People with Down syndrome show cellular and clinical features of dysregulated aging of the immune system, including naïve-memory shift in the T cell compartment and increased incidence of autoimmunity. However, a quantitative understanding of how various immune compartments change with age in Down syndrome remains lacking. Here we performed deep immunophenotyping of a cohort of individuals with Down syndrome across the lifespan, selecting for individuals not affected by autoimmunity. We simultaneously interrogated age- and sex-matched healthy neurotypical controls and people with type 1 diabetes, as a representative autoimmune disease. We built a new analytical software, IMPACD, that enabled us to rapidly identify many features of immune dysregulation in Down syndrome that are recapitulated in other autoimmune diseases. We found significant quantitative and qualitative dysregulation of naïve CD4⁺ and CD8⁺ T cells in Down syndrome and identified IL-6 as a candidate driver of some of these changes, thus extending the consideration of immunopathologic cytokines in Down syndrome beyond interferons. Notably, we successfully used immune cellular composition to generate three quantitative models of aging (i.e. immune clocks) trained on control subjects. All three immune clocks demonstrated significantly advanced immune aging in people with Down syndrome. Notably, one of these clocks, informed by Down syndrome-relevant biology, also showed advanced immune aging in people with type 1 diabetes. Together, our findings demonstrate a novel approach to studying immune aging in Down syndrome which may have implications in the context of other autoimmune diseases.

中文翻译：

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置换免疫分析揭示了炎症、唐氏综合症和自身免疫之间的结构相似性

唐氏综合症患者表现出免疫系统老化失调的细胞和临床特征，包括 T 细胞区室的幼稚记忆转变和自身免疫的发生率增加。然而，仍然缺乏对唐氏综合症中各种免疫区室如何随年龄变化的定量理解。在这里，我们对整个生命周期中患有唐氏综合症的一组个体进行了深度免疫表型分析，选择了不受自身免疫影响的个体。我们同时询问了年龄和性别匹配的健康神经典型对照和 1 型糖尿病患者，作为代表性的自身免疫性疾病。我们构建了一个新的分析软件 IPACCD，它使我们能够快速识别唐氏综合症中免疫失调的许多特征，这些特征在其他自身免疫疾病中有所体现。⁺和 CD8 ⁺ T 细胞在唐氏综合症中，并确定 IL-6 作为其中一些变化的候选驱动因素，从而将唐氏综合症中免疫病理细胞因子的考虑范围扩大到干扰素之外。值得注意的是，我们成功地使用免疫细胞成分生成了三个针对对照受试者训练的衰老定量模型（即免疫时钟）。所有三个免疫时钟都表明唐氏综合症患者的免疫衰老显着提前。值得注意的是，由唐氏综合症相关生物学提供的这些时钟之一也显示出 1 型糖尿病患者的高级免疫老化。总之，我们的研究结果证明了一种研究唐氏综合症免疫衰老的新方法，这可能对其他自身免疫疾病有影响。