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Access Type

WSU Access

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Molecular Biology and Genetics

First Advisor

Kang Chen

Second Advisor

Roger Pique-Regi

Abstract

B cells are a unique subset of immune cells that, in response to antigen, diversify their antibody repertoire to generate progressively higher affinity antibodies of different isotypes through the processes of affinity maturation/somatic hypermutation (SHM) and class switch recombination (CSR). One of the major sites in which this diversification occurs is in T cell dependent microanatomical structures known as germinal centers (GC). Here, we find that GC B cells express the protein, autoimmune regulator (Aire) in a CD40 dependent manner. In these cells, Aire interacts with activation induced cytidine deaminase (AID), the protein responsible for initiating the processes of diversification through the deamination of the immunoglobulin locus and prevents AID function by inhibiting its targeting to the DNA substrate. Mice that receive Aire deficient B cells are unable to clear the fungal pathogen Candida albicans as effectively as mice with wild type B cell Aire and produce increased levels of autoreactive antibodies against Th17 cytokines. These results describe a novel mechanism for the regulation of antibody diversification and potentially provide a new approach to generating high affinity antibodies for both therapeutic and commercial applications.

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