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dc.contributor.authorMatz, Hanover Christian
dc.date.accessioned2022-06-22T16:14:23Z
dc.date.available2022-06-22T16:14:23Z
dc.date.issued2022
dc.identifier.urihttp://hdl.handle.net/10713/19240
dc.descriptionUniversity of Maryland, Baltimore. Molecular Microbiology and Immunology. Ph.D. 2022.en_US
dc.description.abstractAffinity maturation of the B cell immunoglobulin (Ig) repertoire occurs through coordinated somatic hypermutation (SHM) and Darwinian selection of clones in specialized microanatomical structures known as germinal centers (GCs). GCs have only been identified in the endothermic vertebrates, and so it was long presumed that the antigen (Ag)-specific Ig responses of ectothermic vertebrate lineages were “primitive”. However, affinity maturation and immunological memory have subsequently been demonstrated for the oldest extant vertebrate class with Ig-based adaptive immunity, the cartilaginous fishes (Chondrichthyes). In this dissertation, I investigated the cellular model of B cell selection in the nurse shark (Ginglymostoma cirratum) spleen and determined how it influences the dynamics of the Ig repertoire. I found that shark splenic B cell follicles possess many functional analogs of mammalian GCs: (1) segregation of SHM and selection regions by CXCR4/CXCR5 expression in B cells, (2) functional T follicular helper-like cells, (3) presentation of nondegraded Ag, and (4) Ag-driven selection of mutated Ig clones. I also demonstrated that the transcription factor BCL6 likely regulates the shark B cell response. Through a long-term immunization study, I demonstrated that this selection model can generate IgNAR repertoires that are both diverse and of high affinity. In multiple animals immunized by the same methods, I observed uncoupling of the T-dependent isotypes, IgNAR and monomeric IgM. Sharks that produced robust IgNAR titers matured their polyclonal repertoires to subnanomolar binding affinities and generated a diverse pool of memory clones. Together, this suggests that B cell selection in cartilaginous fishes evolved to support both affinity maturation and Ig repertoire diversification, possibly utilizing SHM to anticipate future pathogen variants. Finally, I developed a method of magnetic nanoparticle enrichment to isolate Ag-specific B cell clones directly from the peripheral blood of sharks. Overall, the data presented in this dissertation indicate that all the fundamental components of B cell selection were present at the advent of adaptive immunity in jawed vertebrates. Furthermore, these components were capable of affinity maturation of the B cell repertoire without sacrificing receptor diversity. My findings have many implications for our understanding of the evolution of the B cell response in vertebrate lineages.en_US
dc.language.isoen_USen_US
dc.subject.meshB-Lymphocytesen_US
dc.subject.meshGerminal Centeren_US
dc.subject.meshImmunoglobulinsen_US
dc.subject.meshSharksen_US
dc.titleThe Evolution of B Cell Selection and Affinity Maturation in Cartilaginous Fishesen_US
dc.typedissertationen_US
dc.date.updated2022-06-10T22:13:52Z
dc.language.rfc3066en
dc.contributor.advisorDooley, Helen, Ph.D.
dc.description.embargo12/10/2022
dc.contributor.orcid0000-0002-0669-1696


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