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

Agnieszka Kalinowski; Joanna Liliental; Lauren A. Anker; Omer Linkovski; Collin Culbertson; Jacob N. Hall; Reenal Pattni; Chiara Sabatti; Douglas Noordsy; Joachim F. Hallmayer; Elizabeth D. Mellins; Jacob S. Ballon; Ruth O’Hara; Douglas F. Levinson; Alexander E. Urban

doi:10.1038/s41398-021-01583-5

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

Agnieszka Kalinowski, Joanna Liliental, Lauren A. Anker, Omer Linkovski, Collin Culbertson, Jacob N. Hall, Reenal Pattni, Chiara Sabatti, Douglas Noordsy, Joachim F. Hallmayer, Elizabeth D. Mellins, Jacob S. Ballon, Ruth O’Hara, Douglas F. Levinson, Alexander E. Urban

Department of Psychology

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13 Scopus citations

Abstract

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.

Original language	English
Article number	486
Journal	Translational Psychiatry
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41398-021-01583-5
State	Published - 22 Sep 2021

Bibliographical note

Publisher Copyright:
© 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.

Funding

Funding for this project was provided by the Stanford University Translational Research and Applied Medicine Program Pilot Grant (2018–2020), the Stanford INSPIRE Early Psychosis Clinic, the Stanford Schizophrenia Genetics Research Fund, and NIH grant 5P50HG007735-05 (AEU). The Urban laboratory received funding from Mr. Bruce Blackie and from Dr. William McIvor. DFL received support from the Walter E. Nichols MD Professorship in the School of Medicine, from Dr. William McIvor, and from the Stanford Schizophrenia Genetics Research Fund. AK was supported by fellowship funding from T32 Fellowship funding from the National Institutes of Mental Health 5T32MH019938 and the MIRECC Fellowship. We would like to thank all the participants for their generous participation in this study.

Funders	Funder number
Stanford Schizophrenia Genetics Research Fund
National Institutes of Health	5P50HG007735-05
U.S. Department of Health and Human Services
National Institute of Mental Health	T32MH019938
Stanford University
School of Medicine, Stanford University
Schizophrenia Research Fund
Office of Academic Affiliations, Department of Veterans Affairs

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Kalinowski, A., Liliental, J., Anker, L. A., Linkovski, O., Culbertson, C., Hall, J. N., Pattni, R., Sabatti, C., Noordsy, D., Hallmayer, J. F., Mellins, E. D., Ballon, J. S., O’Hara, R., Levinson, D. F., & Urban, A. E. (2021). Increased activation product of complement 4 protein in plasma of individuals with schizophrenia. Translational Psychiatry, 11(1), Article 486. https://doi.org/10.1038/s41398-021-01583-5

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title = "Increased activation product of complement 4 protein in plasma of individuals with schizophrenia",

abstract = "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.",

author = "Agnieszka Kalinowski and Joanna Liliental and Anker, {Lauren A.} and Omer Linkovski and Collin Culbertson and Hall, {Jacob N.} and Reenal Pattni and Chiara Sabatti and Douglas Noordsy and Hallmayer, {Joachim F.} and Mellins, {Elizabeth D.} and Ballon, {Jacob S.} and Ruth O{\textquoteright}Hara and Levinson, {Douglas F.} and Urban, {Alexander E.}",

note = "Publisher Copyright: {\textcopyright} 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.",

year = "2021",

month = sep,

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doi = "10.1038/s41398-021-01583-5",

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Kalinowski, A, Liliental, J, Anker, LA, Linkovski, O, Culbertson, C, Hall, JN, Pattni, R, Sabatti, C, Noordsy, D, Hallmayer, JF, Mellins, ED, Ballon, JS, O’Hara, R, Levinson, DF & Urban, AE 2021, 'Increased activation product of complement 4 protein in plasma of individuals with schizophrenia', Translational Psychiatry, vol. 11, no. 1, 486. https://doi.org/10.1038/s41398-021-01583-5

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T1 - Increased activation product of complement 4 protein in plasma of individuals with schizophrenia

AU - Kalinowski, Agnieszka

AU - Liliental, Joanna

AU - Anker, Lauren A.

AU - Linkovski, Omer

AU - Culbertson, Collin

AU - Hall, Jacob N.

AU - Pattni, Reenal

AU - Sabatti, Chiara

AU - Noordsy, Douglas

AU - Hallmayer, Joachim F.

AU - Mellins, Elizabeth D.

AU - Ballon, Jacob S.

AU - O’Hara, Ruth

AU - Levinson, Douglas F.

AU - Urban, Alexander E.

PY - 2021/9/22

Y1 - 2021/9/22

N2 - 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.

AB - 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.

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

Abstract

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Funding

UN SDGs

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