Defense Date

2014

Document Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Microbiology & Immunology

First Advisor

Daniel Conrad

Abstract

ADAM10 is a zinc-dependent metalloprotease. ADAM10 has emerged as a key regulator of cellular processes by cleaving and shedding extracellular domains of multiple transmembrane receptors and ligands. In this study, we examined the role of ADAM10 in the immune system. Here, we show that knocking out ADAM10 on the mature B2 cell causes a defect in the development of secondary lymphoid architecture that becomes more severe post-immunization. We also show that overexpression of ADAM10 leads to a defect in hematopoiesis, which eliminates B2 lymphocyte development. This defect additionally induces accumulation of myeloid derived suppressor cells, MDSCs. ADAM10Tg MDSCs function synonymous to tumor MDSCs. Of the two subpopulations of MDSCs, granulocytic MDSCs increase parasitic clearance in a model of N. brasiliensis. Monocytic MDSCs are more immunosuppressive in regards to tumor. Both subpopulations are dependent on the presence of mast cells for activity. It is thought that this relationship is mediated through histamine and IL-13. During N. brasiliensis infection, ADAM10Tg mice, lacking B2 B cells but having intact B1 B cells, makes increased IgE over WT mice. This production of IgE is thought to be produced by the B1 cells. Of the two types of B1 cells, B1a cells make the majority of the IgE. This IgE production is enhanced by MDSC accumulation and can be induced by MDSC adoptive transfer in a parasite-free mouse. Lastly, ADAM10 is the key sheddase for CD23 on B2 cells. When IgE is bound to its antigen to form an immune complex, IC, it binds CD23 and is internalized. After CD23 bound to IgE ICs is internalized, it is sorted into bexosomes. These bexosomes are transferred to dendritic cells which are responsible for presenting to T cells and inducing an increased antigen-specific immune response. Overall, ADAM10 is important for many aspects of the immune response.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

May 2014

Available for download on Wednesday, May 08, 2019

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