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X Chromosome Gene Dosage in Autoimmune Disease Susceptibility and B Cell Development

Liu, Ke (Coco)
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470753675

Abstract Details

2016, PhD, University of Cincinnati, Medicine: Immunology.
Autoimmune disorders are the result of abnormal immune responses that cause tissue damage. Collectively, these diseases affect about 8% of U.S. population. Most autoimmune diseases affect women more than men, with up to 90% of patients being females. No conclusive explanations for this female predominance has been demonstrated with clear mechanisms. Our lab has discovered that men with two X chromosomes (Klinefelter's syndrome, 47,XXY) have the same risk as women for developing the autoimmune diseases, systemic lupus erythematosus (SLE). This is consistent with the possibility that the number of X chromosomes contributes to sex bias in SLE. We explored whether a third X chromosome in women with triple X syndrome (47,XXX) would further increase the risk of developing SLE and other female-biased autoimmune diseases, primary Sjogren's syndrome (pSS), primary biliary cirrhosis (PBC) and rheumatoid arthritis (RA). We found that 47,XXX is more frequent in patients with SLE and pSS. The risk of SLE and pSS were increased approximately 25- and 41- fold, respectively, in 47,XXX women compared to men. We did not find enrichment of 47,XXX in PBC or RA. Therefore, the number of X chromosomes appears to be a key factor impacting the risk of SLE and pSS development. In order to identify what genes on the X chromosome are responsible for SLE gender bias, we took a candidate gene approach by selecting genes that escape X-inactivation in both humans and mice. We hypothesize that overexpression of these genes in women who have twice as many X chromosomes as men will contribute to lupus susceptibility bias. Among the candidate genes, Ddx3x encodes an RNA helicase gene implicated in IFN-ß signaling. We generated conditional knockout mice with Ddx3x deficient in hematopoietic cells (Ddx3x-Vav1). Unexpectedly, Ddx3x expression level was not different among female WT, female heterozygous and male WT mice in relevant immune tissues. However, we discovered a B cell deficiency in the lymphoid tissues of male hemizygous knockout mice (Vav1ddx3x) relative to ddx3x sufficient control male mice. Reduction of Ddx3x expression in hematopoietic cells was associated with reduced numbers of early pro-B, late pre-B, and immature B cells in the bone marrow. In the spleen, the numbers of transitional, follicular, and germinal center B cells, as well as plasmablasts, were decreased. Mixed bone-marrow chimeric mice demonstrated that these B-cell deficit phenotypes were B cell intrinsic. Moreover, Vav1ddx3x B cells were found to proliferate less at the late pro-B cell and early pre-B cell stages, possibly contributing to the generalized phenotype of low B-cell numbers. Surprisingly, despite the paucity of mature B cells, the levels of immunoglobulins in the serum of Vav1ddx3x mice were increased compared to WT mice. Preliminary evidence suggests that marginal zone B cells in the Vav1ddx3x mice may undergo altered class-switching and have an enhanced ability to produce immunoglobulins. Our data reveal that Ddx3x deficiency affects B-cell development resulting in a widespread loss of B cells and a paradoxical increase in serum immunoglobulin levels. These are the first data to link Ddx3x to B-cell development and function.
John Harley, M.D. Ph.D. (Committee Chair)
Kenneth M. Kaufman, Ph.D. (Committee Member)
Betty P. Tsao, Ph.D. (Committee Member)
Hal Scofield, M.D. (Committee Member)
Senad Divanovic, Ph.D. (Committee Member)
Fred Finkelman, M.D. (Committee Member)
126 p.
Immunology
Autoimmune; Systemic lupus erythematosus; female sex bias; Triple X; Ddx3x; B cell

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Citations

  • Liu, K. (2016). X Chromosome Gene Dosage in Autoimmune Disease Susceptibility and B Cell Development [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470753675

    APA Style (7th edition)

  • Liu, Ke (Coco). X Chromosome Gene Dosage in Autoimmune Disease Susceptibility and B Cell Development. 2016. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470753675.

    MLA Style (8th edition)

  • Liu, Ke (Coco). "X Chromosome Gene Dosage in Autoimmune Disease Susceptibility and B Cell Development." Doctoral dissertation, University of Cincinnati, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1470753675

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.