THU0007 Enhanced IGG4 Production by Follicular Helper Type 2 T Cells in IGG4-Related Disease
Authors: M. Akiyama, H. Yasuoka, K. Yamaoka, K. Suzuki, Y. Kaneko, H. Kondo, Y. Kassai, K. Koga, T. Miyazaki, R. Morita, A. Yoshimura, T. Takeuchi
Journal: Annals of the Rheumatic Diseases (2016)

<h3>Background</h3> IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and increased circulating plasmablasts<sup>1</sup>. 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 responses<sup>1</sup>. 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 blood<sup>2</sup>. We previously reported that Tfh2 cells were increased in IgG4-RD<sup>3</sup>, although the functional role of Tfh2 cells remains to be elucidated. <h3>Objectives</h3> To elucidate the function of Tfh2 cells and involvement in the pathogenesis of active, untreated IgG4-RD. <h3>Methods</h3> Active, untreated IgG4-RD (n=17) were compared to healthy controls (HC) (n=12), patients with primary Sjögren syndrome (pSS) (n=20) and multicentric Castleman9s disease (MCD) (n=5). Tfh2 cells (CD3+CD4+CD45RA-CXCR5+CXCR3-CCR6-cells), activated Tfh2 cells (CCR7<sup>lo</sup>PD-1<sup>hi</sup> 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. <h3>Results</h3> 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, <i>P</i> =0.0011) or the percentage of plasmablasts (ρ=0.6127, <i>P</i>=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%, <i>P</i>&lt;0.0001), MCD (1.6±0.5%, <i>P</i>&lt;0.0001) or HC (1.2±0.2%, <i>P</i>&lt;0.0001), and correlated strongly with IgG4-RD RI score (ρ=0.7984, <i>P</i>=0.0002). In particular, the percentage of activated Tfh2 cells associated with the number of affected organs (ρ=0.8152, <i>P</i>=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. <h3>Conclusions</h3> 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. <h3>References</h3> J Allergy Clin Immunol. 2014;134:679–87. Immunity 2011;34:108–21. Arthritis Rheumatol. 2015;67:2476–81. <h3>Acknowledgement</h3> 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. <h3>Disclosure of Interest</h3> None declared