Publication Date

2013-10-30

Availability

Embargoed

Embargo Period

2015-10-30

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2013-08-30

First Committee Member

Wasif N. Khan

Second Committee Member

Richard L. Riley

Third Committee Member

Bonnie Blomberg

Fourth Committee Member

John Bethea

Fifth Committee Member

Nevis Fregien

Sixth Committee Member

James Hartmann

Abstract

Misguided immune reactions against self can cause autoimmunity. Although multiple factors are likely involved, a common feature is altered lymphocyte homeostasis due to dyregulated apoptosis. Here, we show that the integration of signals from the BCR and BAFF-R promotes survival of T2 cells that have passed the self-reactivity checkpoint. BCR engagement produces NF-κB2 protein, a substrate used by the BAFF-R for the activation of the alternative NF-κB pathway. In contrast, pre-checkpoint T1 cells fail to integrate BCR and BAFF-R signals and remain sensitive to BCR-mediated-apoptosis. Btk and c-Rel are critical in this signal integration and B-cell survival. Importantly, BAFF-R promotes B-cell survival by suppressing Bim, a pro-apoptotic protein of the Bcl-2 family. Because Bim suppression promotes B-cell survival, we hypothesized that Bim-dependent apoptosis of autoreactive B-cells is critical in preventing autoimmunity. To test this hypothesis, we constructed mice with B-cell-specific Bim deletion (B-Bim-/-). Loss of Bim in B-cells causes autoimmune disease characteristic of lupus and Sjögren’s Syndrome. B-Bim-/- mice develop tertiary lymphoid organs, developed glomerulonephritis and have lymphoid infiltration of salivary glands. B-cells in the B-Bim-/- mice were activated, and proliferated more robustly to BCR, BAFF-R, TLR4 and TLR9 stimulation than WT B-cells, suggesting that activated B-cells initiate and drive autoimmune pathogenesis. Deletion of Btk reduced the overall pathology in B-Bim-/- mice. Our findings demonstrate a critical role for B-cell developmental-stage-specific regulation of apoptosis and show that the loss of a physiological inducer of apoptosis in B-cells alone is sufficient to initiate generalized systemic immune dysregulation resulting autoimmune pathology.

Keywords

c-Rel, Btk, Bim, apoptosis, autoimmunity, transitional B cell

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