All ETDs from UAB

Advisory Committee Chair

John D Mountz

Advisory Committee Members

Peter D Burrows

John F Kearney

Chander Raman

Troy Randall

Document Type

Dissertation

Date of Award

2017

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

The survival responses of transitional B cells play a key role in shaping the development of mature, antibody producing B cells. Abnormal transitional T1 B cell survival responses are associated with the generation of polyreactive self-antigen-reactive mature B cells in systemic lupus erythematosus (SLE). Type I interferon (IFN) dysregulation is strongly associated with autoantibodies (autoAbs) and disease flares, particularly in African American (AA) patients. B cells produce a variety of immune-modulatory cytokines, but B cell production of high affinity IFNβ in SLE has not been investigated. In the present study, analysis of PBMCs from SLE patients (n=34) and healthy controls (n=9) revealed a significant increase in IFNβ expression within transitional, naïve and memory B cell compartments of SLE patients. Endogenous T1 B cell IFNβ acted in an autocrine mechanism to promote B cell activation and survival and was highly correlated with clinical disease including renal disease and anti-dsDNA, anti-Sm and anti-SSA autoAbs. Transitional B cell IFNβ expression was also significantly correlated with the percent of 9G4+ autoreactive B cells and CD19loCD38hiCD27+ plasma cell formation. African American SLE patients, a population disproportionately affected by SLE had significantly increased expression of IFNβ. Mechanistic studies in mice including analyses of Ifnb-/- and Ifnb+/+ B cells derived from reconstituted chimeric mice revealed that development of germinal center, autoreactive, and IgG class switched anti-DNA, anti-La and anti-Histone autoAb producing B cells were dependent upon B cell endogenous IFN-β. Single-cell examination of Ifnb-/- vs. Ifnb+/+ T1 B cells further revealed distinct gene expression signatures associated with endogenous IFNβ, including significantly lower expression of CD86, TLR7, and PKR, and type I IFN genes in T1 B cells derived from Ifnb-/- mice. Single cell analysis of autoimmune BXD2 T1 B cells that overexpressed IFNβ revealed that IFNβ is expressed in early T1 B cell development with subsequent upregulation of TLR7 and IFNα genes. Indeed IFNβ was specifically required for optimal B cell activation and survival in response to TLR7 stimulation and TLR7 + B cell receptor (BCR) co-stimulation. Together, these studies suggest that endogenous IFNβ-expressing T1 B cells are initially autonomous and that their expression of IFNβ plays a key role in regulating their development and responsiveness to external factors, including externally-derived type I IFNs and TLR7.

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