Increased activation product of complement 4 protein in plasma of individuals with schizophrenia.
Journal
Translational psychiatry
ISSN: 2158-3188
Titre abrégé: Transl Psychiatry
Pays: United States
ID NLM: 101562664
Informations de publication
Date de publication:
22 09 2021
22 09 2021
Historique:
received:
28
04
2021
accepted:
17
08
2021
revised:
28
07
2021
entrez:
23
9
2021
pubmed:
24
9
2021
medline:
12
10
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34552056
doi: 10.1038/s41398-021-01583-5
pii: 10.1038/s41398-021-01583-5
pmc: PMC8458380
doi:
Substances chimiques
Complement C4
0
Complement C4a
80295-49-4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
486Subventions
Organisme : NHGRI NIH HHS
ID : P50 HG007735
Pays : United States
Organisme : NHGRI NIH HHS
ID : RM1 HG007735
Pays : United States
Organisme : NIMH NIH HHS
ID : T32 MH019938
Pays : United States
Informations de copyright
© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.
Références
Mol Immunol. 2013 Dec 15;56(3):232-9
pubmed: 23787367
Nat Genet. 2011 Sep 18;43(10):969-76
pubmed: 21926974
Eur Neuropsychopharmacol. 2014 Oct;24(10):1591-605
pubmed: 25159198
Neurosci Lett. 2005 Feb 1;374(1):35-7
pubmed: 15631892
Annu Rev Immunol. 2018 Apr 26;36:309-338
pubmed: 29677470
Cells. 2020 Dec 21;9(12):
pubmed: 33371217
Drug News Perspect. 2008 May;21(4):200-10
pubmed: 18560619
Schizophr Res. 2018 Jul;197:321-327
pubmed: 29449061
Science. 2018 Dec 14;362(6420):
pubmed: 30545856
J Immunol. 1986 Apr 1;136(7):2542-50
pubmed: 3512717
Neurosci Lett. 2006 Sep 1;404(3):336-41
pubmed: 16860475
Nature. 2020 Jun;582(7813):577-581
pubmed: 32499649
Proc Natl Acad Sci U S A. 2017 Oct 10;114(41):10948-10953
pubmed: 28973891
PLoS Biol. 2020 Jan 14;18(1):e3000604
pubmed: 31935214
Neurosci Lett. 2020 May 1;726:133664
pubmed: 29966749
Front Neurosci. 2020 Feb 05;14:23
pubmed: 32116493
J Immunol. 2003 Sep 1;171(5):2734-45
pubmed: 12928427
Immunobiology. 1998 Jul;199(1):5-13
pubmed: 9717663
Brain Behav Immun. 2020 Nov;90:216-225
pubmed: 32827700
Schizophr Res. 2011 Jun;129(1):42-6
pubmed: 21511440
Am J Physiol Cell Physiol. 2004 Jan;286(1):C31-42
pubmed: 12944324
Exp Neurol. 2004 Jul;188(1):94-103
pubmed: 15191806
Asian J Psychiatr. 2021 Jan;55:102520
pubmed: 33373836
Brain Res Rev. 2007 Dec;56(2):331-45
pubmed: 17915333
J Psychiatr Res. 2014 Feb;49:18-24
pubmed: 24246416
Mol Psychiatry. 2016 Dec;21(12):1696-1709
pubmed: 26903267
BMC Med Ethics. 2013 Jul 23;14:28
pubmed: 23879694
PLoS One. 2013 Nov 14;8(11):e79501
pubmed: 24244513
Front Immunol. 2015 Jun 02;6:262
pubmed: 26082779
Mol Psychiatry. 2020 Jan;25(1):114-130
pubmed: 31439935
Front Cell Neurosci. 2014 Nov 07;8:380
pubmed: 25426028
J Innate Immun. 2015;7(4):333-9
pubmed: 25659340
Nat Neurosci. 2021 Feb;24(2):214-224
pubmed: 33353966
Nat Commun. 2017 May 02;8:15096
pubmed: 28462915
Nature. 2016 Feb 11;530(7589):177-83
pubmed: 26814963
JAMA Psychiatry. 2021 Jan 1;78(1):77-90
pubmed: 32857162
J Neuroinflammation. 2018 May 26;15(1):165
pubmed: 29803226
Clin Exp Immunol. 1990 May;80(2):167-70
pubmed: 2357842
Lancet Psychiatry. 2018 Jan;5(1):79-92
pubmed: 28781208
Schizophr Res. 2020 Aug;222:58-72
pubmed: 32456884
Endocrine. 2018 Dec;62(3):617-627
pubmed: 30132263