B cell dysregulation in immune mediated diseases
Abstract/Contents
- Abstract
- Alterations in B cell homeostasis drive pathogenesis of various immune mediated diseases. Breaks in peripheral tolerance allow autoreactive B cells to differentiate in to pathogenic auto-antibody secreting cells. B cells themselves may directly drive pathogenesis through antigen-presentation capabilities and secretion of pro-fibrotic factors. Lastly, the inability of B cells to mount effective responses against pathogens may trigger subsequent inflammatory or autoimmune reactions. In this work, we dissect various ways in which B cells contribute to pathogenesis of inflammatory disease by evaluating their role in three different immune mediated diseases. In chapter 2 we identify a potential regulatory role for B cells in the context of Systemic Lupus Erythematosus (SLE), an autoimmune disease characterized by the pathogenic secretion of anti-nuclear antibodies. We found that CD52 is a B cell regulatory glycoprotein elevated on the surface of B cells in patients and acts to suppress B cell hyperactivity both through its surface expression and through the secretion of a soluble form that can bind receptor Siglec-10. In chapter 3 we describe a population of B cells that is significantly expanded in IgG4-RD, a fibroinflammatory condition characterized by infiltration of IgG4+ plasma cells into tumefactive lesions and the development of storiform fibrosis. The expanded population of B cells was CD21— and CXCR5+, expressing high levels of pathogenic B cell marker CD11c. Moreover, the frequency of this expanded population correlated with clinical parameters such as IgG4 titers. We observed a tremendous elevation of CXCL13, the ligand for CXCR5, strongly implicating the CXCR5-CXCL13 axis in recruiting B cells to affected tissue, making it a viable therapeutic target. Lastly, in chapter 4 we performed high-dimensional sequencing on B cells from sarcoidosis patients, a disease characterized by spontaneous granuloma formation. Although B cells have not been directly implicated in the inflammation, we observed a less diverse and less mutated B cell receptor repertoire; together, our findings point to the initiation of sarcoidosis after ineffective antibody mediated clearance of pathogen from affected organs. In total, this work sheds novel insights on the role of B cells— from the initial stages of activation and germinal center recruitment, to the development of a diverse antibody repertoire— in the context of poorly understood immune mediated conditions and contributes important knowledge for the advancement of better treatments for affected patients.
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 | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Bhamidipati, Kartik |
|---|---|
| Degree supervisor | Robinson, William (William Hewitt) |
| Thesis advisor | Robinson, William (William Hewitt) |
| Thesis advisor | Maltzman, Jonathan |
| Thesis advisor | Mellins, Elizabeth |
| Degree committee member | Maltzman, Jonathan |
| Degree committee member | Mellins, Elizabeth |
| Associated with | Stanford University, Program in Immunology |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Kartik Bhamidipati. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/ms911hv5230 |
Access conditions
- Copyright
- © 2021 by Kartik Bhamidipati
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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