Department of Human Genetics, National Institute of Mental Health and Neurosciences, Bangalore, India.
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand; Department of Psychiatry, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; Research Center, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria; Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea; Sichuan Provincial Center for Mental Health, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China; Key Laboratory of Psychosomatic Medicine, Chinese Academy of Medical Sciences, Chengdu, 610072, China.
Brain Behav Immun. 2024 Jan;115:505-516. doi: 10.1016/j.bbi.2023.11.013. Epub 2023 Nov 14.
Neurodevelopmental disorders (NDDs) are a spectrum of conditions with commonalities as well as differences in terms of phenome, symptomatome, neuropathology, risk factors and underlying mechanisms. Immune dysregulation has surfaced as a major pathway in NDDs. However, it is not known if neurodevelopmental disorders share a common immunopathogenetic mechanism. In this study, we explored the possibility of a shared immune etiology in three early-onset NDDs, namely Autism Spectrum Disorder (ASD), Attention Deficit Hyperactivity Disorder (ADHD) and Intellectual Disability Disorder (IDD). A panel of 48 immune pathway-related markers was assayed in 135 children with NDDs, represented by 45 children with ASD, ADHD and IDD in each group, along with 35 typically developing children. The plasma levels of 48 immune markers were analyzed on the Multiplex Suspension Assay platform using Pro Human cytokine 48-plex kits. Based on the cytokine/chemokine/growth factor levels, different immune profiles were computed. The primary characteristics of NDDs are depletion of the compensatory immune-regulatory system (CIRS) (z composite of IL-4, IL-10, sIL-1RA, and sIL-2R), increased interleukin (IL)-1 signaling associated with elevated IL-1α and decreased IL-1-receptor antagonist levels, increased neurogenesis, M1/M2 macrophage polarization and increased IL-4 as well as C-C Motif Chemokine Ligand 2 (CCL2) levels. With a cross-validated sensitivity of 81.8% and specificity of 94.4%, these aberrations seem specific for NDDs. Many immunological abnormalities are shared by ASD, ADHD and IDD, which are distinguished by minor differences in IL-9, IL-17 and CCL12. In contrast, machine learning reveals that NDD group consists of three immunologically distinct clusters, with enhanced neurogenesis, Th-1 polarization, or IL-1 signaling as the defining features. NDD is characterized by immune abnormalities that have functional implications for neurogenesis, neurotoxicity, and neurodevelopment. Using machine learning, NDD patients could be classified into subgroups with qualitatively distinct immune disorders that may serve as novel drug targets for the treatment of NDDs.
神经发育障碍 (NDD) 是一组具有表型、症状、神经病理学、危险因素和潜在机制共性和差异的疾病。免疫失调已成为 NDD 的主要途径。然而，尚不清楚神经发育障碍是否具有共同的免疫发病机制。在这项研究中，我们探索了三种早期发病的神经发育障碍（即自闭症谱系障碍 (ASD)、注意力缺陷多动障碍 (ADHD) 和智力障碍障碍 (IDD)）是否存在共同免疫病因的可能性。我们在 135 名患有 NDD 的儿童中检测了一组 48 种与免疫途径相关的标志物，其中每组有 45 名患有 ASD、ADHD 和 IDD 的儿童和 35 名发育正常的儿童。我们使用 Pro Human cytokine 48-plex 试剂盒在 Multiplex Suspension Assay 平台上分析了 48 种免疫标志物的血浆水平。基于细胞因子/趋化因子/生长因子水平，计算了不同的免疫特征。NDD 的主要特征是补偿性免疫调节系统 (CIRS) 的耗竭（IL-4、IL-10、sIL-1RA 和 sIL-2R 的 Z 复合），与 IL-1α 升高和 IL-1 受体拮抗剂水平降低相关的白细胞介素 (IL)-1 信号增加，神经发生增加，M1/M2 巨噬细胞极化以及 IL-4 和 C-C 基序趋化因子配体 2 (CCL2) 水平升高。交叉验证的敏感性为 81.8%，特异性为 94.4%，这些异常似乎是 NDD 的特异性。ASD、ADHD 和 IDD 有许多免疫异常，这些异常通过 IL-9、IL-17 和 CCL12 的微小差异来区分。相比之下，机器学习揭示 NDD 组由三个在免疫上明显不同的簇组成，以增强的神经发生、Th-1 极化或 IL-1 信号作为特征。NDD 的特征是免疫异常，这对神经发生、神经毒性和神经发育有功能影响。使用机器学习，可以将 NDD 患者分为具有不同免疫疾病的亚组，这些亚组可能成为治疗 NDD 的新药物靶点。
