Proper function of the immune system requires the development of a diverse B cell repertoire that remains tolerant to self antigens. Signals through the B cell antigen receptor (BCR) play an important role in numerous events throughout this process. They promote multiple stages of B cell development, support the survival of mature B cells, and drive the activation and differentiation of B cells during an immune response. BCR signals also serve to eliminate and/or inactivate autoreactive B cells, thus preventing autoimmunity. Maintaining an appropriate balance between events that promote BCR signaling and those that dampen it is critical for controlling both the immune response to foreign antigens and the induction and maintenance of tolerance to self antigens. Disruption of this balance can result in immunodeficiency, autoimmune disease, or malignancy.
Our laboratory takes genetic approaches to study the consequences of tipping the balance between positive and negative regulators of BCR signaling for B cell development, activation, and tolerance. We have several ongoing projects in the lab aimed at addressing this issue.
1) The role of B cell signalosome components in B cell development and activation. A signaling complex composed of a tyrosine kinase Btk, an adaptor molecule BLNK, and lipid modifiying enzyme PLCgamma2 plays an important role in transmitting BCR signals throughout B cell development. Using mice expressing varying levels of these molecules alone and in combination, we are defining signaling events that occur downstream of this complex. We have also identified roles for these signaling molecules in B cells independent of their interaction with each other.
2) B cell signaling in lupus. The autoimmune disease systemic lupus erythematosus (SLE) is characterized by loss of tolerance to nuclear antigens. This leads to the production of pathogenic autoantibodies that form immune complexes, deposit in various tissues, and cause inflammation and organ damage. Our laboratory studies the effect of manipulating both positive (i.e. the tyrosine kinase Btk) and negative regulators (i.e. the tyrosine kinase Lyn) of B cell activation on the regulation of B cell tolerance and the production of pathogenic autoantibodies in mouse models of lupus. The long term goal of these studies is to illuminate novel therapeutic targets for SLE.
3) Characterization of novel putative negative regulators of BCR signaling. Microarray screens to identify genes that change in response to BCR crosslinking have revealed potential negative regulators of B cell activation. The Foxo family of transcription factors, which inhibits proliferation and promotes apoptosis in various other cell types, is downregulated at the mRNA level upon B cell activation. This suggests that they may act to keep resting B cells quiescent. We have also found that some molecules with inhibitory properties in other cell types are upregulated during B cell activation. They may limit the extent and duration of B cell responses. We are currently using various transgenic and knockout mouse models to determine the consequences of changes in expression of these molecules for B cell development, activation, and tolerance.
RESEARCH INTERESTS
B cell development
Signal transduction
Immunodeficiency
Autoimmunity
RECENT PUBLICATIONS
Hinman RM, Nichols WA, Diaz TM, Gallardo TD, Castriollon DH, and Satterthwaite AB, "Foxo3-/- mice demonstrate reduced numbers of pre-B and recirculating B cells but normal splenic B cell subpopulations." International Immunology, 21:831-842, July 2009
Halcomb KE, Musuka S, Gutierrez T, Wright HL, Satterthwaite AB, "Btk regulates localization, in vivo activation, and class switching of anti-DNA B cells." Molecular Immunology, 46:233-241, December 2008
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
SIGNIFICANT PUBLICATIONS
Wu T, Qin X, Korepa Z, Raman K, Bhaskarabhalta M, Zhou XJ, Satterthwaite AB, Davis LS, Mohan C., "Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus" J. Clin. Invest., 117:2186-2196, August 2007
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
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