B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

Emanuel Della-Torre, Elena Rigamonti, Cory Perugino, Simona Baghai-Sain, Na Sun, Naoki Kaneko, Takashi Maehara, Lucrezia Rovati, Maurilio Ponzoni, Raffaella Milani, Marco Lanzillotta, Vinay Mahajan, Hamid Mattoo, Ivan Molineris, Vikram Deshpande, John H. Stone, Massimo Falconi, Angelo A. Manfredi, Shiv Pillai

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Abstract

Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory 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. Objective: In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG4-RD. Methods: Total circulating CD19+ B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG4-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed in vitro by using functional experiments and on IgG4-RD tissue sections by using multicolor immunofluorescence studies. Results: B cells from patients with IgG4-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced 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 profibrotic properties. Conclusion: We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.

Original languageEnglish
Pages (from-to)968-981.e14
JournalJournal of Allergy and Clinical Immunology
Volume145
Issue number3
DOIs
Publication statusPublished - Mar 2020

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All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Della-Torre, E., Rigamonti, E., Perugino, C., Baghai-Sain, S., Sun, N., Kaneko, N., ... Pillai, S. (2020). B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease. Journal of Allergy and Clinical Immunology, 145(3), 968-981.e14. https://doi.org/10.1016/j.jaci.2019.07.004