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Access Type

WSU Access

Date of Award

January 2021

Degree Type

Thesis

Degree Name

M.S.

Department

Biochemistry and Molecular Biology

First Advisor

Eric Sebzda

Abstract

B cell therapies can help alleviate pathology caused by autoimmunity, indicating that B cells contribute to diseases such as type 1 diabetes, arthritis, and systemic lupus erythematosus (SLE). Preliminary data in the Sebzda laboratory suggest that defective homeostasis within a subset of B cells, termed B1 cells, directly causes SLE. These studies were achieved by excising the transcription factor, Kruppel-like factor 2 (KLF2), within the B cell compartment (CD19-cre; Klf2fl/fl). Klf2 is a zinc-finger transcription factor (Kruppel-like factor 2) that is found in B cells and other immune cells. This factor causes interruption of mature B cell homeostasis and a breakdown in peripheral tolerance. CD19cre; Klf2fl/fl mice have a knock out of the Klf2 gene in CD19-cre expressing cells. So these mice have a lack of KLF2 solely with the B cell compartment. Specifically, CD19-cre; Klf2fl/fl mice lack B1 cells that are normally found in body cavities and instead have increased numbers of follicular (FO) and marginal zone (MZ) B cells in the spleen. Adoptive transfer experiments using a tamoxifen-inducible Cre-excising system (T2-cre; Klf2fl/fl) suggest that the splenic phenotypes are caused by KLF2-deficient B1 cells. In that case, B1 cells from T2-cre; Klf2fl/fl mice were transferred into wild-type animals then placed on a tamoxifen diet to allow for temporal excision of Klf2 solely within the donor cells. Under these circumstances, KLF2-deficient B1 cells vacated the peritoneal body cavity, homed to the spleen, and altered their lineage-defining surface markers so that they can now appear as FO and MZ cells. Moreover, preliminary data indicates that Klf2-deficient B1 cells alter their homing receptors and antigen presentation machinery so that they could theoretically function as primary antigen-presenting cells for native CD4+T cells in the spleen. At the same time, older CD19-cre; Klf2fl/fl mice present with elevated sera levels of anti-nuclear antibodies and increase protein levels in the urine, both classic symptoms of SLE. Therefore, we hypothesize that a primary function of B1 cells is to maintain tolerance towards antigens found in mucosal tissues (e.g., commensal bacteria in the guts and lungs) and that a breakdown in the process causes autoimmunity, including SLE. In this regard, it is recognized that lupus is caused by a combination of autoreactive lymphocytes (B cells and T cells) and environmental factors.

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