6 research outputs found
Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade
Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination
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Single-molecule characterization of salivary protein aggregates from Parkinson's disease patients: a pilot study.
Acknowledgements: The authors thank the patients and their families for participating in this research study.Funder: UK Dementia Research Institute; doi: https://doi.org/10.13039/501100017510Funder: UK Dementia Research Institute LtdFunder: Alzheimer’s Society; doi: https://doi.org/10.13039/501100017506Funder: Alzheimer’s Research UK; doi: https://doi.org/10.13039/501100002283Funder: Royal Society; doi: https://doi.org/10.13039/501100000288Funder: National Institute for HealthFunder: National Health ServiceFunder: Care ResearchFunder: Department of Health; doi: https://doi.org/10.13039/501100003921Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson's disease. Candidate diagnostic tests for Parkinson's disease to date have predominantly focused on measurements of α-synuclein in CSF, but there is a need for accurate tests utilizing more easily accessible sample types. Prior studies utilizing saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single-molecule approaches can characterize the structure of individual aggregates present in the biofluid and may, therefore, provide greater insight than bulk measurements. We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate numbers and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features. We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost 2-fold in patients with Parkinson's disease (n = 20) compared with controls (n = 20, P < 0.05). Morphological information also provides insight, with saliva from patients with Parkinson's disease containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva (P < 0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone, distinguishing between patients with Parkinson's disease (n = 17) and controls (n = 18) with a high degree of accuracy (area under the curve = 0.87, P < 0.001) and a larger dynamic range. We, therefore, demonstrate for the first time the application of highly sensitive single-molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information, further expanding the potential utility of saliva-based diagnostic methods.The work was supported by a grant from Parkinson’s UK (G-1901), by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council (MR/R007446/1), Alzheimer’s Society and Alzheimer’s Research UK, and by the Royal Society. CHWG is supported by the Medical Research Council (MR/W029235/1), and the NIHR Cambridge Biomedical Research Centre (NIHR203312). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health
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Single-molecule characterization of salivary protein aggregates from Parkinson’s disease patients: a pilot study
Acknowledgements: The authors thank the patients and their families for participating in this research study.Funder: UK Dementia Research Institute; DOI: https://doi.org/10.13039/501100017510Funder: UK Dementia Research Institute LtdFunder: Alzheimer’s Society; DOI: https://doi.org/10.13039/501100017506Funder: Alzheimer’s Research UK; DOI: https://doi.org/10.13039/501100002283Funder: Royal Society; DOI: https://doi.org/10.13039/501100000288Funder: National Institute for HealthFunder: National Health ServiceFunder: Care ResearchFunder: Department of Health; DOI: https://doi.org/10.13039/501100003921Abstract
Saliva is a convenient and accessible biofluid that has potential as a future diagnostic tool for Parkinson’s disease. Candidate diagnostic tests for Parkinson’s disease to date have predominantly focused on measurements of α-synuclein in CSF, but there is a need for accurate tests utilizing more easily accessible sample types. Prior studies utilizing saliva have used bulk measurements of salivary α-synuclein to provide diagnostic insight. Aggregate structure may influence the contribution of α-synuclein to disease pathology. Single-molecule approaches can characterize the structure of individual aggregates present in the biofluid and may, therefore, provide greater insight than bulk measurements. We have employed an antibody-based single-molecule pulldown assay to quantify salivary α-synuclein and amyloid-β peptide aggregate numbers and subsequently super-resolved captured aggregates using direct Stochastic Optical Reconstruction Microscopy to describe their morphological features. We show that the salivary α-synuclein aggregate/amyloid-β aggregate ratio is increased almost 2-fold in patients with Parkinson’s disease (n = 20) compared with controls (n = 20, P &lt; 0.05). Morphological information also provides insight, with saliva from patients with Parkinson’s disease containing a greater proportion of larger and more fibrillar amyloid-β aggregates than control saliva (P &lt; 0.05). Furthermore, the combination of count and morphology data provides greater diagnostic value than either measure alone, distinguishing between patients with Parkinson’s disease (n = 17) and controls (n = 18) with a high degree of accuracy (area under the curve = 0.87, P &lt; 0.001) and a larger dynamic range. We, therefore, demonstrate for the first time the application of highly sensitive single-molecule imaging techniques to saliva. In addition, we show that aggregates present within saliva retain relevant structural information, further expanding the potential utility of saliva-based diagnostic methods.</jats:p
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Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.
Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination.This work was funded by the UK Medical Research Council (project number MC_UU_00025/12), the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798) and The Evelyn Trust (grant number 20/40) to JEDT. NJM was supported by the MRC (TSF ref. MR/T032413/1), NHSBT (grant ref. WPA15-02) and Addenbrooke’s Charitable Trust (grant ref. 900239). MAC was supported by the Medical Research Council (project number MC_UU_00025/10). KRP was supported by the Medical Research Council (project number MC_UU_00025/11). KF held an MRC studentship with support from the Cambridge European Trust and St. John’s College. KW has received funding by the Deutsche Forschungsgemeinschaft (WA 1597/6-1 and WA 1597/7-1). KW and BK received support by the German Federal Ministry of Education and Research (BMBF) through a grant to the German genetic multi-organ Auto-Immunity Network (GAIN), grant code 01GM2206A. FH is an ERC Advanced Investigator (695669). We thank Carola G. Vinuesa for helpful discussion. The authors also thank the Flow Cytometry Facilities at the MRC-Toxicology Unit, University of Cambridge; Katarzyna Kania from CRUK-CI-Genomics, Cambridge UK for advice on single cell RNA sequencing experiments; and Rosalind Kieran from the Department of Oncology, Cambridge University NHS Hospitals Foundation Trust, Cambridge UK, for contributions for patient recruitment and data collection
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Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade.
Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination
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Age-associated B cells predict impaired humoral immunity after COVID-19 vaccination in patients receiving immune checkpoint blockade
Acknowledgements: This work was funded by the UK Medical Research Council (project number MC_UU_00025/12), the Medical Research Foundation (MRF-057-0002-RG-THAV-C0798) and The Evelyn Trust (grant number 20/40) to J.E.D.T. N.J.M. was supported by the MRC (TSF ref. MR/T032413/1), NHSBT (grant ref. WPA15-02) and Addenbrooke’s Charitable Trust (grant ref. 900239). M.A.C. was supported by the Medical Research Council (project number MC_UU_00025/10). K.R.P. was supported by the Medical Research Council (project number MC_UU_00025/11). K.F. held an MRC studentship with support from the Cambridge European Trust and St. John’s College. K.W. has received funding by the Deutsche Forschungsgemeinschaft (WA 1597/6-1 and WA 1597/7-1). K.W. and B.K. received support by the German Federal Ministry of Education and Research (BMBF) through a grant to the German genetic multi-organ Auto-Immunity Network (GAIN), grant code 01GM2206A. F.H. is an ERC Advanced Investigator (695669). We thank Carola G. Vinuesa for helpful discussion. The authors also thank the Flow Cytometry Facilities at the MRC-Toxicology Unit, University of Cambridge; Katarzyna Kania from CRUK-CI-Genomics, Cambridge UK for advice on single cell RNA sequencing experiments; and Rosalind Kieran from the Department of Oncology, Cambridge University NHS Hospitals Foundation Trust, Cambridge UK, for contributions for patient recruitment and data collection.Age-associated B cells (ABC) accumulate with age and in individuals with different immunological disorders, including cancer patients treated with immune checkpoint blockade and those with inborn errors of immunity. Here, we investigate whether ABCs from different conditions are similar and how they impact the longitudinal level of the COVID-19 vaccine response. Single-cell RNA sequencing indicates that ABCs with distinct aetiologies have common transcriptional profiles and can be categorised according to their expression of immune genes, such as the autoimmune regulator (AIRE). Furthermore, higher baseline ABC frequency correlates with decreased levels of antigen-specific memory B cells and reduced neutralising capacity against SARS-CoV-2. ABCs express high levels of the inhibitory FcγRIIB receptor and are distinctive in their ability to bind immune complexes, which could contribute to diminish vaccine responses either directly, or indirectly via enhanced clearance of immune complexed-antigen. Expansion of ABCs may, therefore, serve as a biomarker identifying individuals at risk of suboptimal responses to vaccination