Kodja Kenneth G, Onzivua Sylvester, Kitara David L, Fong Amanda, Kim Patrick, Pollanen Michael S
Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada.
Ontario Forensic Pathology Service, Toronto, Ontario, Canada.
Biochem Biophys Rep. 2023 Jun 8;35:101498. doi: 10.1016/j.bbrep.2023.101498. eCollection 2023 Sep.
Nodding syndrome is a neurological disease of children in northern Uganda. Infection with the nematode parasite has been epidemiologically implicated as the cause of the disease. It has been proposed that an autoantibody directed against the human protein leiomodin-1 cross reacts with a tropomyosin-like nematode protein, thus suggesting that nodding syndrome is an autoimmune brain disease due to extra-cerebral parasitism. This hypothesis is dependent on constitutive neuronal expression of leiomodin-1. We tested this hypothesis by studying the distribution of leiomodin-1 in the normal human brain and other human tissues using immunohistochemistry. We found that immunostaining for leiomodin-1 follows a smooth muscle cell specific pattern. In the brain, it is confined to the smooth muscle cells of cerebral blood vessels and is not generally present in neurons or glia. However, immunoreactivity was identified in human Purkinje cell membrane and the body wall of (as a proxy for ) but only when immunostained with an antibody recognizing the N-terminal of leiomodin-1. Homology between leiomodin-1 and tropomodulin, specifically at the N-terminus, could explain why leiomodin-1 antibody cross reactivity between human Purkinje cells and . However, we cannot provide proof confirming that the immunoreactivity in the membranes of Purkinje cells is specifically caused by the expression of tropomodulin. To overcome this limitation, further investigations using additional immunohistochemical and biochemical studies are required to corroborate our findings and provide more comprehensive evidence. Nevertheless, our findings do not support to the autoimmunity hypothesis involving and leiomodin-1. To gain a more comprehensive understanding of the cause and pathogenesis of NS, it is essential to explore alternative hypotheses.
点头综合征是乌干达北部儿童的一种神经系统疾病。从流行病学角度来看，线虫寄生虫感染被认为是该疾病的病因。有人提出，一种针对人类蛋白平滑肌瘤素-1的自身抗体与一种原肌球蛋白样线虫蛋白发生交叉反应，这表明点头综合征是一种由于脑外寄生虫感染引起的自身免疫性脑病。这一假说依赖于平滑肌瘤素-1在神经元中的组成性表达。我们通过免疫组织化学研究平滑肌瘤素-1在正常人类大脑和其他人体组织中的分布来验证这一假说。我们发现，平滑肌瘤素-1的免疫染色呈现出平滑肌细胞特异性模式。在大脑中，它局限于脑血管的平滑肌细胞，在神经元或神经胶质细胞中通常不存在。然而，在人类浦肯野细胞膜和（作为的替代物）的体壁中发现了免疫反应性，但仅在用识别平滑肌瘤素-1 N端的抗体进行免疫染色时才出现。平滑肌瘤素-1与原肌球蛋白之间的同源性，特别是在N端，可能解释了为什么平滑肌瘤素-1抗体在人类浦肯野细胞和之间发生交叉反应。然而，我们无法提供证据证实浦肯野细胞膜中的免疫反应性是由原肌球蛋白的表达特异性引起的。为了克服这一局限性，需要使用额外的免疫组织化学和生化研究进行进一步调查，以证实我们的发现并提供更全面的证据。尽管如此，我们的发现并不支持涉及和平滑肌瘤素-1的自身免疫假说。为了更全面地了解点头综合征的病因和发病机制，探索其他假说至关重要。
