Department of Pediatric Surgery, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangdong Provincial Children's Medical Research Center, Guangzhou Institute of Pediatrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, Guangdong, China.
J Immunol Res. 2024 Oct 26;2024:4838514. doi: 10.1155/2024/4838514. eCollection 2024.
Hirschsprung's disease (HSCR) is a congenital enteric nervous system (ENS) disorder. Genetics cannot explain most sporadic cases. To explore the relationship between pathogen infection, autoantibodies, innate immune, and HSCR. Pathogen microarray was conducted in the serum of the prospective neonatal abdominal distension (NAD) cohort, consisting of 56 children followed for at least 6 months until the final diagnosis of HSCR was determined or excluded. We conducted an autoantibody microarray in an HSCR cohort, which is comprised of diagnosed HSCR patients (HSCR) and healthy control subjects (HC). RNA-seq of colon tissues from aganglionic and ganglionic segments of HSCR patients was performed. Experimental results show that the serum lgM and lgG of enterovirus 71 (EV71) were significantly higher in HSCR than in the gastrointestinal dysfunction (GI) group, with a prediagnose value reaching area under the curve (AUC) over 0.76. We discovered that a group of autoantibodies were significantly higher in HSCR including neuronal pentraxin 1 (NPTX1), amyloid, neuron lysate, and myelin-associated oligodendrocytic basic protein (MOBP) than that in the HC group. These four autoantibodies could distinguish HSCR from the HC group, with a combined AUC of over 0.90 using both serum IgG and IgM. Further analysis showed that wide activation of innate immune pathways, including toll-like receptor (TLR) signaling pathway, neutrophil-to-lymphocyte ratio (NLR) signaling pathway, red cell distribution width to lymphocyte ratio (RLR) signaling pathway, and cyclic adenosine monophosphate (cAMP) signaling pathway in aganglionic compared to ganglionic segments of HSCR. This study suggested that virus-triggered autoimmunity may contribute to HSCR through activation of innate immunity, which facilitates the diagnosis and prevention of HSCR.
先天性巨结肠症（HSCR）是一种先天性肠神经系统（ENS）疾病。遗传学无法解释大多数散发性病例。为了探讨病原体感染、自身抗体、先天免疫与 HSCR 之间的关系。在前瞻性新生儿腹胀（NAD）队列的血清中进行了病原体微阵列检测，该队列由 56 名儿童组成，至少随访 6 个月，直到最终确定或排除 HSCR 的诊断。我们对一组诊断为先天性巨结肠症（HSCR）的患者（HSCR）和健康对照组（HC）进行了自身抗体微阵列检测。对 HSCR 患者无神经节和神经节段的结肠组织进行了 RNA-seq 分析。实验结果表明，血清中肠道病毒 71（EV71）的 lgM 和 lgG 在 HSCR 中明显高于胃肠功能障碍（GI）组，其预诊断值的曲线下面积（AUC）超过 0.76。我们发现一组自身抗体在 HSCR 中明显高于健康对照组，包括神经元五聚体蛋白 1（NPTX1）、淀粉样蛋白、神经元裂解物和髓鞘相关少突胶质细胞碱性蛋白（MOBP）。这四种自身抗体可以区分 HSCR 和 HC 组，使用血清 IgG 和 IgM 的联合 AUC 超过 0.90。进一步分析表明，先天免疫途径的广泛激活，包括 Toll 样受体（TLR）信号通路、中性粒细胞与淋巴细胞比值（NLR）信号通路、红细胞分布宽度与淋巴细胞比值（RLR）信号通路和环磷酸腺苷（cAMP）信号通路，在 HSCR 的无神经节段比神经节段中更为活跃。这项研究表明，病毒触发的自身免疫可能通过先天免疫的激活导致 HSCR，这有助于 HSCR 的诊断和预防。
