Background IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and increased circulating plasmablasts1. The high degree of somatic hypermutation and emergence of distinct plasmablast clones at disease relapse suggests the de novo recruitment of naïve B cells into T-cell–dependent responses1. Follicular helper T (Tfh) cells play a major role in T-cell–dependent B cell responses, and their counterparts and subsets (Tfh1, Tfh2 or Tfh17 cells) have only been recognized in peripheral blood2. We previously reported that Tfh2 cells were increased in IgG4-RD3, although the functional role of Tfh2 cells remains to be elucidated.
Objectives To elucidate the function of Tfh2 cells and involvement in the pathogenesis of active, untreated IgG4-RD.
Methods Active, untreated IgG4-RD (n=17) were compared to healthy controls (HC) (n=12), patients with primary Sjögren syndrome (pSS) (n=20) and multicentric Castleman's disease (MCD) (n=5). Tfh2 cells (CD3+CD4+CD45RA-CXCR5+CXCR3-CCR6-cells), activated Tfh2 cells (CCR7loPD-1hi subset in Tfh2 cells) and plasmablasts (CD19+CD20-CD27+CD38+cells) were detected by flow cytometry. The function of Tfh2 cells was evaluated by co-culture with autologous naïve B cells in vitro. Disease activity was evaluated by IgG4-RD Responder Index (IgG4-RD RI) score.
Results The percentage of Tfh2 cells was significantly increased in IgG4-RD compared to pSS, MCD or HC, and correlated with serum IgG4 levels (ρ=0.7377, P =0.0011) or the percentage of plasmablasts (ρ=0.6127, P=0.0104). In vitro, Tfh2 cells induced a greater percentage of differentiation of naïve B cells into plasmablasts in IgG4-RD and HC compared to Tfh1 and Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells were comparable between IgG4-RD and HC, IgG4 production was significantly higher in IgG4-RD compared to HC. Accordingly, IgG4/IgG ratio in culture supernatants was also significantly higher only with Tfh2 cells from IgG4-RD. In addition, the percentage of activated Tfh2 cells was significantly increased in IgG4-RD (8.0 ± 1.6%) compared to pSS (1.4±0.2%, P<0.0001), MCD (1.6±0.5%, P<0.0001) or HC (1.2±0.2%, P<0.0001), and correlated strongly with IgG4-RD RI score (ρ=0.7984, P=0.0002). In particular, the percentage of activated Tfh2 cells associated with the number of affected organs (ρ=0.8152, P=0.0001), and decreased with glucocorticoid treatment in parallel with disease improvement. Of note, the percentage of activated Tfh2 cells was re-elevated at disease relapse.
Conclusions Tfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and IgG4 production in patients with active, untreated IgG4-RD. This increase in activated Tfh2 cells is linked to disease activity, suggesting that Tfh2 cells play a pivotal role in the pathogenesis of IgG4-RD.
J Allergy Clin Immunol. 2014;134:679–87.
Arthritis Rheumatol. 2015;67:2476–81.
Acknowledgement We thank the patients and healthy individuals who participated in this study. We thank Mr. Noriyasu Seki, Mr. Humitsugu Yamane, Mrs. Yoshiko Yogiashi and Ms. Yuki Otomo for their technical assistance.
Disclosure of Interest None declared
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