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

Emanuel Della-Torre, E. Rigamonti, Cory Perugino, Simona Baghai-Sain, Na Sun, N. Kaneko, takashi maehara, Lucrezia Rovati, Maurilio Ponzoni, Raffaella Milani, M. Lanzillotta, V. Mahajan, H. Mattoo, Ivan Molineris, Vikram Deshpande, John H. Stone, Massimo Falconi, Angelo A. Manfredi, Shiv Pillai

研究成果: ジャーナルへの寄稿記事

抄録

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.

元の言語英語
ジャーナルJournal of Allergy and Clinical Immunology
DOI
出版物ステータス受理済み/印刷中 - 1 1 2019

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Fibrosis
B-Lymphocytes
Immunoglobulin G
Fibroblasts
Wound Healing
Collagen
Protein-Lysine 6-Oxidase
Proto-Oncogene Proteins c-sis
RNA Sequence Analysis
B-Lymphocyte Subsets
Chemotactic Factors
Coculture Techniques
Chemokines
Fluorescent Antibody Technique
Extracellular Matrix
Enzyme-Linked Immunosorbent Assay
Polymerase Chain Reaction
Enzymes
Genes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

これを引用

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

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease. / Della-Torre, Emanuel; Rigamonti, E.; Perugino, Cory; Baghai-Sain, Simona; Sun, Na; Kaneko, N.; maehara, takashi; Rovati, Lucrezia; Ponzoni, Maurilio; Milani, Raffaella; Lanzillotta, M.; Mahajan, V.; Mattoo, H.; Molineris, Ivan; Deshpande, Vikram; Stone, John H.; Falconi, Massimo; Manfredi, Angelo A.; Pillai, Shiv.

:: Journal of Allergy and Clinical Immunology, 01.01.2019.

研究成果: ジャーナルへの寄稿記事

Della-Torre, E, Rigamonti, E, Perugino, C, Baghai-Sain, S, Sun, N, Kaneko, N, maehara, T, Rovati, L, Ponzoni, M, Milani, R, Lanzillotta, M, Mahajan, V, Mattoo, H, Molineris, I, Deshpande, V, Stone, JH, Falconi, M, Manfredi, AA & Pillai, S 2019, 'B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease', Journal of Allergy and Clinical Immunology. https://doi.org/10.1016/j.jaci.2019.07.004
Della-Torre, Emanuel ; Rigamonti, E. ; Perugino, Cory ; Baghai-Sain, Simona ; Sun, Na ; Kaneko, N. ; maehara, takashi ; Rovati, Lucrezia ; Ponzoni, Maurilio ; Milani, Raffaella ; Lanzillotta, M. ; Mahajan, V. ; Mattoo, H. ; Molineris, Ivan ; Deshpande, Vikram ; Stone, John H. ; Falconi, Massimo ; Manfredi, Angelo A. ; Pillai, Shiv. / B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease. :: Journal of Allergy and Clinical Immunology. 2019.
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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.",
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T1 - B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

AU - Della-Torre, Emanuel

AU - Rigamonti, E.

AU - Perugino, Cory

AU - Baghai-Sain, Simona

AU - Sun, Na

AU - Kaneko, N.

AU - maehara, takashi

AU - Rovati, Lucrezia

AU - Ponzoni, Maurilio

AU - Milani, Raffaella

AU - Lanzillotta, M.

AU - Mahajan, V.

AU - Mattoo, H.

AU - Molineris, Ivan

AU - Deshpande, Vikram

AU - Stone, John H.

AU - Falconi, Massimo

AU - Manfredi, Angelo A.

AU - Pillai, Shiv

PY - 2019/1/1

Y1 - 2019/1/1

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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