Our research employs both genetic and biochemical approaches to study the signals that mediate B lymphocyte development and activation. We have focused primarily on Brutons tyrosine kinase (Btk), a Tec family kinase whose absence results in the B cell immunodeficiency X-linked agammaglobulinemia (XLA) in humans. The B cell developmental block that occurs in the complete absence of Btk has made it difficult to understand the role of Btk in processes mediated by mature B cells. To address this issue, we use a model in which a transgene expressing a low dosage of Btk (Btklo) completely restores mature conventional B cell numbers in Btk-/- mice. However, it confers only partial rescue of response to B cell antigen receptor (BCR) crosslinking due to insufficient Btk levels. Thus, the Btk-mediated processes of B cell developmental and function can be uncoupled and require different threshold levels of Btk.
We are using both Btk-/- and Btklo mice to define the role of Btk in the following processes:
BCR signaling: By comparing BCR-induced biochemical events and changes in gene expression in wild type and Btklo B cells, we have found several genes whose expression is regulated by Btk signals. Current studies are aimed at assessing the role of these genes in B cell development and activation. We are also defining components of Btk signaling pathways using a candidate gene approach to identify mutations that enhance or suppress the phenotypes of Btklo and/or Btk-/- mice.
Autoimmunity: Btk is required for the production of pathogenic autoantibodies in several murine models of systemic lupus erythematosus (SLE). Using the Btklo system, we have shown that Btk contributes to lupus-like autoimmune disease via functions other than, or in addition to, its role in B cell development and BCR signaling. We are currently assessing how Btk contributes to B cell tolerance checkpoints and the terminal differentiation of autoreactive B cells into plasma cells.
RESEARCH INTERESTS
B cell development
Signal transduction
Immunodeficiency
Autoimmunity
RECENT PUBLICATIONS
Wu T, Qin X, Korepa Z, Raman K, Bhaskarabhalta M, Zhou XJ, Satterthwaite AB, Davis LS, and Mohan C., "Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus" J. Clin. Invest., epub ahead of print July 2007
Halcomb KE, Contreras CM, Coursey TG, Hinman RM, Wright HL, and Satterthwaite AB, "Btk and PLCg2 can function independently during B cell development" Eur. J. Immunol., 37:1033-42, April 2007
Contreras CM, Halcomb KE, Randle L, Hinman RM, Gutierrez T, Clarke SH, and Satterthwaite AB, "Btk regulates multiple stages in the development and survival of B-1 cells" Mol. Immunol., 44:2719-28, April 2007
Hinman RM, Bushanam JN, Nichols WA, and Satterthwaite AB, "B cell receptor signaling down-regulates forkhead box transcription factor class O 1 mRNA expression via phosphatidylinositol 3-kinase and Brutons tyrosine kinase." J. Immunol., 178:740-7, January 2007
29. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, and Bolland S., "Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication" Science, 312:1660-72, June 2006
SIGNIFICANT PUBLICATIONS
29. Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, and Bolland S, "Autoreactive B Cell Responses to RNA-Related Antigens Due to TLR7 Gene Duplication" Science, 312:1669-72, June 2006
Whyburn LR, Halcomb KE, Contreras C, Lowell CA, Witte ON, and Satterthwaite AB, "Reduced dosage of Brutons tyrosine kinase uncouples B cell hyperresponsiveness from autoimmunity in Lyn-/- mice." J. Immunol., 171:1850-58., August 2003
Satterthwaite AB, Lowell CA, Khan WN, Sideras P, Alt F, and Witte ON, "Independent and opposing roles for Btk and lyn in B and myeloid signaling pathways" Journal of Experimental Medicine, 188/5:833-44, September 1998
Satterthwaite AB, Cheroutre H, Khan WN, Sideras P, and Witte ON, "Btk dosage determines sensitivity to B cell antigen receptor crosslinking" Proceedings of the National Academy of Sciences, 94/24:13152-7, November 1997
Li T, Tsukada S, Satterthwaite A, Havlik MH, Park H, Takatsu K, and Witte ON, "Activation of Brutons tyrosine kinase (BTK) by a point mutation in its pleckstrin homology (PH) domain" Immunity, 2/5:451-60, May 1995
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