Advisor

Pullen, Nicholas A.

Committee Member

Haughian, James

Committee Member

DeKrey, Gregory

Committee Member

Stewart, Laura

Department

College of Natural and Health Sciences; School of Biological Sciences, Biological Education

Institution

University of Northern Colorado

Type of Resources

Text

Place of Publication

Greeley, (Colo.)

Publisher

University of Northern Colorado

Date Created

12-2021

Extent

150 pages

Digital Origin

Born digital

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.

Degree type

PhD

Degree Name

Doctoral

Local Identifiers

Vita_unco_0161D_10976.pdf

Rights Statement

Copyright is held by the author.

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