The high potential of CD19.CAR-T cells to treat autoimmune diseases such as Systemic Sclerosis (SSc) supposedly relies on the disappearance of autoantibodies. Here we investigated effects of CAR-T cells on the innate immune system which is an important contributor to pathology in SSc. Longitudinal analysis of peripheral blood mononuclear cells from an Scl70 + SSc patient treated with CAR-T cells sampled over 18 months by 29-color spectral flow cytometry, in vitro experiments using sera from patient cohorts. In the patient treated with CAR-T cells, the substantial clinical improvement was paralleled by dynamic changes in innate lymphoid cells, namely Fcγ-receptor IIIA-expressing natural killer (NK) cells. NK cells adopted a more juvenile, less activated, and less differentiated phenotype. In parallel, the potency of serum to form Scl70-containing immune complexes that activate Fcγ-receptor IIIA decreased over time. These observations suggested a mechanistic link between reversal of adaptive autoimmunity and recovering Fcγ-receptor IIIA-expressing innate immune cells after CAR-T cell therapy via regressing immune complex activity. Experiments with sera from the non-CAR-T-treated SSc cohort confirmed that Scl70-containing immune complexes activate Fcγ-receptor IIIA-expressing NK cells in a dose-dependent manner, substantiating the relevance of this link between adaptive and innate immunity in SSc. This report describes for the first time the phenotypic recovery of innate Fcγ-receptor-expressing cells in an SSc patient treated with CAR-T cells. Decreasing autoantibody levels associated with a reduced ability to form functional immune complexes, the latter appearing to contribute to pathology in SSc via activation of Fcγ receptor IIIA + cells such as NK cells. Proposed mechanism of involvement of NK cells and soluble Immune Complexes (sICs) in disease progression during active autoimmunity in SSc (left) and resolution of fibrosis after deep B cell depletion by CD19.CAR-T cells and disappearance of autoantibodies (right).

中文翻译：

---

CD19 的免疫作用。系统性硬化症中的 CAR-T 细胞疗法：扩展案例研究


CD19 的高潜力。据称，用于治疗系统性硬化症 （SSc） 等自身免疫性疾病的 CAR-T 细胞依赖于自身抗体的消失。在这里，我们研究了 CAR-T 细胞对先天免疫系统的影响，这是 SSc 病理学的重要贡献者。对 Scl70 + SSc 患者的外周血单核细胞进行纵向分析，通过 29 色光谱流式细胞术在 18 个月内取样，使用来自患者队列的血清进行体外实验。在接受 CAR-T 细胞治疗的患者中，临床的显著改善与先天淋巴细胞（即表达 Fcγ 受体 IIIA 的自然杀伤 （NK） 细胞）的动态变化平行。NK 细胞采用更幼年、活化程度较低和分化程度较低的表型。同时，血清形成激活 Fcγ 受体 IIIA 的含 Scl70 的免疫复合物的效力随着时间的推移而降低。这些观察结果表明，适应性自身免疫的逆转与CAR-T细胞治疗后通过消退免疫复合物活性恢复表达Fcγ受体IIIA的先天免疫细胞之间存在机制联系。来自非 CAR-T 处理的 SSc 队列的血清实验证实，含有 Scl70 的免疫复合物以剂量依赖性方式激活表达 Fcγ 受体 IIIA 的 NK 细胞，证实了 SSc 中适应性免疫和先天免疫之间的这种联系的相关性。本报告首次描述了接受 CAR-T 细胞治疗的 SSc 患者先天表达 Fcγ 受体细胞的表型恢复。与形成功能性免疫复合物的能力降低相关的自身抗体水平降低，后者似乎通过激活 Fcγ 受体 IIIA + 细胞（如 NK 细胞）导致 SSc 的病理学。 提出 NK 细胞和可溶性免疫复合物 （sIC） 参与 SSc 主动自身免疫期间疾病进展的机制（左）和 CD19 深部 B 细胞耗竭后纤维化的消退。CAR-T 细胞和自身抗体的消失（右）。