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.
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.
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DOI：
10.1186/s13075-016-1064-4
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发表时间：
2016-07-13
影响因子：
4.9
通讯作者：
Takeuchi T
中科院分区：
文献类型：
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作者：
Akiyama M;Yasuoka H;Yamaoka K;Suzuki K;Kaneko Y;Kondo H;Kassai Y;Koga K;Miyazaki T;Morita R;Yoshimura A;Takeuchi T
本研究的目的是阐明循环滤泡辅助性T细胞亚群(TFH)在活动期未治疗的IgG4相关疾病(IgG4-RD)患者辅助B细胞中的作用，并确定其与疾病活动性的关系。17例活动期未经治疗的IgG4-RD患者、20例原发性干燥综合征(PSS)、5例多中心Castleman病(MCD)患者和12例健康对照(HC)纳入研究。通过与幼稚B细胞体外共培养的方法检测TFH细胞亚群功能。活化的TFH细胞亚群定义为TFH细胞亚群中CCR7lowPD-1高的亚群。以IgG4-RD反应者指数(IgG4-RD RI)评分评价疾病活动性。IgG4-RD组Tfh2细胞数显著高于PSS、MCD和HC组，且与血清IgG4水平和浆母细胞数呈正相关。在体外，Tfh2细胞比Tfh1或Tfh17细胞更有效地诱导幼稚B细胞分化为浆母细胞。值得注意的是，虽然IgG4-RD和HC的Tfh2细胞培养上清液中的IgG4的产生相似，但IgG4-RD患者的Tfh2细胞的IgG4的产生明显高于HC。相应地，来自IgG4-RD的Tfh2细胞的培养上清液中的IgG4/Ig G比率也显著高于HC。此外，与PSS、MCD或HC相比，IgG4-RD组活化的Tfh2细胞数更多，且与基线活动期的IgG4-RD RI评分密切相关。活化的Tfh2细胞数与受累器官数和血清IgG4水平相关。重要的是，糖皮质激素治疗和平行疾病改善后，活化的Tfh2细胞数量减少。此外，与PSS、MCD和HC相比，IgG4-RD患者活化的Tfh1细胞数量也增加，且与IgG4-RD RI评分相关，但与血清IgG4水平无关。Tfh2细胞，而不是Tfh1或Tfh17细胞，可诱导未经治疗的活动期IgG4-RD患者的幼稚B细胞分化为浆母细胞，并增加IgG4的产生。此外，活化的Tfh2细胞反映了疾病的活动性，提示这一T细胞亚群参与了IgG4-RD的发病。有趣的是，在IgG4-RD患者中，活化的Tfh1细胞数量也增加，与疾病活动性相关，但与血清IgG4水平无关，提示Tfh1细胞参与了IgG4-RD患者的IgG4产生过程。本文的在线版本(doi：10.1186/s1307510161064-4)包含补充材料，授权用户可以使用。
The 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. Seventeen 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. The 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. Tfh2 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. The online version of this article (doi:10.1186/s13075-016-1064-4) contains supplementary material, which is available to authorized users.