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Inhibition by Proxy: Modulation of TLR4-driven B cell responses by RP105

Allen, Jessica L.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275658195

Abstract Details

2010, PhD, University of Cincinnati, Medicine : Immunobiology.
Consistent with their important roles in both adaptive and innate immune responses, B lymphocytes express both somatically-recombined, antigen-specific receptors of the adaptive immune system and germline-encoded, pattern-recognition receptors of the innate immune system. The B cell immunobiology of an important class of innate immune receptors, the Toll-like receptors (TLRs), has recently gained considerable experimental attention. TLR signaling affects B cell function in both B cell-intrinsic and B cell-extrinsic ways. RP105, a TLR homolog that lacks a Toll/IL-1/resistance (TIR) signaling domain, has appeared to have dichotomous, cell type-specific effects on TLR4 signaling. While RP105 inhibits TLR4-driven signaling in cell lines and primary myeloid cells, the impaired lipopolysaccharide-driven proliferation of B cells from RP105-deficient mice has suggested that RP105 facilitates TLR4 signaling in B cells. Studies in this thesis demonstrate that RP105-mediated modulation of TLR4-driven B cell proliferation is not a function of B cell-intrinsic expression of RP105. These studies further identify a mechanism underlying the proliferative abnormalities of B cells from RP105-deficient mice: dysregulated expression of B cell-activating factor (BAFF). Serum BAFF levels are elevated in RP105-deficient mice, transgenic overexpression of BAFF recapitulates the impaired TLR4-driven proliferation in B cells from RP105-deficient mice, and partial neutralization of BAFF rescues the proliferative abnormalities of B cells from RP105-deficient mice. These data indicate that RP105 does not in fact have dichotomous effects on TLR4 signaling in myeloid cells and B cells, settling a controversy that has hindered insight into the biology of this understudied TLR. Ongoing studies aim to define what B cell-intrinsic roles are played by RP105— in particular, whether RP105 functions as a TLR antagonist in B cells, similar to its role in myeloid cells.
Karp Christopher, MD (Committee Chair)
Edith Janssen, PhD (Committee Member)
Bob Colbert, MD, PhD (Committee Member)
Fred Finkelman, MD (Committee Member)
Marsha Wills-Karp, PhD (Committee Member)
192 p.
Immunology
TLR4; RP105; B cells; BAFF

Recommended Citations

Citations

  • Allen, J. L. (2010). Inhibition by Proxy: Modulation of TLR4-driven B cell responses by RP105 [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275658195

    APA Style (7th edition)

  • Allen, Jessica. Inhibition by Proxy: Modulation of TLR4-driven B cell responses by RP105. 2010. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275658195.

    MLA Style (8th edition)

  • Allen, Jessica. "Inhibition by Proxy: Modulation of TLR4-driven B cell responses by RP105." Doctoral dissertation, University of Cincinnati, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1275658195

    Chicago Manual of Style (17th edition)

ucin1275658195
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© 2010, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.