通过细胞因子、CD4 T 细胞和 CD11c + B 细胞实现唐氏综合症的自身免疫。唐氏综合征患者的自身免疫易感状态，这背后可能是长期病理性增高的细胞因子、高活化的CD4 T细胞和持续的B细胞活化对免疫耐受的破坏。失调的细胞因子与激活的T细胞促进了容易产生自身免疫的B细胞的形成。唐氏综合征患者的血浆中检测到多达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。
学术经纬
2023/02/28
论文
论文标题：Autoimmunity in Down’s syndrome via cytokines, CD4 T cells and CD11c+ B cells
作者：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
期刊：Nature
发表时间：2023/02/22
数字识别码：10.1038/s41586-023-05736-y
摘要：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.
