TSLP 促进 B 细胞增殖和滤泡辅助性 T 细胞极化，是 IgG4 相关疾病的治疗靶点。

TSLP promoting B cell proliferation and polarizing follicular helper T cell as a therapeutic target in IgG4-related disease.

机构信息

Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.

出版信息

J Transl Med. 2022 Sep 8;20(1):414. doi: 10.1186/s12967-022-03606-1.

OBJECTIVE

To figure out the functions of thymic stromal lymphopoietin (TSLP) in IgG4-related disease (IgG4-RD).

METHODS

Plasma TSLP levels were tested by Elisa, and its receptors were detected by flow cytometry. Expressions of TSLP and TSLPR in involved tissues were stained by immunohistochemistry and immunofluorescence. Proliferation, apoptosis, and B subsets of TSLP stimulated-B cells were analyzed by flow cytometry. TSLP-stimulated B cells were co-cultured with CD4+ Naïve T cells. Signaling pathway was identified by RNA-sequencing and western blot. Anti-TSLP therapy was adapted in Lat knock-in mice (Lat, IgG4-RD mouse model).

RESULTS

Plasma TSLP level was increased in IgG4-RD patients and was positively correlated with serum IgG4 level and responder index (RI). TSLPR was co-localized with CD19+ B cells in the submandibular glands (SMGs) of IgG4-RD. TSLP promoted B cell proliferation, and TSLP-activated B cells polarized CD4+ naive T cells into follicular helper T (Tfh) cells through OX40L. RNA-sequencing identified JAK-STAT signaling pathway in TSLP-activated B cells and it was verified by western blot. Anti-TSLP therapy alleviated the inflammation of lung in Lat mice.

CONCLUSION

Elevated TSLP in IgG4-RD promoted B cells proliferation and polarized Tfh cells and might be served as a potential therapeutic target.

目的

探讨胸腺基质淋巴细胞生成素（TSLP）在 IgG4 相关疾病（IgG4-RD）中的作用。

方法

采用 ELISA 法检测血浆 TSLP 水平，流式细胞术检测其受体表达。免疫组织化学和免疫荧光法检测 TSLP 和 TSLPR 在受累组织中的表达。采用流式细胞术分析 TSLP 刺激的 B 细胞增殖、凋亡和 B 亚群。将 TSLP 刺激的 B 细胞与 CD4+Naive T 细胞共培养。采用 RNA 测序和 Western blot 鉴定信号通路。采用 Lat 敲入小鼠（Lat，IgG4-RD 小鼠模型）进行抗 TSLP 治疗。

结果

IgG4-RD 患者血浆 TSLP 水平升高，与血清 IgG4 水平和应答指数（RI）呈正相关。TSLPR 与 IgG4-RD 患者下颌下腺（SMG）中的 CD19+B 细胞共定位。TSLP 促进 B 细胞增殖，TSLP 激活的 B 细胞通过 OX40L 将 CD4+Naive T 细胞极化为滤泡辅助 T（Tfh）细胞。RNA 测序鉴定 TSLP 激活的 B 细胞中的 JAK-STAT 信号通路，并通过 Western blot 进行验证。抗 TSLP 治疗可减轻 Lat 小鼠肺部炎症。