TY - JOUR
T1 - B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease
AU - Della-Torre, Emanuel
AU - Rigamonti, Elena
AU - Perugino, Cory
AU - Baghai-Sain, Simona
AU - Sun, Na
AU - Kaneko, Naoki
AU - Maehara, Takashi
AU - Rovati, Lucrezia
AU - Ponzoni, Maurilio
AU - Milani, Raffaella
AU - Lanzillotta, Marco
AU - Mahajan, Vinay
AU - Mattoo, Hamid
AU - Molineris, Ivan
AU - Deshpande, Vikram
AU - Stone, John H.
AU - Falconi, Massimo
AU - Manfredi, Angelo A.
AU - Pillai, Shiv
N1 - Funding Information:
The study was funded by a “Giovani Ricercatori 2018–Research Grant” award from the “Cariplo Foundation” (to E.D.-T.), by a “TRIDEO 2014–Research Grant” award (to E.D.-T). from the “Italian Association for Cancer Research (AIRC)/Cariplo Foundation,” by an AIRC IG 2017-20351 (to A.A.M.), by the “5×1000” Italian Ministry of Health, and by National Institutes of Health (NIH) grant U19 AI110495 (to S.P.). E.D.-T. received support from the “Collegio Ghislieri” (Pavia, Italy), C.P. was supported by NIH grant T32 AR007258, V.M. was supported by NIH grant AI 113163, and T.M. was supported by a Japanese Society for the Promotion of Science Postdoctoral Fellowship for Studies Abroad.
Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
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U2 - 10.1016/j.jaci.2019.07.004
DO - 10.1016/j.jaci.2019.07.004
M3 - Article
C2 - 31319101
AN - SCOPUS:85070714446
SN - 0091-6749
VL - 145
SP - 968-981.e14
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 3
ER -
