Immunoglobulin G4-related disease (IgG4-RD) is an uncommon disorder that demonstrates characteristic clinicopathologic features including sclerosing lesions with storiform fibrosis, increased IgG4+ plasma cells with an increased IgG4+/IgG+ plasma cell ratio, obliterative phlebitis, and often an increased serum IgG4 level. This review summarizes the characteristic histopathologic and clinical features of IgG4-RD with detailed discussion of the histopathologic characteristics of the most commonly involved anatomic sites. We also present recent advances in our understanding of the pathophysiologic mechanisms of IgG4-RD and discuss updates on the treatment, prognosis, and outcomes of this rare disease, including discussion of the possible association between IgG4-RD and malignancy.

A subset of CD8α-CD4+SLAMF7+ cytotoxic T cells is oligoclonally expanded in patients with active IgG4-RD. This T cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.

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.