Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease

Abstract

BackgroundThe aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity.MethodsSeventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman’s disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score.ResultsThe number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level.ConclusionsTfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-016-1064-4) contains supplementary material, which is available to authorized users.

T Cell Polarization toward TH2/TFH2 and TH17/TFH17 in Patients with IgG4-Related Disease

“…Significant variation of T FH cells after treatment with steroids has also been recently reported in Japanese patients with modification of T FH 1 cells, which we did not observe in our larger study (29). However, organ involvement was significantly different from our study.…”

IgG4-Related Diseases in the Gastrointestinal Tract: Clinical Presentation, Diagnosis and Treatment Challenges

“…The concentrations of these cells correlate with the activity and the diagnosis of IgG4-related diseases. This hypothesis is corroborated by the observation that the Tfh2-specific cytokine interleukin-4 is significantly decreased after steroid therapy [9,17].…”

Emerging Treatment Models in Rheumatology: IgG4‐Related Disease: Insights Into Human Immunology and Targeted Therapies

“…This degree of expansion correlated with disease activity, and T FH2 cell expansions declined after glucocorticoid treatment. 51 These two studies support the role of T FH2 cells in orchestrating the B cell immune response in IgG4-RD. However, given the challenge of interpreting T FH data from the blood, where the T FH cells represent memory cells rather than effector cell populations, these findings must be validated at the tissue level.…”

“…51 T FH2 cells from IgG4-RD patients induced naïve B cells to differentiate into IgG4-producing plasmablasts more efficiently in vitro than did the same cells from healthy donor subjects. 51 In addition, expansions of both circulating T FH1 and T FH2 populations were observed in IgG4-RD subjects. This degree of expansion correlated with disease activity, and T FH2 cell expansions declined after glucocorticoid treatment.…”