Single-cell analysis of immunity in inflammatory bowel diseases
Abstract/Contents
- Abstract
- Inflammatory bowel disease (IBD) includes Crohn's disease and ulcerative colitis. Each disease is characterized by a diverse set of potential manifestations, which determine patients' disease phenotype. Disease phenotype heterogeneity is a major contributor to frequent loss or lack of therapeutic response. Gut trafficking molecules allow leukocytes to home from the periphery to the gut, which may be altered in disease phenotypes. Current understanding of phenotype determinants is limited, despite increasing prevalence and healthcare costs of IBD. Diagnosis and monitoring of disease requires invasive procedures, such as endoscopy and tissue biopsy. Here we report signatures of heterogeneity between disease diagnoses and phenotypes. Using mass cytometry, we analyze leukocyte subsets, characterize their function(s), and examine gut-homing molecule expression in blood and intestinal tissue from healthy and/or IBD subjects. Some signatures persist in IBD despite remission, and many signatures are highly represented by leukocytes that express gut trafficking molecules. Moreover, distinct systemic and local immune signatures suggest patterns of cell localization in disease. Our findings highlight the importance of gut tropic leukocytes in circulation and reveal that blood-based immune signatures differentiate clinically relevant subsets of IBD. In addition, we show that B cells are differentially dysregulated in IBD subsets despite their lack of representation by literature in the field. B cells have important functions in the pathogenesis of autoimmune diseases, which to date has been particularly well-demonstrated for rheumatic diseases. In addition to producing autoantibodies, B cells contribute to autoimmunity by serving as professional antigen presenting cells (APCs), producing cytokines and through additional mechanisms. B cell activation and effector functions are regulated by immune checkpoints, including both activating and inhibitory checkpoint receptors that contribute to the regulation of B cell tolerance, activation, antigen presentation, T cell help, class switching, antibody production and cytokine production. The various activating checkpoint receptors include B cell activating receptors that engage with cognate receptors on T cells or other cells, as well as Toll-like receptors that can provide dual-stimulation to B cells via co-engagement with the B cell receptor. Furthermore, various inhibitory checkpoint receptors, including B cell inhibitory receptors, have important functions in regulating B cell development, activation and effector functions. Therapeutically targeting B cell checkpoints represents a promising strategy for the treatment of a variety of autoimmune diseases. Based on these findings, it is likely that B cells play an important role in IBD and thus are an important area of future investigation.
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 | 2019; ©2019 |
| Publication date | 2019; 2019 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Rubin, Samuel J. S |
|---|---|
| Degree supervisor | Habtezion, Aida |
| Degree supervisor | Robinson, William (William Hewitt) |
| Thesis advisor | Habtezion, Aida |
| Thesis advisor | Robinson, William (William Hewitt) |
| Thesis advisor | Engleman, Edgar G |
| Thesis advisor | Fathman, C. Garrison |
| Thesis advisor | Maecker, Holden |
| Degree committee member | Engleman, Edgar G |
| Degree committee member | Fathman, C. Garrison |
| Degree committee member | Maecker, Holden |
| Associated with | Stanford University, Program in Immunology. |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Samuel J. S. Rubin. |
|---|---|
| Note | Submitted to the Program in Immunology. |
| Thesis | Thesis Ph.D. Stanford University 2019. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2019 by Samuel J. S. Rubin
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
Also listed in
Loading usage metrics...