Doctor of Philosophy in Pathology and Laboratory Medicine (PhD)
Characterization and expansion of regulatory natural killer cells for the therapy of chronic graft-versus-host disease
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The proper differentiation and survival of human peripheral immature B cells relies on two critical signaling pathways: B cell receptor (BCR) signaling and the B cell activating factor (BAFF)/BAFF-receptor (BAFF-R) signaling axis. The quality of the BCR signal is regulated in a developmental manner. Self-reactive early immature B cells are eliminated in response to strong BCR-induced signals, while late immature B cells require BCR-induced signals for survival and further differentiation. Although components and events downstream of the BCR are well known, the mechanisms of BCR signaling and its role in the regulation of BAFF signaling are still poorly understood. Through the use of transgenic and knockout murine models, the effects of BAFF on murine B cell maturation and survival are well characterized. There is a crucial need to better understand the functions of BAFF in humans. High levels of soluble BAFF, reduced expression of BAFF-R and BCR signaling abnormalities in B cells have been identified in a large group of clinically heterogeneous diseases including autoimmune and inflammatory conditions, allergy, viral infections and lymphoid cancers.In order to better understand BCR signaling mechanisms, functional properties of human BAFF and factors regulating BAFF-R expression, this thesis describes: 1) the phenotypic, molecular and functional characterization of rare unknown inherited monogenic immunodeficiencies involving defects in early B cell development and the BAFF/BAFF-R pathway and, 2) the functional characterization of dysregulated BAFF/BAFF-R signaling in B cell malignancy. This led to the discovery of two novel primary immunodeficiencies involving MALT1 deficiency and gain-of-function PLCγ2 mutation. Our results indicate that MALT1 is essential for antigen-receptor mediated NF-κB activation and plays a role in the surface expression of BAFF-R and proper development of human B cells. The PLCγ2 mutation led to hyper-reactive BCR signaling and increased apoptosis of transitional B cells. Work-up of this patient also allowed us to investigate how soluble BAFF down-modulates surface expression of it’s principal receptor, BAFF-R, through receptor internalization, in normal B cells. Further analysis of the BAFF/BAFF-R pathway in pre-B acute lymphoblastic leukemia provides evidence of different structural and functional BAFF isoforms.