扁桃体Tfh细胞与记忆B细胞协同参与IgA肾病的发病机制

文献信息

中文摘要

引言： 免疫球蛋白A肾病（IgAN）是一种以系膜区IgA沉积为特征的慢性肾小球疾病，可进展至终末期肾衰竭。扁桃体切除术被用作治疗干预措施，以减缓疾病进展并提供早期临床获益。然而，参与IgAN发病机制的腭扁桃体免疫机制仍未完全阐明。
方法： 为了明确调节病理性抗体产生的扁桃体免疫环境，我们分析了T和B淋巴细胞亚群与肾功能的关系。我们还进行了功能研究，以评估半乳糖缺陷型IgA（Gd-IgA）和抗Tn（GalNAc-Ser/Thr）抗体的产生，这两种抗体均与致病性免疫复合物的形成有关。
结果： 与疾病对照组相比，IgAN扁桃体中的滤泡间T滤泡辅助（IF-Tfh）细胞（CD3+CD4+CD8-PD-1loCXCR5lo）显著扩增，并与肾脏异常的临床标志物密切相关。对来自IgAN扁桃体的IF-Tfh细胞的转录组分析揭示了一种独特的基因表达谱，富集了与肾功能损害相关的效应记忆T细胞样特征。功能研究表明，IF-Tfh细胞能有效促进类别转换的记忆B细胞产生Gd-IgA1和抗Tn（GalNAc-Ser/Thr）抗体。
结论： 这些发现表明，IF-Tfh细胞主导的免疫环境驱动了IgAN的发病机制，并可能成为非侵入性治疗方法的靶点。

英文摘要

INTRODUCTION: Immunoglobulin A nephropathy (IgAN) is a chronic glomerular disease characterized by mesangial IgA deposition, which can progress to end-stage renal failure. Tonsillectomy is used as a therapeutic intervention to slow disease progression and provide early clinical benefit. However, the immune mechanisms within the palatine tonsils that contribute to IgAN pathogenesis remain incompletely understood.
METHODS: To define the tonsillar immune environment that regulates pathological antibody production, we analyzed T and B lymphocyte subsets in relation to renal function. We also conducted functional studies to evaluate the production of galactose-deficient IgA (Gd-IgA) and anti-Tn (GalNAc-Ser/Thr) antibodies, both of which are implicated in the formation of pathogenic immune complexes.
RESULTS: Interfollicular T follicular helper (IF-Tfh) cells (CD3+CD4+CD8-PD-1loCXCR5lo) were significantly expanded in IgAN tonsils compared with disease controls and strongly correlated with clinical markers of renal abnormalities. Transcriptomic analysis of IF-Tfh cells from IgAN tonsils revealed a distinct gene expression profile enriched for effector memory T cell-like features associated with kidney impairment. Functional studies demonstrated that IF-Tfh cells potently promoted class-switched memory B cells to produce Gd-IgA1 and anti-Tn (GalNAc-Ser/Thr) antibodies.
CONCLUSION: These findings suggest that an IF-Tfh cell-dominant immune environment drives IgAN pathogenesis and may represent a target for noninvasive therapeutic approaches.