Understanding how B lymphocytes develop and how immunoglobulin is produced is critical for development of effective vaccines and for intervention in immunologic diseases where antibodies are either over-or under-expressed. Appropriate immunoglobulin expression is directly linked to normal B cell development. The transcription factor, Bright (B cell regulator of immunoglobulin heavy chain transcription) enhances immunoglobulin transcription and associates with Bruton's tyrosine kinase (Btk), the defective enzyme in X-linked immunodeficiency disease. Mice and patients with Btk deficiencies exhibit blocks in B cell differentiation that result in abnormally low serum immunoglobulin levels. Data now suggest that Bright activity critically requires Btk function. Therefore, the objectives of this proposal are to determine how Bright activity is regulated and whether it is required for normal B cell development and immunoglobulin production. Transgenic mice producing dominant negative Bright have been produced and will be assessed for appropriate immune responses and development of B cell subpopulations. A third protein has been implicated in Bright function, and it will be further characterized and its contribution to Bright activity and heavy chain transcription will be addressed using conventional reporter assays. In addition, the transcriptional and post-translational regulatory events that result information of active Bright complexes will be identified by direct analysis of the Bright promoter, by identifying signaling intermediates necessary for Bright transcription and by determining the requirements for protein interactions among members of the Bright complex. The results of these experiments will contribute to our understanding of immunoglobulin heavy chain transcription in general, and will provide important insights regarding the relationships between Bright activity, normal B cell development and immunodeficiency disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI044215-10
Application #
7586743
Study Section
Cellular and Molecular Immunology - B (CMI)
Program Officer
Johnson, David R
Project Start
2005-03-01
Project End
2011-02-28
Budget Start
2009-03-01
Budget End
2011-02-28
Support Year
10
Fiscal Year
2009
Total Cost
$295,792
Indirect Cost
Name
Oklahoma Medical Research Foundation
Department
Type
DUNS #
077333797
City
Oklahoma City
State
OK
Country
United States
Zip Code
73104
Ratliff, Michelle L; Mishra, Meenu; Frank, Mark B et al. (2016) The Transcription Factor ARID3a Is Important for In Vitro Differentiation of Human Hematopoietic Progenitors. J Immunol 196:614-23
Ward, Julie M; Ratliff, Michelle L; Dozmorov, Mikhail G et al. (2016) Human effector B lymphocytes express ARID3a and secrete interferon alpha. J Autoimmun 75:130-140
Ratliff, Michelle L; Templeton, Troy D; Ward, Julie M et al. (2014) The Bright Side of Hematopoiesis: Regulatory Roles of ARID3a/Bright in Human and Mouse Hematopoiesis. Front Immunol 5:113
Oldham, Athenia L; Miner, Cathrine A; Wang, Hong-Cheng et al. (2011) The transcription factor Bright plays a role in marginal zone B lymphocyte development and autoantibody production. Mol Immunol 49:367-79
Nixon, Jamee C; Ferrell, Scott; Miner, Cathrine et al. (2008) Transgenic mice expressing dominant-negative bright exhibit defects in B1 B cells. J Immunol 181:6913-22
Shankar, Malini; Nixon, Jamee C; Maier, Shannon et al. (2007) Anti-nuclear antibody production and autoimmunity in transgenic mice that overexpress the transcription factor Bright. J Immunol 178:2996-3006
Rajaiya, Jaya; Nixon, Jamee C; Ayers, Neil et al. (2006) Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol 26:4758-68
Rajaiya, Jaya; Hatfield, Melissa; Nixon, Jamee C et al. (2005) Bruton's tyrosine kinase regulates immunoglobulin promoter activation in association with the transcription factor Bright. Mol Cell Biol 25:2073-84
Nixon, Jamee C; Rajaiya, Jaya; Webb, Carol F (2004) Mutations in the DNA-binding domain of the transcription factor Bright act as dominant negative proteins and interfere with immunoglobulin transactivation. J Biol Chem 279:52465-72
Goebel, Peter; Montalbano, Alina; Ayers, Neil et al. (2002) High frequency of matrix attachment regions and cut-like protein x/CCAAT-displacement protein and B cell regulator of IgH transcription binding sites flanking Ig V region genes. J Immunol 169:2477-87

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