Frequency and distribution of CD4(+)CXCR5(+) follicular B helper T cells within involved tissues in IgG4-related ophthalmic disease

Immonoglobulin G4-related ophthalmic disease (IgG4-ROD) is a IgG4-RD and exhibits two main characteristics: Fibrosis that is not necessarily marked histopathologically; and frequent formation of germinal centers (GCs). Follicular B helper T (Tfh) cells are now recognized as the true helper cells for B cells in antibody responses. In the present study, the profile and distribution of Tfh cells in involved tissues from patients with IgG4-ROD was compared to those of type 1 autoimmune pancreatitis (AIP) and patients with IgG4-related lymphadenopathy (IgG4-RL). A total of 7 patients with IgG4-ROD, 7 patients with type 1 AIP or IgG4-RL and 7 IgG4-negative controls were evaluated. The expression of Tfh-cell immunological proteins, the inducible T-cell costimulator, B-cell lymphoma 6 protein, C-X-C chemokine receptor type 5 (CXCR5) and interleukin-21 (IL-21) in affected tissues was analyzed using immunohistochemical staining and dual immunofluorescence. It was demonstrated that patients with IgG4-RD exhibited a significantly increased number of CD4(+)CXCR5(+) Tfh cells compared with the IgG4-negative controls. Furthermore, CD4(+)CXCR5(+) Tfh cells were detected in and outside of GCs in patients with IgG4-ROD and IgG4-RLF, whereas CD4(+)CXCR5(+) Tfh cells were randomly distributed in areas demonstrating type 1 AIP. Fewer CD4(+)CXCR5(+) Tfh cells were observed in patients with type 1 AIP compared with patients with IgG4-ROD and IgG4-RL. In addition, increased expression of IL-21 was observed in patients with IgG4-ROD and IgG4-RL compared with type 1 AIP. IL-21 expression was positively correlated with the IgG4/IgG ratio in immunohistochemically-positive cells. The results of the present study indicate that Tfh cells are involved in the histopathological pathogenesis of IgG4-RD and may serve a different role in IgG4-ROD and type 1 AIP. Tfh cells may serve a direct role in the IL-21-mediated pathogenesis of IgG4-ROD.