzillotta M, Doglioni C. Immunology of IgG4-related disease. Clin Exp Immunol2015;181:191-206. [2] Carruthers MN, Topazian MD, Khosroshahi A, Witzig TE, Wallace ZS, Hart PA, et al. Rituximab for IgG4-related disease: a prospective, open-label trial. Ann Rheum Dis. 2015;74:1171-7. [3] Della-Torre E, Feeney E, Deshpande V, Mattoo H, Mahajan V, Kulikova M, et al. B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease. Ann Rheum Dis2015;74:2236-43. Disclosure of Interests Emanuel Della Torre: None declared, Elena Rigamonti: None declared, Cory Perugino: None declared, Massimo Falconi: None declared, John H. Stone Grant/research support from: F. Hoffmann-La Roche, Genentech, Xencor, Consultant for: Chugain, F. Hoffmann-La Roche, Genentech, Xencor, Angelo Manfredi: None declared, Shiv Pillai: None declared