ORCID
https://orcid.org/0000-0003-2584-1407
Date of Award
8-8-2023
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Crohn’s disease, one of the most common forms of inflammatory bowel disease, is marked by local intestinal inflammation. However, pathology in CD patients is not strictly limited to the gastrointestinal system, and almost 50% of CD patients exhibit extraintestinal manifestations of disease. Many, though not all, of these systemic pathologies are linked to intestinal inflammation and, thus, resolution of local gastrointestinal disease also ameliorates systemic disease. How the connection between local and systemic inflammation is mediated is not well understand, nor is why only some patients exhibit these extraintestinal manifestations of disease. Blocking dissemination of inflammatory signals generated in the intestine may protect against systemic pathology. Lymphatic vessels carry lymph, immune cells, and dietary lipids from the intestine, and, ever since the first characterization of CD, it’s been observed that CD patients have dramatic alternations in their lymphatic vessels in areas of intestinal inflammation. We and others have shown that these abnormalities in lymphatics extend into the mesentery, where B cell-rich tertiary lymphoid structures [TLS] arise in close association with these altered lymphatic vessels in patients with ileal Crohn’s disease and in the TNFΔARE mouse model of ileal inflammation. Use of this model revealed that mesenteric TLSs block cellular and molecular trafficking from the ileum, allowing us to ask the question if preventing TLS formation would block local inflammation in the ileum and if this would change systemic manifestations of disease. As B cells are the most abundant immune cell in these TLSs, and B cell production of lymphotoxin has been implicated as critical for both lymphatic vessel expansion in inflamed lymph nodes and in TLS organization in cancer, we hypothesized that B cell derived lymphotoxin might be directly responsible for both phenotypes. In the context of total B cell deficiency in TNFΔARE/+ mice, we found that B cells were dispensable for development of ileal inflammation but were required for TLS organization and mesenteric lymphatic remodeling. Additionally, we found that B cells protect against excessive weight loss in ileal inflammation. B cell-derived secretory antibodies in TNFΔARE/+ mice partially protect against local ileitis, but do not affect mesenteric TLS development or systemic weight loss. B cell-selective production of LTα or LTβ and signaling through LTβR-fc is required for TLS organization and mesenteric lymphatic remodeling, but only B cell-specific deletion of LTα phenocopied the weight loss phenotype seen in B cell deficient TNFΔARE/+ mice. Through blockage of LTα3, we found that LTα has an independent role in controlling body weight of mice with ileitis that can be partially blocked by neutralizing TNF. Our work shows that B cells play a multifactorial role in ileitis that include production of locally protective secretory immunoglobulin, LTα3 for systemic protection against weight loss, and LTα1β2 for TLS organization and lymphangiogenesis.
Language
English (en)
Chair and Committee
Gwendalyn Randolph
Recommended Citation
Erlich, Emma Claire, "Distinct Roles for LTα3 and LTα1β2 Produced by B cells Contribute to their Multi-Faceted Impact on Ileitis" (2023). Arts & Sciences Electronic Theses and Dissertations. 3129.
https://openscholarship.wustl.edu/art_sci_etds/3129