Bellur S. Prabhakar
bprabhak@uic.edu
312-996-4945
Professor and Head,
Ph.D., The Johns Hopkins University
Molecular Pathogenesis of Autoimmune Diseases
Previous work has shown that antibodies to thyrotropin receptor can cause functional perturbation of the thyroid gland. Antibodies that cause thyroid hypertrophy, stimulate or block the thyrotropin receptor-mediated activation of thyroid gland are found in patients with non-toxic goiters, Graves' disease and primary myxedema, respectively. A mouse model has been developed to understand the immunological mechanisms that lead to the production of these functionally different autoantibodies. Structural biology studies to map functionally relevant epitopes on the thyrotropin receptor are underway. Our working hypothesis is that "antibodies with different functional effects are produced by the interaction of specific B cells with T cells having specificity for a given peptide presented in the context of a given MHC class II molecule and that the antibodies bind to different sites on the receptor to mediate their effects." To address this, we have produced large amounts of the extracellular domain of human thyrotropin receptor (ETSHR) protein in insect and mammalian cells. We have over 40 synthetic peptides that span the entire ETSHR, recombinant fragmrnts of TSHR, cDNA constructs encoding TSH-R/LH-HCG-R chimeric proteins, and monoclonal antibodies. Studies are underway using multiple approaches to decipher the structure-function relationship of the TSHR.
Our laboratory is also actively involved in studies related to pemphigus vulgaris, an autoimmune disease of the skin that is mediated by autoantibodies. We have expressed full-length pemphigus vulgaris antigen (PVA) and its extracellular domain (EPVA) in insect cells. Both PVA and EPVA adsorb blister-causing antibodies from PV patient sera. However, rabbit anti-PVA; but not "anti-EPVA"; induces blisters in neonatal mice. In addition, only "anti-PVA" induces intracellular calcium mobilization. These data show that although pathogenic antibodies interact with EPVA, only PVA, and not EPVA, can elicit antibodies that induce blisters in neonatal mice and mediate intracellular signaling through calcium mobilization. Using approaches similar to those described above for TSHR, we have recently developed an animal model for PV to understand the molecular interactions involved in the pathogenesis of pemphigus vulgaris. The long term objective of these studies is to develop antigen- specific immunotherapies.
Fan, J.L., Memar, O., McCormick, D.J., and B.S. Prabhakar. BALB/c mice produce blister causing antibodies upon immunization with a recombinant human desmogein 3. J. Immunology, in press, due Dec. 1999.
Kaithamana,S.,Fan, J-L.,Osuga,Y., Liang, S-G. and Prabhakar, B.S. Induction of experimental autoimmune Graves' disease in BALB/c mice. J. Immunol. (In press, due Nov 1999)
Patibandla, S., Fan, J-L., Prabhakar, B.S. and Seetharamaiah, G.S. Comparison of immune responses to extracellular domains of mouse and human thyrotropin receptor. J. Autoimmunity. 13: 205-213.1999.
Seetharamaiah, G.S., Dallas, J.S., Patibandla, S.A., Rao, T.N. and Prabhakar, B.S. Requirement of glycosylation of the human thyrotropin receptor ectodomain for its reactivity with autoantibodies in patients sera. J. Immunol. 158: 2798-2804, 1997.
Memar, O., Christensen B., Rajaraman, S., Goldblum, R., Tyring, S.K., Brysk, M.M. McCormick, D.J. and Prabhakar, B.S. Induction of blister-causing antibodies by a recombinant full-length, but not the extracellular domain of the pemphigus vulgaris antigen (desomoglein 3). J. Immunol., 157: 3171-3177, 1996.
Prabhakar, B.S., Seetharamaiah, G.S., and Fan., J.L. Thyrotropin receptor mediated diseases - a paradigm for receptor autoimmunity. Immunology Today. 18: 437-442, 1997
Other Publications