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

Abstract

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 1 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 IgG 4-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for woundhealing processes in physiologic conditions.

Advances in the diagnosis and management of IgG4 related disease

“…The first inflammatory phase of IgG4-RD is characterized by the appearance of antigen experienced B and T lymphocytes that accumulate at disease sites, engage in mutual activating antigen driven interactions, and secrete pro-fibrotic molecules such as interleukin 1β, interleukin 6, interferon γ, transforming growth factor β, platelet derived growth factor B, and lysyl oxidase homologue 2 414243. These populations of activated lymphocytes include circulating plasmablasts, T effector memory (T EM ) cytotoxic T lymphocytes (CTLs), and CD45RA+TEM (T EMRA ) CTLs 3233343536.…”

“…Both plasmablasts and effector memory T cells express the signaling lymphocytic activation molecule F7 (SLAMF7), a surface protein that has been implicated in cell-cell interaction and chronic lymphocyte activation 3233343536. Although involvement of T EM and T EMRA CTLs in tissue fibrosis has not been clearly demonstrated, plasmablasts/plasma cells from patients with IgG4-RD have been shown to prompt fibroblast activation and collagen production in vitro, thus partially explaining the improvement of fibrotic lesions with B cell depletion 34414243…”

“…Rituximab decreases circulating expanded plasmablasts and CD4 CTLs, indicating that it likely interferes with chronic activation of CD4 CTLs by disrupting B-T cell interactions and antigen presentation 43. B cell depletion also improves tissue fibrosis in IgG4-RD by directly targeting a subset of B lymphocytes with pro-fibrotic properties involved in fibroblast activation and recruitment of inflammatory cells 4142. Rituximab was effective when administered either as two 1 g infusions 15 days apart (rheumatological protocol) or in four weekly 375 mg/m 2 infusions (hematological protocol), as well as at lower doses (single 1 g infusion) in a few reports 138139.…”

New paradigm of B-cell biology regarding the elucidation of a new mechanism of tissue fibrosis in IgG4-related disease

“…Recent reports have shown that LOXL2 is associated with various types of fibrotic diseases. 9 In the study by Della-Torre et al, 8 immunohistochemistry data demonstrated abundant LOXL2 expression in B cells infiltrating IgG 4 -RD tissue. Moreover, the intriguing finding is that plasmablasts from patients with IgG 4 -RD expressed type I collagen genes.…”

“…In this issue of the Journal of Allergy and Clinical Immunology, Della-Torre et al 8 reported the direct contribution of B lymphocytes to tissue fibrosis in patients with IgG 4 -RD. Of note, they provided the first evidence that plasmablasts (which the authors focused on as a population with major involvement in IgG 4 -RD pathophysiology) represent a B-cell subset with intrinsic fibrogenic potential in IgG 4 -RD in contrast to both naive and memory B cells.…”