Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects
OBJECTIVES: To compare seroprevalence/characteristics of 49 autoantibodies (AB) against brain-antigens in neuropsychiatric patients and healthy individuals and elucidate predisposing factors. DESIGN/SETTING: Exploratory cross-sectional cohort study (N=7025). PARTICIPANTS: Subjects originate from the...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | Journal of Affective Disorders Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S266691532300077X |
| _version_ | 1797854466481848320 |
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| author | Hannelore Ehrenreich Vinicius Daguano Gastaldi Justus BH Wilke |
| author_facet | Hannelore Ehrenreich Vinicius Daguano Gastaldi Justus BH Wilke |
| author_sort | Hannelore Ehrenreich |
| collection | DOAJ |
| description | OBJECTIVES: To compare seroprevalence/characteristics of 49 autoantibodies (AB) against brain-antigens in neuropsychiatric patients and healthy individuals and elucidate predisposing factors. DESIGN/SETTING: Exploratory cross-sectional cohort study (N=7025). PARTICIPANTS: Subjects originate from the GRAS Data Collection of deeply phenotyped neuropsychiatric patients and healthy controls across Germany. OUTCOMES: Presence/characteristics of 49 brain-directed serum-AB, GWAS of NMDAR1-AB carriers, analysis of immune check-point genotypes, APOE4, neurotrauma. RESULTS: Analysis of N=7025 subjects (55.8% male; 41±16 years) reveals N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% confidence interval 1.015-1.022) emerges, but no disease association, neither general nor with neuropsychiatric disease subgroups. Males have higher AB seroprevalence (OR=1.303, 1.144-1.486). Overall immunoglobulin class distribution (N for IgM:462; IgA:487; IgG:477) and titer ranges (1:10-1:3200) are similar. Abundant are NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) is seen for most AB (amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65, Ma2, Yo, NF115, AP3B2, NF186, CNTN1, myelin, neurochondrin, flotillin1/2, CNTN2, IgLON5, AMPA, Sez6l2, recoverin, neurexin, mGluR1, ITPR1, GABA-b, LGI1, mGluR5, DRD2, CV2, Hu, Tr/DNER, AQP4, GluDR2, Zic-4, ERC1). Non-detectable are others (GABA-a, MBP, AT1A3, Ri, AGNA, CARPVIII, PCA-2, ANNA-3, DPPX, MAG). GWAS of NMDAR1-AB carriers reveals three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovers effects on humoral anti-brain autoimmunity (OR=1.55, 1.058-2.271) and disease likelihood (OR=1.43, 1.032-1.985). APOE4 carriers (∼19%) have lower seropositivity (OR=0.766, 0.625-0.933), likely because of AB-binding to brain tissue (ꞌimmunoprecipitationꞌ) upon chronic blood-brain-barrier leakiness, but no higher disease prevalence. Confirming preclinical findings, neurotrauma, inducing acute blood-brain-barrier disruption, predisposes to NMDAR1-AB (IgM: OR=1.599, 1.022-2.468). CONCLUSIONS: Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Important for clinical practice: Seroprevalence, immunoglobulin class, or titers do not predict disease. |
| first_indexed | 2024-04-09T20:07:36Z |
| format | Article |
| id | doaj.art-666925f28ae8471ea3062c8ab33a2b88 |
| institution | Directory Open Access Journal |
| issn | 2666-9153 |
| language | English |
| last_indexed | 2024-04-09T20:07:36Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Affective Disorders Reports |
| spelling | doaj.art-666925f28ae8471ea3062c8ab33a2b882023-04-01T08:51:38ZengElsevierJournal of Affective Disorders Reports2666-91532023-04-0112100538Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjectsHannelore Ehrenreich0Vinicius Daguano Gastaldi1Justus BH Wilke2Clinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, GermanyClinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, GermanyClinical Neuroscience, Max Planck Institute for Multidisciplinary Sciences, City Campus, Göttingen, GermanyOBJECTIVES: To compare seroprevalence/characteristics of 49 autoantibodies (AB) against brain-antigens in neuropsychiatric patients and healthy individuals and elucidate predisposing factors. DESIGN/SETTING: Exploratory cross-sectional cohort study (N=7025). PARTICIPANTS: Subjects originate from the GRAS Data Collection of deeply phenotyped neuropsychiatric patients and healthy controls across Germany. OUTCOMES: Presence/characteristics of 49 brain-directed serum-AB, GWAS of NMDAR1-AB carriers, analysis of immune check-point genotypes, APOE4, neurotrauma. RESULTS: Analysis of N=7025 subjects (55.8% male; 41±16 years) reveals N=1133 (16.13%) carriers of any AB against 49 defined brain-antigens. Overall, age dependence of seroprevalence (OR=1.018/year; 95% confidence interval 1.015-1.022) emerges, but no disease association, neither general nor with neuropsychiatric disease subgroups. Males have higher AB seroprevalence (OR=1.303, 1.144-1.486). Overall immunoglobulin class distribution (N for IgM:462; IgA:487; IgG:477) and titer ranges (1:10-1:3200) are similar. Abundant are NMDAR1-AB (7.7%). Low seroprevalence (1.25%-0.02%) is seen for most AB (amphiphysin, KCNA2, ARHGAP26, GFAP, CASPR2, MOG, Homer-3, KCNA1, GLRA1b, GAD65, Ma2, Yo, NF115, AP3B2, NF186, CNTN1, myelin, neurochondrin, flotillin1/2, CNTN2, IgLON5, AMPA, Sez6l2, recoverin, neurexin, mGluR1, ITPR1, GABA-b, LGI1, mGluR5, DRD2, CV2, Hu, Tr/DNER, AQP4, GluDR2, Zic-4, ERC1). Non-detectable are others (GABA-a, MBP, AT1A3, Ri, AGNA, CARPVIII, PCA-2, ANNA-3, DPPX, MAG). GWAS of NMDAR1-AB carriers reveals three genome-wide significant SNPs, two intergenic, one in TENM3, previously autoimmune disease-associated. Targeted analysis of immune check-point genotypes (CTLA4, PD1, PD-L1) uncovers effects on humoral anti-brain autoimmunity (OR=1.55, 1.058-2.271) and disease likelihood (OR=1.43, 1.032-1.985). APOE4 carriers (∼19%) have lower seropositivity (OR=0.766, 0.625-0.933), likely because of AB-binding to brain tissue (ꞌimmunoprecipitationꞌ) upon chronic blood-brain-barrier leakiness, but no higher disease prevalence. Confirming preclinical findings, neurotrauma, inducing acute blood-brain-barrier disruption, predisposes to NMDAR1-AB (IgM: OR=1.599, 1.022-2.468). CONCLUSIONS: Humoral autoimmunity against brain-antigens, frequent across health and disease, is predicted by age, gender, genetic predisposition, and brain injury. Important for clinical practice: Seroprevalence, immunoglobulin class, or titers do not predict disease.http://www.sciencedirect.com/science/article/pii/S266691532300077X |
| spellingShingle | Hannelore Ehrenreich Vinicius Daguano Gastaldi Justus BH Wilke Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects Journal of Affective Disorders Reports |
| title | Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects |
| title_full | Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects |
| title_fullStr | Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects |
| title_full_unstemmed | Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects |
| title_short | Factors predisposing to humoral autoimmunity against brain-antigens in health and disease: Analysis of 49 autoantibodies in over 7000 subjects |
| title_sort | factors predisposing to humoral autoimmunity against brain antigens in health and disease analysis of 49 autoantibodies in over 7000 subjects |
| url | http://www.sciencedirect.com/science/article/pii/S266691532300077X |
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