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Immunobiology and Cancer Research Program

Carol F. Webb, Ph.D. Member, Immunobiology and Cancer Research Program Adjunct Professor, Departments of Microbiology and Immunology and   Cell Biology, University of Oklahoma Health Sciences Center

Research Interests
My long-term goal has been to develop a better understanding of the molecular mechanisms involved in B lymphocyte development and antibody production. A major focus of the lab has been to understand the function of the ARID (A+T interaction domain) family member ARID3a, or Bright (B cell regulator of immunoglobulin transcription), in this process. Several years ago we showed that Bright upregulates immunoglobulin heavy chain transcription as a member of a protein complex containing Bruton’s tyrosine kinase (Btk) and the ubiquitously expressed transcription factor TFII-I. Deficiencies in Btk result in immunodeficiency disease in both mice and humans and some of our work has focused on how inhibition of Bright function may cause immunodeficiency.

We first investigated Bright function by producing dominant negative forms of the protein. Bright binds to DNA as a dimer, so we generated and expressed mutants with defective DNA-binding activity that form sterile dimers with the endogenous protein resulting in inhibition of its function. Transgenic mice were also generated that express either dominant negative Bright, or constitutively over-express a wild type form of the protein specifically in B lymphocytes. Transgenic mice that expressed dominant negative Bright had reduced levels of serum IgM due to deficient function of a subpopulation of B lymphocytes. Because Bright interacts with Btk, and Btk deficiencies in man are much more severe than in mice, we extended our inhibition studies to human cells. Interestingly, myelopoiesis was blocked when ARID3a was over-expressed in early hematopoietic progenitors. Dominant negative ARID3a did not block myelopoiesis. We are now learning more about patterns of expression in human hematopoietic cells and continue to explore its roles in lympho-myeloid differentiation.

To our surprise, the transgenic mice that over-expressed wild type Bright were not immunodeficient, but rather, exhibited autoimmune symptoms. The Bright transgenic mice represent a unique model for studying how B cell tolerance is breached and should be informative about mechanisms responsible for early anti-nuclear antibody production.

Anti-nuclear antibody production is an early symptom in patients who develop lupus erythematosis. Therefore, in collaboration with Dr. Joan Merrill, we examined mononuclear blood samples from randomly selected lupus patients and discovered that more than half of those patients had measurable levels of ARID3a/Bright in their peripheral blood, while ARID3a was not detected in any of the age-matched control samples. These data suggest a link may exist between autoimmune disease and ARID3a expression in people. Further studies are in progress to determine the nature of this link.

Joined OMRF Scientific Staff in 1990.

Mailing Address
Immunobiology and Cancer Research Program, MS 29
Oklahoma Medical Research Foundation
825 N.E. 13th Street
Oklahoma City, Oklahoma 73104

Contact Information
Phone: (405) 271-7999
Fax: (405) 271-2864
E-mail: Carol-Webb@omrf.org