Increased activation product of complement 4 protein in plasma of individuals with schizophrenia,Translational Psychiatry

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Increased activation product of complement 4 protein in plasma of individuals with schizophrenia
Translational Psychiatry ( IF 6.8 ) Pub Date : 2021-09-22 , DOI: 10.1038/s41398-021-01583-5
Agnieszka Kalinowski _{1,

2} , Joanna Liliental _{3,

4,

5} , Lauren A Anker _{1,

2} , Omer Linkovski _{1,

6} , Collin Culbertson ₇ , Jacob N Hall _{7,

8} , Reenal Pattni _{1,

9} , Chiara Sabatti ₁₀ , Douglas Noordsy ₁ , Joachim F Hallmayer _{1,

2} , Elizabeth D Mellins ₁₁ , Jacob S Ballon ₁ , Ruth O'Hara _{1,

2} , Douglas F Levinson ₁ , Alexander E Urban _{1,

9}

Affiliation

Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Sierra Pacific Mental Illness Research Education and Clinical Center (MIRECC), VA Palo Alto Health Care System, Palo Alto, CA, USA.
Translational Applications Service Center, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Translational Research and Applied Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Psychology, Bar-Ilan University, Ramat-Gan, Israel.
Department of Neurology, Stanford University School of Medicine, Stanford, CA, 94305, USA.
The Neurology Center of Southern California, Temecula, CA, 92592, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Biomedical Data Science and Statistics, Stanford University School of Medicine, Stanford, CA, 94305, USA.
Department of Pediatrics, Stanford Program in Immunology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Structural variation in the complement 4 gene (C4) confers genetic risk for schizophrenia. The variation includes numbers of the increased C4A copy number, which predicts increased C4A mRNA expression. C4-anaphylatoxin (C4-ana) is a C4 protein fragment released upon C4 protein activation that has the potential to change the blood–brain barrier (BBB). We hypothesized that elevated plasma levels of C4-ana occur in individuals with schizophrenia (iSCZ). Blood was collected from 15 iSCZ with illness duration < 5 years and from 14 healthy controls (HC). Plasma C4-ana was measured by radioimmunoassay. Other complement activation products C3-ana, C5-ana, and terminal complement complex (TCC) were also measured. Digital-droplet PCR was used to determine C4 gene structural variation state. Recombinant C4-ana was added to primary brain endothelial cells (BEC) and permeability was measured in vitro. C4-ana concentration was elevated in plasma from iSCZ compared to HC (mean = 654 ± 16 ng/mL, 557 ± 94 respectively, p = 0.01). The patients also carried more copies of the C4AL gene and demonstrated a positive correlation between plasma C4-ana concentrations and C4A gene copy number. Furthermore, C4-ana increased the permeability of a monolayer of BEC in vitro. Our findings are consistent with a specific role for C4A protein in schizophrenia and raise the possibility that its activation product, C4-ana, increases BBB permeability. Exploratory analyses suggest the novel hypothesis that the relationship between C4-ana levels and C4A gene copy number could also be altered in iSCZ, suggesting an interaction with unknown genetic and/or environmental risk factors.

中文翻译：

精神分裂症患者血浆中补体 4 蛋白激活产物增加

补体 4 基因 ( C4 ) 的结构变异会带来精神分裂症的遗传风险。该变异包括增加的C4A拷贝数，这预示着 C4A mRNA 表达的增加。C4-过敏毒素 (C4-ana) 是 C4 蛋白激活后释放的 C4 蛋白片段，有可能改变血脑屏障 (BBB)。我们假设精神分裂症 (iSCZ) 患者血浆 C4-ana 水平升高。从病程 < 5 年的 15 名 iSCZ 和 14 名健康对照 (HC) 中采集血液。通过放射免疫测定法测量血浆C4-ana。还测量了其他补体激活产物 C3-ana、C5-ana 和末端补体复合物 (TCC)。使用数字液滴PCR确定C4基因结构变异状态。将重组 C4-ana 添加到原代脑内皮细胞 (BEC) 中，并在体外测量通透性。与 HC 相比，iSCZ 血浆中的 C4-ana 浓度升高（平均值分别为 654 ± 16 ng/mL、557 ± 94，p = 0.01）。患者还携带更多的C4AL基因拷贝，并证明血浆 C4-ana 浓度与C4A基因拷贝数之间呈正相关。此外，C4-ana 增加了单层 BEC 的体外通透性。我们的研究结果与 C4A 蛋白在精神分裂症中的特定作用一致，并提出了其激活产物 C4-ana 增加 BBB 通透性的可能性。探索性分析提出了新的假设，即 iSCZ 中 C4-ana 水平和 C4A 基因拷贝数之间的关系也可能发生改变，这表明与未知的遗传和/或环境风险因素存在相互作用。

更新日期：2021-09-22

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