Date of Award


Document Type


Degree Name

Doctor of Philosophy (PhD)


Microbiology and Immunology


College of Graduate Studies

First Advisor

Gary Gilkeson

Second Advisor

Jim Oates

Third Advisor

Maria Trojanowska

Fourth Advisor

Janardan Pandey

Fifth Advisor

John Zhang


PBMC from patients with SLE and splenic lymphocytes from murine models of SLE demonstrate increased expression of the ETS transcription factor Fli-1. Transgenic overexpression of Fli-1 in normal mice leads to SLE-like disease. These findings suggest investigation of the role of Fli-1 in SLE may elucidate etiology of the disease and potential therapies. The MRL/lpr mouse is a model of SLE exhibiting increased lymphocytic expression of Fli-1. Reduction of Fli-1 expression by heterozygousity at the Fli-1 locus (Fli1+/-) results in decreased auto- and alloantibodies, proteinuria, and renal pathology; and drastically decreased mortality. Disruption of the C-terminal transactivation domain (Fli1ΔCTA/ΔCTA) reduces the ability of Fli-1 to activate target genes, but does not affect expression or DNA-binding. Effect of Fli-1 deficiency on B cell proliferation was evaluated in three models - Fli-1+/- MRL/lpr, Fli-1+/- C57BL/6, and Fli- ΔCTA/ΔCTA C57BL/6 mice. Proliferative responses of naive B cells from Fli-1-deficient mice to anti­IgM, a combination of PMA and ionomycin, CpG DNA, or LPS were significantly reduced compared to those of Fli-1-wild-type mice of similar strain. Expression of corresponding mitogen receptors was also evaluated. Surface expression of BCR components IgM and Iga, TLR4, and TLR9, and intracellular expression of TLR9 was only slightly and inconsistently reduced in naive B cells of Fli-1-deficient mice compared to Fli-1-wild-type mice of similar strain. Transcript expression of several TLR and BCR signaling-related genes was also evaluated. IL12a transcripts were upregulated in Fli-1-deficient MRL/lpr B cells. Transcription of the gene encoding the transcription factor NFAT, a known activator of proliferation, was downregulated in Fli-1-deficient MRL/lpr B cells. The results of these studies clearly demonstrate that Fli-1 deficiency affects B cell proliferative responses to mitogens, independent of BCR and TLR expression. Also, IL12a and NFAT were identified as potentially regulated by Fli-1. Based on published evidence, the differential expression of these genes may dampen proliferative responses of B cells to mitogens. Ultimately, this may be a mechanism by which overexpression of Fli-1 contributes to B cell hyperactivity and subsequent SLE pathogenesis.


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