Into the Dark Serum Proteome: Personalized Features of IgG1 and IgA1 Repertoires in Severe COVID-19 Patients
peer-reviewed · Molecular & Cellular Proteomics · 2024
| Date | 2024-01-01 |
| Type | peer-reviewed |
| Venue | Molecular & Cellular Proteomics |
| Publisher | Elsevier BV |
| Contribution | downstream-application |
| DOI | 10.1016/j.mcpro.2023.100690 |
| Citations (OpenAlex) | 20 |
| Venue 2-year citedness | 4.69 |
Preprint version: No patient is the same; lessons learned from antibody repertoire profiling in hospitalized severe COVID-19 patients (2022-12-26, medRxiv)
Abstract
Serum proteomics has matured and is now able to monitor hundreds of proteins quantitatively in large cohorts of patients. However, the fine characteristics of some of the most dominant proteins in serum, the immunoglobulins, are in these studies often ignored, due to their vast, and highly personalized, diversity in sequences. Here, we focus exclusively on these personalized features in the serum proteome and distinctively chose to study individual samples from a low diversity population: elderly donors infected by severe acute respiratory syndrome corona virus 2 (SARS-CoV-2). By using mass spectrometry-based methods, immunoglobulin IgG1 and IgA1 clonal repertoires were monitored quantitatively and longitudinally in more than 50 individual serum samples obtained from 17 Corona virus disease 2019 patients admitted to intensive care units. These clonal profiles were used to examine how each patient reacted to a severe SARS-CoV-2 infection. All 17 donors revealed unique polyclonal repertoires and substantial changes over time, with several new clones appearing following the infection, in a few cases leading to a few, very high, abundant clones dominating their repertoire. Several of these clones were de novo sequenced through combinations of top-down, middle-down, and bottom-up proteomics approaches. This revealed sequence features in line with sequences deposited in the SARS-CoV-specific antibody database. In other patients, the serological Ig profiles revealed the treatment with tocilizumab, that subsequently dominated their serological IgG1 repertoire. Tocilizumab clearance could be monitored, and a half-life of approximately 6 days was established. Overall, our longitudinal monitoring of IgG1 and IgA1 repertoires of individual donors reveals that antibody responses are highly personalized traits of each patient, affected by the disease and the chosen clinical treatment. The impact of these observations argues for a more personalized and longitudinal approach in patients’ diagnostics, both in serum proteomics as well as in monitoring immune responses.
Methods and tools
- COVID-19 IgG1/IgA1 repertoire profiling: Longitudinal intact-mass profiling of IgG1 and IgA1 clonal repertoires in severe COVID-19 patients, with dominant clones sequenced de novo by combined top-down, middle-down and bottom-up proteomics.
Cites (8)
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Cited by (9)
- Mass Spectrometry-based Antibody Sequencing Technologies (2026) both
- Sequencing of Polyclonal Antibodies by Integrating Intact Mass, Middle–Down, and De Novo Bottom–Up Mass Spectrometry (2025) both
- Systematic benchmarking of mass spectrometry-based antibody sequencing reveals methodological biases (2025) both
- Simultaneous polyclonal antibody sequencing and epitope mapping by cryo electron microscopy and mass spectrometry (2025) crossref
- Systematic benchmarking of mass spectrometry-based antibody sequencing reveals methodological biases (2024) crossref
- De novo protein sequencing of antibodies for identification of neutralizing antibodies in human plasma post SARS-CoV-2 vaccination (2024) both
- A Handle on Mass Coincidence Errors in De Novo Sequencing of Antibodies by Bottom-up Proteomics (2024) both
- Reverse-engineering the anti-MUC1 antibody 139H2 by mass spectrometry–based de novo sequencing (2024) both
- de Novo Sequencing of Antibodies for Identification of Neutralizing Antibodies in Human Plasma Post SARS-CoV-2 Vaccination (2024) both