Major histocompatibility Complex (MHC) encoded class II molecules function to insure self versus non-self discrimination during an immune response. It is widely accepted that the interaction between the T cell receptor for antigen (TCR) and CD4 on the helper T cell with an MHC class II molecule bearing processed antigen (peptide) on the antigen presenting cell (including the primed B cell) is required for activation of the T cell. However, only recently has it been established that these same sets of interactions simultaneously initiate a signal-transducing cascade in the B cell on which the class II molecule is expressed. These signals, the results of the so-called """"""""cognate"""""""" interaction between T and an appropriately antigen primed B cell, ultimately lead to activation and/or differentiation of the B cell. In contrast, the engagement of class II molecules on a resting B cell has recently been demonstrated to inhibit subsequent mitogenic signals. Therefore, it is possible that engagement of class II molecules on a resting, unprimed B cell by the TCR and/or CD4 molecule(s), initiates a signaling cascade in the B cell that leads to B cell inactivation, anergy, or death. In this case, inactivation of the B cell would prevent aberrant, antigen non-specific activation of an unprimed B cell. The purpose of this proposal is to analyze the molecular mechanism(s) involved in coupling the class II molecule to the pathway that results in B cell inactivation and to understand how the structure of the class II molecule and/or its associated molecules dictate its role in this pathway. These goals will be achieved through the completion of three specific aims: 1) biochemical characterization of those molecules associated with MHC class II on resting versus activated B cells, including amino acid sequence analysis, biochemical characterization of truncated I-Ak molecules and elucidation of the role of the cytoplasmic domains in coupling the class Il molecules to the inactivation pathway, and an analysis of subcellular compartmentalization of the class II associated molecules; 2) analysis of molecular mechanism(s) of signaling through class II; and 3) analysis of the molecular mechanism(s) of class II mediated apoptosis, including establishing the basic parameters and kinetics of class II mediated apoptosis, establishing the functional significance of PKC and PKA in the apoptosis pathway, and determining the role played by the proto-oncogene c-myc in apoptosis in resting B cells. These studies derive relevance to disease because they are directed at understanding the mechanism(s) by which non-specific stimulation of B cells results in polyclonal B cell activation and the production of autoantibodies. The failure of such processes may well be a major factor in polyclonal B cell activation, oligoclonal expansion of autoreactive cells, and ultimately the production of autoantibodies characteristic of autoimmune diseases such as Systemic Lupus Erythematosus.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
Immunobiology Study Section (IMB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
National Jewish Health
United States
Zip Code
Huber, S A; Sakkinen, P; David, C et al. (2001) T helper-cell phenotype regulates atherosclerosis in mice under conditions of mild hypercholesterolemia. Circulation 103:2610-6
Desbarats, J; Stone, J E; Lin, L et al. (2000) Rapid early onset lymphocyte cell death in mice resistant, but not susceptible to Leishmania major infection. Apoptosis 5:189-96
Huber, S A; Kupperman, J; Newell, M K (1999) Hormonal regulation of CD4(+) T-cell responses in coxsackievirus B3-induced myocarditis in mice. J Virol 73:4689-95
Chien, M M; Zahradka, K E; Newell, M K et al. (1999) Fas-induced B cell apoptosis requires an increase in free cytosolic magnesium as an early event. J Biol Chem 274:7059-66
Huber, S A; Kupperman, J; Newell, M K (1999) Estradiol prevents and testosterone promotes Fas-dependent apoptosis in CD4+ Th2 cells by altering Bcl 2 expression. Lupus 8:384-7
Desbarats, J; Duke, R C; Newell, M K (1998) Newly discovered role for Fas ligand in the cell-cycle arrest of CD4+ T cells. Nat Med 4:1377-82
Bhushan, A; Kupperman, J L; Stone, J E et al. (1998) Drug resistance results in alterations in expression of immune recognition molecules and failure to express Fas (CD95). Immunol Cell Biol 76:350-6
Folzenlogen, D; Hofer, M F; Leung, D Y et al. (1997) Analysis of CD80 and CD86 expression on peripheral blood B lymphocytes reveals increased expression of CD86 in lupus patients. Clin Immunol Immunopathol 83:199-204
Desbarats, J; Freed, J H; Campbell, P A et al. (1996) Fas (CD95) expression and death-mediating function are induced by CD4 cross-linking on CD4+ T cells. Proc Natl Acad Sci U S A 93:11014-8
Wagner Jr, D H; Hagman, J; Linsley, P S et al. (1996) Rescue of thymocytes from glucocorticoid-induced cell death mediated by CD28/CTLA-4 costimulatory interactions with B7-1/B7-2. J Exp Med 184:1631-8