New insights into IgG4-related disease: emerging new CD4+ T-cell subsets

Abstract

Purpose of review New insights into IgG4-related disease (IgG4-RD) have recently been obtained. A better understanding of the mechanisms underlying this disease is important for identification of therapeutic targets, which will lead to the development of specific strategies for treatment. Recent findings Infiltration of activated T follicular helper (Tfh) cells is observed in affected tissues of IgG4-RD. Such Tfh cells have a greater capacity than tonsillar Tfh cells to help B cells produce IgG4. Circulating PD-1 hi CXCR5 - peripheral T helper (Tph)-like cells are also increased in patients with IgG4-RD. Because Tph-like cells express high levels of chemokine receptors and granzyme A, they have the capacity to infiltrate affected tissues and exert a cytotoxic function. Tph-like cells can also produce CXCL13, and CXCR5 + Tfh cells and B cells are therefore preferentially recruited to form ectopic lymphoid structures in the sites. Tph cells may have a role to ignite inflammation and maintain persistent fibroinflammation in collaboration with Tfh cells in lesions of IgG4-RD. Summary Recent advances in understanding the pathogenesis of IgG4-RD are remarkable. In this review, we summarize and discuss the possible pathologic role of CD4 + T-cell subsets in IgG4-RD.

Patterns of T‐Cell Phenotypes in Rheumatic Diseases From Single‐Cell Studies of Tissue

“…IL‐4 + Tfh cells were associated with AID + B cells predominantly outside germinal centers, and their frequency in blood correlated with serum IgG4 levels ( 68 ). Consistent with other rheumatic diseases, Tregs are found in IgG4‐RD lesions as well ( 71 , 72 , 73 , 74 ).…”

IgG4-related gastric disease with plasma cell-rich obliterative arteritis accompanied by early-stage gastric cancer: a case report

“…Multiple lines of evidence indicate that IgG4-RD is an autoimmune condition; however, the exact pathogenesis remains incompletely understood. There is an emerging consensus that the IgG4 antibodies in IgG4-RD are not pathogenic, and that T cells, especially CD4+ cytotoxic and T-follicular helper cells, have a more important role [ 3 ]. Elevations in serum and tissue IgG4 concentrations are not specific to IgG4-RD; they are also found in several other disorders such as multicentric Castleman disease, eosinophilic granulomatosis with polyangiitis, sarcoidosis and allergic diseases [ 4 ].…”

Significance of high serum IgG4 in complete or non-full-fledged IgG4-related disease—a retrospective investigation of 845 patients and its clinical relevance

“…IgG4-RD occurs mostly in middle to elderly people with a male to female ratio of 3:1 to 4:1, especially in AIP [12,[18][19][20]. The immunopathogenesis of IgG4-RD has not been clearly elucidated but previously studies have suggested that B cell and CD4 + T cells such as cytotoxic T lymphocytes (CTLs) and follicular helper T cells (T FH ) may be involved [10,21]. CD4 CTLs have been associated with fibrotic process through pro-fibrotic cytokine secretion, such as interferons (IFNs), transforming growth factor-β (TGF-β), and various interleukins (ILs), or through inducing their targeting cell to undergo apoptosis [21][22][23].…”

“…The immunopathogenesis of IgG4-RD has not been clearly elucidated but previously studies have suggested that B cell and CD4 + T cells such as cytotoxic T lymphocytes (CTLs) and follicular helper T cells (T FH ) may be involved [10,21]. CD4 CTLs have been associated with fibrotic process through pro-fibrotic cytokine secretion, such as interferons (IFNs), transforming growth factor-β (TGF-β), and various interleukins (ILs), or through inducing their targeting cell to undergo apoptosis [21][22][23]. Different from excreting profi- brotic cytokines by CD4 + CTLs, CD4 T FH secretes IL-4 and IL-10 to stimulate B cell differentiation into IgG4-producing plasma cells [24].…”