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<p>Systemic lupus erythematosus (SLE) pathogenesis involves the dysregulated production of mutated, high-affinity autoantibodies, a process primarily orchestrated within germinal centers (GCs). However, the precise regulatory mechanisms governing the GC-mediated generation of autoantibodies in SLE remain elusive. In lupus-prone NZM2328 mice, we observed progressive accumulation of immunoglobulin heavy chain (<i>Igh</i>) mutations in GC B cells during disease progression, accompanied by increased clonotype sharing between GC B cells and plasmablast/plasma cell populations. Immunophenotyping revealed that follicular helper T cells (Tfh) express high levels of choline acetyltransferase (ChAT), a key enzyme for acetylcholine (ACh) biosynthesis. Notably, ChAT expression is predominantly upregulated in Tfh cells during the induction of systemic autoimmunity. Furthermore, sustained ChAT expression in Tfh cells relies on autocrine IL-21. Conditional ablation of ChAT in CD4<sup>+</sup> T cells results in impaired GC reactions, manifested as a reduced mutation frequency in <i>Igh</i> variable regions and decreased high-affinity antibody production, leading to significantly reduced selection of autoreactive GC B cells and mitigated glomerular immune complex deposition. In contrast, AID-Cre-mediated GC B-cell ChAT knockout fails to alter GC dynamics or autoimmune progression. Single-cell RNA sequencing analysis further demonstrated that ablation of ChAT in CD4<sup>+</sup> T cells reduced the clonal expansion and somatic hypermutation of GC B cells. Collectively, our findings identify a Tfh cell-dependent cholinergic checkpoint in which ACh drives the affinity maturation of pathogenic autoantibodies via somatic hypermutation, thereby promoting SLE pathogenesis.</p>

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A cholinergic checkpoint controls autoantibody selection via somatic hypermutation in lupus germinal centers

  • 期刊论文

  • 发表日期：

    2026年6月22日

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  • Jin Li,
  • Yimei Lai,
  • Huijin Zou,
  • Yichao Qian,
  • Xinyuan Ruan,
  • Lili Zhuang,
  • Zhangmei Lin,
  • Yumeng Wang,
  • Niansheng Yang,
  • Shuyi Wang,
  • Hui Zhang

摘要

Systemic lupus erythematosus (SLE) pathogenesis involves the dysregulated production of mutated, high-affinity autoantibodies, a process primarily orchestrated within germinal centers (GCs). However, the precise regulatory mechanisms governing the GC-mediated generation of autoantibodies in SLE remain elusive. In lupus-prone NZM2328 mice, we observed progressive accumulation of immunoglobulin heavy chain (Igh) mutations in GC B cells during disease progression, accompanied by increased clonotype sharing between GC B cells and plasmablast/plasma cell populations. Immunophenotyping revealed that follicular helper T cells (Tfh) express high levels of choline acetyltransferase (ChAT), a key enzyme for acetylcholine (ACh) biosynthesis. Notably, ChAT expression is predominantly upregulated in Tfh cells during the induction of systemic autoimmunity. Furthermore, sustained ChAT expression in Tfh cells relies on autocrine IL-21. Conditional ablation of ChAT in CD4+ T cells results in impaired GC reactions, manifested as a reduced mutation frequency in Igh variable regions and decreased high-affinity antibody production, leading to significantly reduced selection of autoreactive GC B cells and mitigated glomerular immune complex deposition. In contrast, AID-Cre-mediated GC B-cell ChAT knockout fails to alter GC dynamics or autoimmune progression. Single-cell RNA sequencing analysis further demonstrated that ablation of ChAT in CD4+ T cells reduced the clonal expansion and somatic hypermutation of GC B cells. Collectively, our findings identify a Tfh cell-dependent cholinergic checkpoint in which ACh drives the affinity maturation of pathogenic autoantibodies via somatic hypermutation, thereby promoting SLE pathogenesis.