All ETDs from UAB

Advisory Committee Chair

John D Mountz

Advisory Committee Members

Thomas Clemens

Louis Justement

Robinna Lorenz

Chander Raman

Casey Weaver

Document Type

Dissertation

Date of Award

2009

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Type I IFN is a known pro-inflammatory cytokine that is associated with the development of systemic lupus erythematosus (SLE). At the level of B-cell regulation, current literature primarily attributes the formation of autoantibodies at the post-germinal center stage when type I IFN is known to promote plasmablast differentiation. However, our findings here point to a type I IFN effect at the pre-germinal stage. Type I IFN promotes T-dependent antibody response, activation-induced cytidine deaminase (AID) expression, germinal center formation, all of which are processes before the onset of plasmablast differentiation. We have determined a subset of splenic transitional B-cells, that is known as the precursors to the development of marginal zone (MZ) B-cell population, and are termed marginal zone B-cell precursors (MZPs), whose trafficking from the MZ border to the inner follicle (FO) is promoted by type I IFN. MZPs are more efficient antigen-presenting cells than MZ or FO B cells. Type I IFN up-regulates expression of CD69 and down-regulates expression of S1P1 to promote migration of MZPs into the inner follicle to interact with CD4 T-cells. Together, these observations suggest a novel pathway by which type I IFN can promote the presentation of antigen to CD4 T-cells by MZPs to initiate germinal center reaction prior to type I IFN induction of plasmablast differentiation.

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