Goldwaser Eric L, Swanson Randel L, Arroyo Edgardo J, Venkataraman Venkat, Kosciuk Mary C, Nagele Robert G, Hong L Elliot, Acharya Nimish K
Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, United States.
Center for Neurotrauma, Neurodegeneration, and Restoration, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States.
Front Hum Neurosci. 2022 Mar 31;16:836980. doi: 10.3389/fnhum.2022.836980. eCollection 2022.
Though hippocampal volume reduction is a pathological hallmark of schizophrenia, the molecular pathway(s) responsible for this degeneration remains unknown. Recent reports have suggested the potential role of impaired blood-brain barrier (BBB) function in schizophrenia pathogenesis. However, direct evidence demonstrating an impaired BBB function is missing. In this preliminary study, we used immunohistochemistry and serum immunoglobulin G (IgG) antibodies to investigate the state of BBB function in formalin-fixed postmortem samples from the hippocampus and surrounding temporal cortex of patients with schizophrenia ( = 25) and controls without schizophrenia ( = 27) matched for age, sex, and race. Since a functional BBB prevents the extravasation of IgGs, detection of IgGs in the parenchyma is used as direct evidence of BBB breakdown. We also developed a semi-quantitative approach to quantify the extent of IgG leak and therein BBB breach. Analysis of our immunohistochemistry data demonstrated a significantly higher incidence of IgG leak in patients with schizophrenia compared to controls. Further, BBB permeability was significantly higher in advanced-age patients with schizophrenia than both advanced-age controls and middle-aged patients with schizophrenia. Male patients with schizophrenia also demonstrated a significant increase in IgG permeability compared to control males. Interestingly, the extravasated IgGs also demonstrated selective immunoreactivity for neurons. Based on these observations, we suggest that BBB dysfunction and IgG autoantibodies could be two key missing pathoetiological links underwriting schizophrenia hippocampal damage.
尽管海马体体积缩小是精神分裂症的一个病理标志，但导致这种退化的分子途径仍然未知。最近的报告表明，血脑屏障（BBB）功能受损在精神分裂症发病机制中可能发挥作用。然而，缺乏直接证据证明血脑屏障功能受损。在这项初步研究中，我们使用免疫组织化学和血清免疫球蛋白G（IgG）抗体，调查了来自精神分裂症患者（n = 25）和无精神分裂症对照者（n = 27）的海马体及周围颞叶皮质的福尔马林固定尸检样本中的血脑屏障功能状态，这些对照者在年龄、性别和种族方面与患者相匹配。由于功能性血脑屏障可防止IgG外渗，因此在实质组织中检测到IgG被用作血脑屏障破坏的直接证据。我们还开发了一种半定量方法来量化IgG渗漏的程度以及血脑屏障破坏的程度。对我们的免疫组织化学数据的分析表明，与对照组相比，精神分裂症患者中IgG渗漏的发生率显著更高。此外，老年精神分裂症患者的血脑屏障通透性显著高于老年对照组和中年精神分裂症患者。与对照男性相比，男性精神分裂症患者的IgG通透性也显著增加。有趣的是，外渗的IgG对神经元也表现出选择性免疫反应性。基于这些观察结果，我们认为血脑屏障功能障碍和IgG自身抗体可能是精神分裂症海马体损伤的两个关键的、缺失的病理病因联系。
