期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 145, 期 3, 页码 968-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.07.004
关键词
IgG(4); IgG(4)-related disease; B cells; plasmablasts; fibrosis; fibroblasts; rituximab; lysyl oxidase homolog 2; platelet-derived growth factor
资金
- Cariplo Foundation [TRIDEO 2014-Research]
- Italian Association for Cancer Research (AIRC)/Cariplo Foundation
- AIRC [IG 2017-20351, 531000]
- National Institutes of Health (NIH) [U19 AI110495]
- Collegio Ghislieri'' (Pavia, Italy)
- NIH [AI 113163]
- Japanese Society for the Promotion of Science Postdoctoral Fellowship for Studies Abroad
Background: IgG(4)-related disease (IgG(4)-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 IgG(4)-RD. Methods: Total circulating CD19(+) B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG(4)-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 IgG(4)-RD tissue sections by using multicolor immunofluorescence studies. Results: B cells from patients with IgG(4)-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.
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