The ability of most patients with selective immunoglobulin A (IgA) deficiency (SIgAD) to remain apparently healthy has been a persistent clinical conundrum. Compensatory mechanisms, including IgM, have been proposed, yet it remains unclear how secretory IgA and IgM work together in the mucosal system and, on a larger scale, whether the systemic and mucosal anti-commensal responses are redundant or have unique features. To address this gap in knowledge, we developed an integrated host-commensal approach combining microbial flow cytometry and metagenomic sequencing (mFLOW-Seq) to comprehensively define which microbes induce mucosal and systemic antibodies. We coupled this approach with high-dimensional immune profiling to study a cohort of pediatric patients with SIgAD and household control siblings. We found that mucosal and systemic antibody networks cooperate to maintain homeostasis by targeting a common subset of commensal microbes. In IgA-deficiency, we find increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota. Associated features of immune system dysregulation in IgA-deficient mice and humans included elevated levels of inflammatory cytokines, enhanced follicular CD4 T helper cell frequency and activation, and an altered CD8 T cell activation state. Although SIgAD is clinically defined by the absence of serum IgA, the symptomatology and immune dysregulation were concentrated in the SIgAD participants who were also fecal IgA deficient. These findings reveal that mucosal IgA deficiency leads to aberrant systemic exposures and immune responses to commensal microbes, which increase the likelihood of humoral and cellular immune dysregulation and symptomatic disease in patients with IgA deficiency.

中文翻译：

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IgA 缺乏会破坏肠道微生物的稳态并增加全身免疫失调

大多数患有选择性免疫球蛋白 A (IgA) 缺乏症 (SIgAD) 的患者能否保持明显的健康一直是一个持续存在的临床难题。已经提出了包括 IgM 在内的补偿机制，但尚不清楚分泌型 IgA 和 IgM 如何在粘膜系统中协同工作，以及在更大范围内，全身和粘膜的反共生反应是多余的还是具有独特的特征。为了解决这一知识差距，我们开发了一种整合的宿主共生方法，结合微生物流式细胞术和宏基因组测序 (mFLOW-Seq)，以全面定义哪些微生物诱导粘膜和全身抗体。我们将这种方法与高维免疫分析相结合，以研究一组患有 SIgAD 的儿科患者和家庭对照兄弟姐妹。我们发现粘膜和全身抗体网络通过针对共生微生物的一个共同子集来合作维持体内平衡。在 IgA 缺乏症中，我们发现特定细菌类群的易位增加与针对粪便微生物群的全身 IgG 水平升高有关。IgA 缺陷小鼠和人类免疫系统失调的相关特征包括炎症细胞因子水平升高、滤泡 CD4 T 辅助细胞频率和激活增强以及 CD8 T 细胞激活状态改变。尽管 SIgAD 的临床定义是血清 IgA 缺失，但症状学和免疫失调集中在粪便 IgA 缺乏的 SIgAD 参与者中。这些发现表明，粘膜 IgA 缺乏会导致异常的全身暴露和对共生微生物的免疫反应，