Macrophage migration inhibitory factor in Nodding syndrome.
Macrophage migration inhibitory factor in Nodding syndrome.
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DOI：
10.1371/journal.pntd.0009821
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发表时间：
2021-10
影响因子：
3.8
通讯作者：
Levite M
中科院分区：
文献类型：
--
作者：
Benedek G;Abed El Latif M;Miller K;Rivkin M;Ahmed Ramadhan Lasu A;P Riek L;Lako R;Edvardson S;Arbel-Alon S;Galun E;Levite M
点头综合征（NS）是一种灾难性和神秘的儿童癫痫，伴有多种神经损伤和神经炎症。在所有与NS相关的传染、环境和心理因素中，罪魁祸首是盘尾丝虫（Ov）——一种由黑蝇传播给人类的寄生虫。NS似乎是一种“自身免疫性癫痫”，因为最近在NS患者中发现了针对谷氨酸受体和leomotin - 1的有害自身免疫抗体。此外，我们最近在HLA肽结合凹槽中发现了与NS保护或易感性相关的免疫遗传指纹。巨噬细胞迁移抑制因子（Macrophage migration inhibitory factor， MIF）是一种免疫调节因子，在调节先天免疫和适应性免疫中发挥核心作用。MIF还涉及各种病理：感染性疾病、自身免疫性疾病和神经退行性疾病、癫痫等。本文对49名NS患者和51名来自南苏丹的健康对照者进行了MIF基因的两个功能多态性（- 794 CATT5-8微卫星重复序列和- 173 G/C单核苷酸多态性）的评估。我们还测量了已确诊的NS患者和健康对照者的MIF血浆水平。我们发现，与健康对照组相比，NS患者中含有高表达MIF -173C基因型的频率显著降低。有趣的是，NS患者血浆中MIF水平明显高于健康对照组。我们进一步证明HLA保护和易感性关联比MIF与NS的关联更重要。我们的研究结果表明，MIF可能在NS中具有双重作用。基因控制的高表达MIF基因型与疾病保护有关。然而，血浆中MIF升高可能导致有害的自身免疫、神经炎症和癫痫。点头综合征（NS）是一种具有破坏性和神秘性的儿童疾病，伴有多种神经损伤和神经炎症。NS与盘尾盘尾虫（Onchocerca volvulus, Ov）寄生虫和其他环境因素有关。结果表明，NS似乎是一种“自身免疫性癫痫”。然而，目前尚不清楚为什么在南苏丹，同一个家庭、部落和地区中只有一些儿童患上这种疾病。最近，我们假设免疫遗传因素可能解决了这个问题，并确实证明了人类白细胞抗原（HLA）肽结合槽中很少有氨基酸与NS的保护或易感性相关。在本研究中，我们评估巨噬细胞迁移抑制因子（MIF）在NS病理中的作用。MIF是一种免疫调节细胞因子，参与多种疾病，从传染病、自身免疫到神经退行性疾病。南苏丹NS患者和健康对照的MIF免疫遗传学分析为该病的流行病学提供了新的线索。我们的研究结果表明，与高蛋白表达相关的MIF启动子基因型与疾病保护有关。然而，在已确定NS的受影响患者中，与对照组相比，MIF血浆水平升高，可能与自身免疫和神经炎症有关。
Nodding syndrome (NS) is a catastrophic and enigmatic childhood epilepsy, accompanied by multiple neurological impairments and neuroinflammation. Of all the infectious, environmental and psychological factors associated with NS, the major culprit is Onchocerca Volvulus (Ov)–a parasitic worm transmitted to human by blackflies. NS seems to be an ’Autoimmune Epilepsy’ in light of the recent findings of deleterious autoimmune antibodies to Glutamate receptors and to Leiomodin-I in NS patients. Moreover, we recently found immunogenetic fingerprints in HLA peptide-binding grooves associate with protection or susceptibility to NS. Macrophage migration inhibitory factor (MIF) is an immune-regulatory cytokine playing a central role in modulating innate and adaptive immunity. MIF is also involved in various pathologies: infectious, autoimmune and neurodegenerative diseases, epilepsy and others. Herein, two functional polymorphisms in the MIF gene, a −794 CATT5–8 microsatellite repeat and a −173 G/C single-nucleotide polymorphism, were assessed in 49 NS patients and 51 healthy controls from South Sudan. We also measured MIF plasma levels in established NS patients and healthy controls. We discovered that the frequency of the high-expression MIF -173C containing genotype was significantly lower in NS patients compared to healthy controls. Interestingly however, MIF plasma levels were significantly elevated in NS patients than in healthy controls. We further demonstrated that the HLA protective and susceptibility associations are dominant over the MIF association with NS. Our findings suggest that MIF might have a dual role in NS. Genetically controlled high-expression MIF genotype is associated with disease protection. However, elevated MIF in the plasma may contribute to the detrimental autoimmunity, neuroinflammation and epilepsy. Nodding syndrome (NS) is a devastating and enigmatic childhood disease, accompanied by multiple neurological impairments and neuroinflammation. NS is associated with the parasite Onchocerca volvulus (Ov) and other environmental factors. It was shown that NS seems to be an "Autoimmune-Epilepsy". However, it is still not clear why only some children, within the same family, tribe and district, develop this malady in South-Sudan. Recently, we hypothesized that immunogenetic factors might address this question, and indeed demonstrated that few amino acids in human leukocyte antigen (HLA) peptide-binding grooves associate with either protection or susceptibility to NS. In the current study, we evaluate the contribution of macrophage migration inhibitory factor (MIF) to NS pathology. MIF is an immune-regulatory cytokine that is involved in numerous pathologies, which vary from infectious diseases, autoimmunity to neurodegenerative diseases. Immunogenetic analysis of MIF in South-Sudanese NS patients and healthy controls shed new light on the epidemiology of this disease. Our findings suggest that MIF promoter genotypes that are linked with high-protein expression are associated with disease protection. However, in affected patients, with established NS, MIF plasma levels are elevated compared to control subjects and might be involved with autoimmunity and neuroinflammation.
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