Antigen-driven B cell responses in RA and Sars-Cov-2 vaccination
Abstract/Contents
- Abstract
- B cells play a central role in protective immunity by secreting antibodies directed against antigens from pathogens, and by activating T cells via antigen presentation of the cognate antigen. Conversely, in autoimmunity, B cells play a pathogenic role by secreting autoantibodies against self-antigens and triggering autoreactive T cells. However, the exact mechanisms mediating the development of antigen specific B cell responses in autoimmunity and vaccination warrant further investigation. Here, we characterize the B cell responses in patients with seropositive rheumatoid arthritis (RA) and in individuals who received the BNT162b2 mRNA vaccine against SARS-CoV-2. By sequencing the plasmablasts repertoire of RA patients, we demonstrate that extensively somatically hypermutated RA blood plasmablasts encode anti-citrullinated protein antibodies (ACPA) that target both citrullinated human autoantigens and in situ citrullinated epitopes from oral bacteria. In RA patients with periodontitis, oral bacteremias result in systemic translocation of these citrullinated oral bacteria into blood activating ISG15+ inflammatory monocytes, a myeloid population associated with clinical arthritis flares and present in RA synovium. Our findings indicate that repeated oral bacterial mucosal breaks mediate autoimmunity by driving activation and epitope spreading of the ACPA response to target both citrullinated bacterial and human antigen(s) via molecular mimicry. Additionally, we characterize the B cell response to the novel BNT162b2 mRNA vaccine against SARS-CoV-2 spike (S). The first vaccine dose elicits IgA+ plasmablasts against S protein subunit S2 (S2) on day 7, consistent with a secondary memory response derived from prior infections with betacoronaviruses that cause the common cold. On day 21, we observed an influx of minimally mutated IgG+ switched memory B cells against the S protein subunit S1 (S1) that contains the receptor binding domain (RBD), representing a primary response of recently matured naive B cells. The second vaccine dose boosted the anti-S1 and anti-RBD B cell response and produced high titers of antibodies that potently neutralize Wuhan-Hu-1 SARS-CoV-2 pseudovirus and partially neutralize novel variants. Taken together, our results demonstrate how B cell responses continuously evolve to contribute to health and autoimmunity.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2022; ©2022 |
| Publication date | 2022; 2022 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Brewer, Rebeccah Camille |
|---|---|
| Degree supervisor | Robinson, William (William Hewitt) |
| Thesis advisor | Robinson, William (William Hewitt) |
| Thesis advisor | Davis, Mark M |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Kim, Peter, 1958- |
| Degree committee member | Davis, Mark M |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Kim, Peter, 1958- |
| Associated with | Stanford University, Department of Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | R. Camille Brewer. |
|---|---|
| Note | Submitted to the Department of Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2022. |
| Location | https://purl.stanford.edu/vy419yq2179 |
Access conditions
- Copyright
- © 2022 by Rebeccah Camille Brewer
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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