Dopamine receptor autoantibody signaling in infectious sequelae differentiates movement versus neuropsychiatric disorders.

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-08 DOI:10.1172/jci.insight.164762
Chandra M Menendez, Jonathan Zuccolo, Susan E Swedo, Sean Reim, Brian Richmand, Hilla Ben-Pazi, Abraham Kovoor, Madeleine W Cunningham
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Abstract

Despite growing recognition, neuropsychiatric diseases associated with infections are a major unsolved problem worldwide. Group A streptococcal (GAS) infections can cause autoimmune sequelae characterized by movement disorders, such as Sydenham chorea, and neuropsychiatric disorders. The molecular mechanisms underlying these diseases are not fully understood. Our previous work demonstrates that autoantibodies (AAbs) can target dopaminergic neurons and increase dopamine D2 receptor (D2R) signaling. However, AAb influence on dopamine D1 receptor (D1R) activity is underexplored. We found evidence that suggests GAS-induced cross-reactive AAbs promote autoimmune encephalitis of the basal ganglia, a region of high dopamine receptor density. Here, we report a mechanism whereby neuropsychiatric syndromes are distinguished from movement disorders by differences in D1R and D2R AAb titers, signaling, receiver operating characteristic curves, and immunoreactivity with D1R and D2R autoreactive epitopes. D1R AAb signaling was observed through patient serum AAbs and novel patient-derived monoclonal antibodies (mAbs), which induced both D1R G protein- and β-arrestin-transduced signals. Furthermore, patient AAbs and mAbs enhanced D1R signaling mechanisms mediated by the neurotransmitter dopamine. Our findings suggest that AAb-mediated D1R signaling may contribute to the pathogenesis of neuropsychiatric sequelae and inform new options for diagnosis and treatment of GAS sequelae and related disorders.

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感染后遗症中的多巴胺受体自身抗体信号转导可区分运动障碍和神经精神障碍。
尽管越来越多的人认识到,与感染相关的神经精神疾病是全世界尚未解决的一个重大问题。A 组链球菌(GAS)感染可导致以运动障碍(如西登纳姆舞蹈症(SC))和神经精神障碍为特征的自身免疫后遗症。这些疾病的分子机制尚不完全清楚。我们之前的研究表明,自身抗体(AAbs)可以靶向多巴胺能神经元并增加多巴胺受体D2(D2R)信号传导。然而,AAb对多巴胺受体D1(D1R)活性的影响尚未得到充分探索。我们发现有证据表明,GAS 诱导的交叉反应性 AAb 会促进基底节(BGE)自身免疫性脑炎,而基底节是多巴胺受体密度较高的区域。在这里,我们报告了一种新的机制,即神经精神综合征可通过 D1R 和 D2R AAb 滴度、信号传导、接收者操作特征曲线(ROC)以及 D1R 和 D2R 自身反应表位的免疫反应的差异而与运动障碍区分开来。通过患者血清 AAb 和新型患者衍生 mAb 观察到了 D1R AAb 信号传导,它们可诱导 D1R G 蛋白和 -arrestin 转导信号。此外,患者AAb和mAb增强了由神经递质多巴胺介导的D1R信号转导机制。我们的研究结果表明,AAb介导的D1R信号转导可能有助于神经精神后遗症的发病机制,并为诊断和治疗GAS后遗症及相关疾病提供了新的选择。.
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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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