IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder signified by aberrant infiltration of IgG4-restricted plasma cells into a variety of organs. Clinical presentation is heterogeneous, and pathophysiological mechanisms of IgG4-RD remain elusive. There are very few cases of IgG4-RD with isolated central nervous system manifestation. By leveraging single-cell sequencing of the cerebrospinal fluid (CSF) of a patient with an inflammatory intracranial pseudotumor, we provide novel insights into the immunopathophysiology of IgG4-RD. Our data illustrate an IgG4-RD-associated polyclonal T-cell response in the CSF and an oligoclonal T-cell response in the parenchymal lesions, the latter being the result of a multifaceted cell–cell interaction between immune cell subsets and pathogenic B cells. We demonstrate that CD8⁺ T effector memory cells might drive and sustain autoimmunity via macrophage migration inhibitory factor (MIF)-CD74 signaling to immature B cells and CC-chemokine ligand 5 (CCL5)-mediated recruitment of cytotoxic CD4⁺ T cells. These findings highlight the central role of T cells in sustaining IgG4-RD and open novel avenues for targeted therapies.

中文翻译：

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CD8+记忆T细胞在IgG4相关脑实质疾病中的鞘内激活

IgG4 相关疾病 (IgG4-RD) 是一种纤维炎症性疾病，表现为 IgG4 限制性浆细胞异常浸润到各种器官中。临床表现是异质的，IgG4-RD 的病理生理机制仍然难以捉摸。具有孤立性中枢神经系统表现的 IgG4-RD 病例很少。通过对患有炎性颅内假瘤的患者的脑脊液 (CSF) 进行单细胞测序，我们为 IgG4-RD 的免疫病理生理学提供了新的见解。我们的数据说明了 CSF 中与 IgG4-RD 相关的多克隆 T 细胞反应和实质病变中的寡克隆 T 细胞反应，后者是免疫细胞亚群和致病性 B 细胞之间多方面细胞相互作用的结果。我们证明 CD8 ⁺T 效应记忆细胞可能通过巨噬细胞迁移抑制因子 (MIF)-CD74 信号传导至未成熟的 B 细胞和 CC-趋化因子配体 5 (CCL5) 介导的细胞毒性 CD4 ⁺ T 细胞的募集来驱动和维持自身免疫。这些发现突出了 T 细胞在维持 IgG4-RD 中的核心作用，并为靶向治疗开辟了新途径。