小柯机器人

美国西奈山伊坎医学院Dusan Bogunovic团队发现，细胞因子、CD4 T细胞和CD11c⁺B细胞介导唐氏综合征中自身免疫性。2023年2月22日，《自然》杂志在线发表了这项成果。

为了研究自身免疫易感性的机制，研究人员绘制了唐氏综合征（DS）患者的可溶性和细胞免疫图谱。研究人员发现在稳定状态下有多达22种细胞因子持续升高（其水平往往超过急性感染患者），并检测到基础细胞激活：CD4 T细胞中的慢性IL-6信号和高比例的浆细胞和CD11c⁺Tbet^highCD21^low B细胞（Tbet也被称为TBX21）。众所周知，这个亚群容易发生自身免疫，在DS中显示出更大的自体反应特征，包括具有较少非参考核苷酸的受体和较高的IGHV4-34利用率。在体外，与对照血浆或未受刺激的T细胞相比，在DS患者的血浆中或与IL-6激活的T细胞中孵化初始B细胞，分别导致浆细胞分化增加。

最后，研究人员在DS患者的血浆中检测到365种自身抗体，这些抗体针对胃肠道、胰腺、甲状腺、中枢神经系统和免疫系统本身。这些数据共同指出了DS的自身免疫易感状态，其中稳态细胞因子病变、高活化的CD4 T细胞和持续的B细胞活化都有助于破坏免疫耐受。这些研究结果也开辟了治疗途径，因为研究人员证明T细胞激活不仅可以用广泛的免疫抑制剂（如Jak抑制剂）来解决，还可以用更有针对性的IL-6抑制方法。

据介绍，DS表现为一系列的心脏、神经认知和生长障碍。患有唐氏综合症的人也容易发生严重的感染和自身免疫，包括甲状腺炎、1型糖尿病、乳糜泻和秃头症。

附：英文原文

Title: Autoimmunity in Down’s syndrome via cytokines, CD4 T cells and CD11c+ B cells

Author: Malle, Louise, Patel, Roosheel S., Martin-Fernandez, Marta, Stewart, O Jay, Philippot, Quentin, Buta, Sofija, Richardson, Ashley, Barcessat, Vanessa, Taft, Justin, Bastard, Paul, Samuels, Julie, Mircher, Clotilde, Rebillat, Anne-Sophie, Maillebouis, Louise, Vilaire-Meunier, Marie, Tuballes, Kevin, Rosenberg, Brad R., Trachtman, Rebecca, Casanova, Jean-Laurent, Notarangelo, Luigi D., Gnjatic, Sacha, Bush, Douglas, Bogunovic, Dusan

Issue&Volume: 2023-02-22

Abstract: Down’s syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS are also prone to severe infections and autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata1,2. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels often exceeding those in patients with acute infection) and detected basal cellular activation: chronic IL-6 signalling in CD4 T cells and a high proportion of plasmablasts and CD11c+TbethighCD21low B cells (Tbet is also known as TBX21). This subset is known to be autoimmune-prone and displayed even greater autoreactive features in DS including receptors with fewer non-reference nucleotides and higher IGHV4-34 utilization. In vitro, incubation of naive B cells in the plasma of individuals with DS or with IL-6-activated T cells resulted in increased plasmablast differentiation compared with control plasma or unstimulated T cells, respectively. Finally, we detected 365 auto-antibodies in the plasma of individuals with DS, which targeted the gastrointestinal tract, the pancreas, the thyroid, the central nervous system, and the immune system itself. Together, these data point to an autoimmunity-prone state in DS, in which a steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation all contribute to a breach in immune tolerance. Our findings also open therapeutic paths, as we demonstrate that T cell activation is resolved not only with broad immunosuppressants such as Jak inhibitors, but also with the more tailored approach of IL-6 inhibition.

DOI: 10.1038/s41586-023-05736-y

Source: https://www.nature.com/articles/s41586-023-05736-y

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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