Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment
Abstract Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein mis...
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BMC
2025-06-01
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| Series: | Immunity & Ageing |
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| Online Access: | https://doi.org/10.1186/s12979-025-00516-w |
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| author | Julius Hoffmann Marie-Luise Machule Jakob Kreye Laura Stöffler Péter Körtvelyessy Maria Buthut Rosa Rößling Petra Bacher Alexander Scheffold Harald Prüss |
| author_facet | Julius Hoffmann Marie-Luise Machule Jakob Kreye Laura Stöffler Péter Körtvelyessy Maria Buthut Rosa Rößling Petra Bacher Alexander Scheffold Harald Prüss |
| author_sort | Julius Hoffmann |
| collection | DOAJ |
| description | Abstract Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4+ TH cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated TH cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific TH cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects (‘immune senescence’). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific TH cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific TH cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific TH cells decline with age and are not a major driver of dementia development. |
| format | Article |
| id | doaj-art-c29d61fbd2c0449598ae9bf959ea7cfb |
| institution | OA Journals |
| issn | 1742-4933 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Immunity & Ageing |
| spelling | doaj-art-c29d61fbd2c0449598ae9bf959ea7cfb2025-08-20T02:37:35ZengBMCImmunity & Ageing1742-49332025-06-0122111010.1186/s12979-025-00516-wFrequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairmentJulius Hoffmann0Marie-Luise Machule1Jakob Kreye2Laura Stöffler3Péter Körtvelyessy4Maria Buthut5Rosa Rößling6Petra Bacher7Alexander Scheffold8Harald Prüss9German Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinDepartment of Neurology and Experimental Neurology, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of HealthGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinInstitute of Immunology, Christian-Albrecht-University of KielInstitute of Immunology, Christian-Albrecht-University of KielGerman Center for Neurodegenerative Diseases (DZNE) Berlin, c/o Charité – Universitätsmedizin BerlinAbstract Neurodegenerative dementias including Alzheimer disease severely impair cognitive and social abilities and are a major cause of mortality with no causal treatment yet. Autoimmune mechanisms have been increasingly considered to contribute to disease progression, e.g. by enhancing protein misfolding or pro-inflammatory immune responses. Understanding this contribution may lead to novel treatment options beyond removing neurodegeneration-associated proteins. We hypothesized that CD4+ TH cells against synaptic proteins may play a role in dementia, given the profound changes of synaptic proteins in the disease. We investigated TH cell frequencies and phenotypes after antigen-reactive T cell enrichment (ARTE) using three important synaptic antigens known to play a role in cognitive function, N-Methyl-D-Aspartate receptor (NMDAR), Leucine-rich, glioma inactivated 1 (LGI1) and metabotropic glutamate receptor 5 (mGluR5). Our data revealed that synaptic autoantigen-specific TH cells occurred in all cohorts and were similarly frequent in patients with dementia and sex- and age-matched controls. However, they were significantly reduced compared to young healthy subjects, indicating strong age-related effects (‘immune senescence’). Compared to the ubiquitously available Candida albicans antigen, synaptic autoantigen-specific TH cell responses were strongly driven by IFNγ-producing T cells, expression of which markedly decreased with age. Patients with dementia had significantly less IL-17-producing synaptic autoantigen-specific TH cells than aged healthy controls. This first direct ex vivo quantitative and qualitative analysis of circulating T cells autoreactive to three synaptic autoantigens in dementia shows no correlation with cognitive impairment. It suggests that synaptic autoantigen-specific TH cells decline with age and are not a major driver of dementia development.https://doi.org/10.1186/s12979-025-00516-wSynaptic autoantigensImmune senescenceT cellsDementiaNMDA receptorLGI1 |
| spellingShingle | Julius Hoffmann Marie-Luise Machule Jakob Kreye Laura Stöffler Péter Körtvelyessy Maria Buthut Rosa Rößling Petra Bacher Alexander Scheffold Harald Prüss Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment Immunity & Ageing Synaptic autoantigens Immune senescence T cells Dementia NMDA receptor LGI1 |
| title | Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment |
| title_full | Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment |
| title_fullStr | Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment |
| title_full_unstemmed | Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment |
| title_short | Frequency of synaptic antigen-specific CD4+ T cells in dementia is age-dependent but not correlated with cognitive impairment |
| title_sort | frequency of synaptic antigen specific cd4 t cells in dementia is age dependent but not correlated with cognitive impairment |
| topic | Synaptic autoantigens Immune senescence T cells Dementia NMDA receptor LGI1 |
| url | https://doi.org/10.1186/s12979-025-00516-w |
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