Although many germinal centers (GCs) have been reported in immunoglobulin (Ig) G4-related disease, the significance of GCs in IgG4-related disease has not received attention. Both T follicular regulatory cells (Tfr), which are regulatory T cells (Treg) in GCs, and T follicular helper cells (Tfh) produce the cytokine interleukin (IL)-10 and regulate GC development. In whole-slide image analysis in surgical specimens using immunohistochemistry, IgG4-related sclerosing sialadenitis (IgG4-SS, n = 17) was characterized by markedly numerous, large, and irregular-shaped GCs with increased IL-10 + cells and Tfr and Tfh in the total area of the salivary gland compared with controls, including patients with chronic sialadenitis (n = 17) and Sjögren syndrome (n = 15). In particular, the central area of GC in IgG4-SS showed a higher Tfr number and Tfr/Tfh ratio than controls. The number of Tfr in the central area was significantly correlated with the number of IgG4 + plasmacytes and the number, size, and irregularity of GCs. In the mantle area, which surrounds GCs, IgG4-SS showed a higher Treg number and Treg/T helper cells (Th) ratio than controls. In IgG4-SS, the Treg/Th ratio was highest in the mantle area outside GCs and the Tfr/Tfh ratio was highest in the central area inside GCs. However, in controls, the Treg/Th ratio gradually decreased from outside to inside GCs. Our findings reveal that the morphological abnormality of GCs and the characteristic localization and altered balance of Treg and Th in the different compartments of inside and outside GCs would be the novel hallmarks of IgG4-SS.

尽管在免疫球蛋白 (Ig) G4 相关疾病中已经报道了许多生发中心 (GCs)，但 GCs 在 IgG4 相关疾病中的意义尚未受到关注。T 滤泡调节细胞 (Tfr) 是 GC 中的调节性 T 细胞 (Treg) 和 T 滤泡辅助细胞 (Tfh) 都产生细胞因子白细胞介素 (IL)-10 并调节 GC 发育。在使用免疫组织化学对手术标本进行全切片图像分析时，IgG4 相关硬化性唾液腺炎（IgG4-SS，n  = 17）的特征是显着大量、大且形状不规则的 GC，伴有 IL-10 + 细胞和 Tfr 和 Tfh 增加唾液腺总面积与对照组相比，包括慢性唾液腺炎 ( n  = 17) 和干燥综合征 ( n = 15)。特别是，IgG4-SS 中 GC 的中心区域显示出比对照更高的 Tfr 数和 Tfr/Tfh 比率。中心区域的 Tfr 数量与 IgG4 + 浆细胞的数量以及 GC 的数量、大小和不规则性显着相关。在围绕 GCs 的地幔区域中，IgG4-SS 显示出比对照组更高的 Treg 数量和 Treg/T 辅助细胞 (Th) 比率。在 IgG4-SS 中，Treg/Th 比率在 GCs 外的地幔区域最高，而 Tfr/Tfh 比率在 GCs 内部的中心区域最高。然而，在对照组中，Treg/Th 比率从 GC 外部到内部逐渐降低。我们的研究结果表明，GCs 的形态异常以及 Treg 和 Th 在内外 GCs 不同区室中的特征性定位和平衡改变将是 IgG4-SS 的新标志。