First Advisor
Pullen, Nicholas A.
Document Type
Dissertation
Date Created
12-2021
Department
College of Natural and Health Sciences, Biological Sciences, Biological Sciences Student Work
Abstract
The primary focus of this research was to determine the effect of berberine (BBR), a clinically relevant plant-derived alkaloid, on follicular T helper (Tfh) cell activation and differentiation, with implications for the generation of T cell-dependent humoral responses. This research revealed a novel function of BBR as a suppressor of Tfh cell proliferation in secondary lymphoid organs of BBR-treated mice that underwent immunization for arthritis induction in a collagen-induced arthritis (CIA) mouse model. Tfh cells provide signaling to B cells that is crucial for the generation of T cell-dependent humoral responses, such as affinity maturation, isotype class switching, and the differentiation of germinal center B cells into plasma cells and memory B cells. While this may be beneficial for patients with antibody-mediated autoimmune diseases, the results of our preliminary research raise concern that the prolonged use of BBR could suppress these humoral immunological responses in individuals taking BBR for non-immune related issues (e.g., management of glucose or lipid metabolism). To address this concern and support our preliminary observations, we have further delved into the suppressive impact of BBR on Tfh cell activation and differentiation, as well as the specific mechanisms of BBR inhibition on these cells. Through these studies we observed that BBR has selective suppressive effects on signaling pathways downstream of the T cell receptor (TCR) in activated Tfh cells. Specifically, the phosphorylation of ZAP-70, Lck, and PLCγ1 and the cytoplasmic store of NFATc1 were unaffected by BBR treatment. However, intracellular Ca2+ mobilization, STAT3 phosphorylation, and IL-21 production in response to TCR complex stimulus were all significantly inhibited by BBR treatment. This work reveals previously unknown cellular and molecular mechanisms of BBR action in the context of immunosuppression. Further research in the binding partners of BBR, as well as anatomical studies of lymphoid tissue proliferation, will be necessary to further guide the clinical use of this widely available alternative medicine.
Extent
150 pages
Local Identifiers
Vita_unco_0161D_10976.pdf
Rights Statement
Copyright is held by the author.
Recommended Citation
Vita, Alexandra Adorno, "The Role of Berberine, a Clinically Relevant Plant Derived Alkaloid, in T Cell-Mediated Immunosuppression" (2021). Dissertations. 768.
https://digscholarship.unco.edu/dissertations/768
Comments
Fall 2021 Graduate Dean's Citation for Outstanding Thesis, Dissertation, and Scholarly Project