Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove
Protection or susceptibility to devastating childhood epilepsy: Nodding Syndrome associates with immunogenetic fingerprints in the HLA binding groove
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DOI：
10.1371/journal.pntd.0008436
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发表时间：
2020-07-01
影响因子：
3.8
通讯作者：
Levite, Mia
中科院分区：
文献类型：
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作者：
Benedek, Gil;El Latif, Mahmoud Abed;Levite, Mia
点头综合征（NS）是一种毁灭性的和神秘的儿童癫痫。NS伴有多种神经功能损害和神经炎症，并与寄生虫盘尾丝虫（Onchocerca volvulus，Ov）和其他环境因素有关。此外，NS似乎是一种“自身免疫性癫痫”，因为：1。类似于50%的NS患者具有神经毒性交叉反应性Ov/Leimodin-I自身免疫抗体。2.我们最近发表的研究结果：大多数（约86%）NS患者具有谷氨酸受体AMPA-GluR 3B肽自身免疫抗体，其结合、诱导活性氧物质并杀死神经细胞和T细胞。此外，NS患者的IgG诱导癫痫发作，类似于NS患者脑中发生的脑多发性损伤，以及正常小鼠脑中T细胞和活化的小胶质细胞和星形胶质细胞的升高。人类白细胞抗原（HLA）I类和II类分子对于启动针对外来微生物的有效有益免疫和促进适当的脑功能至关重要，但也易患针对自身肽的有害自身免疫。我们分析了7个HLA位点，无论是通过下一代测序或序列特异性寡核苷酸探针，在48 NS患者和51名健康对照从南苏丹。我们发现NS与HLA-B肽结合沟中的保护性HLA单倍型HLA-B*42：01、C*17：01、DRB 1 *03：02、DQB 1 *04：02和DQA 1 *04：01以及易感基序Ala 24、Glu 63和Phe 67显著相关。这些氨基酸产生疏水性和空间封闭的肽结合HLA口袋，有利于脯氨酸残基。我们的研究结果表明，在HLA肽结合凹槽的免疫遗传指纹暂时与NS的保护或易感性。因此，不同的HLA分子可以解释为什么在相似的环境因素下，只有一些儿童，在相同的家庭，部落和地区，发展NS，而其他人则没有。作者摘要点头综合征（NS）是一种毁灭性的和神秘的神经系统疾病，影响5-15岁的儿童，主要在苏丹，乌干达和坦桑尼亚。NS与由黑蝇传播的寄生虫Oncocherca Volvulus（Ov）感染密切相关，影响了世界各地的许多人。此外，NS最有可能是一种“自身免疫性癫痫”，特别是鉴于我们最近的发现，NS患者的自身免疫性GluR 3B抗体诱导ROS并杀死神经细胞和T细胞。NS患者的IgG还可诱导癫痫发作、多发性脑损伤和脑中的炎症诱导细胞。HLA I类基因在所有有核细胞的表面上表达，并将肽呈递给细胞毒性CD 8 + T细胞。HLA II类基因主要在抗原呈递细胞的表面上表达，并将肽呈递给辅助性CD 4 + T细胞。对南苏丹NS患者和健康对照的HLA分析表明，HLA肽结合沟中的少数氨基酸与NS的保护或易感性相关。这些氨基酸通过影响有益的免疫和/或有害的自身免疫在NS中可能是关键的。
Nodding syndrome (NS) is a devastating and enigmatic childhood epilepsy. NS is accompanied by multiple neurological impairments and neuroinflammation, and associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. Moreover, NS seems to be an 'Autoimmune Epilepsy' since: 1. similar to 50% of NS patients have neurotoxic cross-reactive Ov/Leimodin-I autoimmune antibodies. 2. Our recently-published findings: Most (similar to 86%) of NS patients have glutamate-receptor AMPA-GluR3B-peptide autoimmune-antibodies that bind, induce Reactive-Oxygen-Species, and kill both neural cells and T cells. Furthermore, NS patient's IgG induce seizures, brain multiple damage alike occurring in brains of NS patients, and elevation of T cells and activated microglia and astrocytes, in brains of normal mice. Human Leukocyte antigen (HLA) class I and II molecules are critical for initiating effective beneficial immunity against foreign microorganisms and contributing to proper brain function, but also predispose to detrimental autoimmunity against self-peptides. We analyzed seven HLA loci, either by next-generation-sequencing or Sequence-Specific-Oligonucleotide-Probe, in 48 NS patients and 51 healthy controls from South Sudan. We discovered that NS associates significantly with both protective HLA haplotype: HLA-B*42:01, C*17:01, DRB1*03:02, DQB1*04:02 and DQA1*04:01, and susceptible motif: Ala24, Glu63 and Phe67, in the HLA-B peptide-binding groove. These amino acids create a hydrophobic and sterically closed peptide-binding HLA pocket, favoring proline residue. Our findings suggest that immunogenetic fingerprints in HLA peptide-binding grooves tentatively associate with protection or susceptibility to NS. Accordingly, different HLA molecules may explain why under similar environmental factors, only some children, within the same families, tribes and districts, develop NS, while others do not.Author summaryNodding syndrome (NS) is a devastating and mysterious neurological disorder affecting 5-15 years old children, primarily in Sudan, Uganda and Tanzania. NS strongly associates with an infection with the parasitic worm Oncocherca Volvulus (Ov), transmitted by the black fly, affecting many people worldwide. Moreover, NS is most probably an 'Autoimmune Epilepsy', especially in view of our recent findings that NS patient's autoimmune GluR3B antibodies induce ROS and kill both neural cells and T cells. NS patient's IgG also induce seizures, multiple brain damage and inflammation-inducing cells in the brain. HLA class I genes are expressed on the surface of all nucleated cells and present peptides to cytotoxic CD8+ T cells. HLA class II genes are expressed mainly on the surface of antigen presenting cells and present peptides to helper CD4+ T cells. Analysis of HLA of South-Sudanese NS patients and healthy controls revealed that that few amino acids in HLA peptide-binding grooves associate with either protection or susceptibility to NS. Theses amino acids could be critical in NS by affecting beneficial immunity and/or detrimental autoimmunity.