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Dissertation Information for Nathan Wade Schmidt

NAME:
- Nathan Wade Schmidt

DEGREE:
- Ph.D.

DISCIPLINE:
- Microbiology

SCHOOL:
- Indiana University (USA) (2005)

ADVISORS:
- Mark A. Kaplan

COMMITTEE MEMBERS:
- Janice Blum
- Mark G. Goebl
- Gotz U vonBulow

MPACT Status: Incomplete - Not_Inspected

Title: Bruton's tyrosine kinase: Regulator of innate and humoral immunity

Abstract: Host immune responses to pathogens involve both the acquired and innate immune system. While these two systems are comprised of different cell populations, the protein tyrosine kinase, Btk, is expressed in cells of both systems. Btk has a critical role in signaling pathways downstream of the B cell antigen receptor and in its absence there are multiple defects in B cell development and function. Additionally, Btk is involved in cells of the innate immune system where it is involved in responding to pathogen-associated molecular patterns (PAMPs). Btk regulation of proteins that control the cell-cycle is important for B cell development and function. To further characterize how Btk regulates B cell development and function, through regulation of proteins involved in cell-cycle control, Btk- and p53-deficient mice were mated to generate Btk/p53-deficient mice. The loss of p53 on the Btk-deficient background did not lead to a recovery in B cell development nor immunoglobulin production. However, there was a recovery in some B cell proliferative responses in Btk/p53-deficient mice compared to Btk-deficient mice. Btk was shown to have a limited role in IL-4 signaling which is an important B cell mitogen. Finally, the importance of Btk in responding to PAMPs, which signal through Toll-like Receptors (TLRs), were examined in Btk-deficient macrophages. In the absence of Btk, TLR stimulation led to an increase in inflammatory cytokine production and a decrease in anti-inflammatory IL-10 production. The increased production of inflammatory cytokines was in part due to altered signaling pathways known to be activated by TLRs. The skewed inflammatory response seen in vitro was also observed in vivo, compared to wild-type mice, where Btk-deficient mice had altered fecal bacteria populations and had an increased susceptibility to endotoxic shock in response to the bacterial product LPS. These data suggest Btk has an important role in regulating the immune response in both the acquired immune system where it is required for B cell mediated humoral responses and the innate immune system where it regulates inflammatory cytokine production.

MPACT Scores for Nathan Wade Schmidt

A = 0
C = 0
A+C = 0
T = 0
G = 0
W = 0
TD = 0
TA = 0
calculated 2010-09-26 20:54:32

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