Modulation of the immune response by complement may occur through the interaction of C3- and C4-derived ligands with complement receptors on lymphocytes and macrophages. Two structurally related complement receptors, CRl and CR2, that bind C3b/C4b and C3dg, respectively, are present on B lymphocytes. Analysis of their role in proliferative and antigen-presenting reactions of B cells is the aim of this project. Three functions of CR2 on B cells that are potentially growth promoting have been identified. First, crosslinking CR2 and membrane IgM on B cells caused a synergistic increase in free intracellular calcium concentration relative to that observed with crosslinking IgM alone; CR2 alone had no affect. CRl also was without affect alone and did not synergize with membrane IgM. Studies are proposed to determine the basis for this interaction between CR2 and membrane IgM. Second, preincubation of B cells with C3dg for 24 hr caused the cells to enter S phase more rapidly following stimulation with anti-IgM. The role of CR2 in this priming reaction will be defined. Third, addition of C3dg to serum-free culture medium prolonged by four-fold the half-life of B cells. The requirement for crosslinking CR2 in this reaction will be examined. The antigen-presenting functions of CRl and CR2 on B cells will be analyzed by preparing fluorescein (FL)- conjugated oligomers of C3b, C3bi, and C3dg. EBV-transformed B cells that have been pulsed with the FL-C3/C4 fragments or with FL- albumin as a control will be assessed for their capacity to present FL to autologous, FL-specific T cell lines. The T cells that have been activated in this manner will be examined for their capacity to activate reciprocally the antigen-presenting B cell. Demonstration of these reactions would provide a model that describes a role for complement in antigen-specific activation of T cells, and in T cell-dependent, antigen-non-specific, polyclonal B cell activation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028191-04
Application #
3142477
Study Section
Allergy & Clinical Immunology-1 (AITC)
Project Start
1988-09-30
Project End
1993-08-31
Budget Start
1991-09-01
Budget End
1992-08-31
Support Year
4
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Kalli, K R; Fearon, D T (1994) Binding of C3b and C4b by the CR1-like site in murine CR1. J Immunol 152:2899-903
Matsumoto, A K; Martin, D R; Carter, R H et al. (1993) Functional dissection of the CD21/CD19/TAPA-1/Leu-13 complex of B lymphocytes. J Exp Med 178:1407-17
Tuveson, D A; Carter, R H; Soltoff, S P et al. (1993) CD19 of B cells as a surrogate kinase insert region to bind phosphatidylinositol 3-kinase. Science 260:986-9
Carter, R H; Fearon, D T (1992) CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256:105-7
Martin, D R; Yuryev, A; Kalli, K R et al. (1991) Determination of the structural basis for selective binding of Epstein-Barr virus to human complement receptor type 2. J Exp Med 174:1299-311
Carter, R H; Tuveson, D A; Park, D J et al. (1991) The CD19 complex of B lymphocytes. Activation of phospholipase C by a protein tyrosine kinase-dependent pathway that can be enhanced by the membrane IgM complex. J Immunol 147:3663-71
Matsumoto, A K; Kopicky-Burd, J; Carter, R H et al. (1991) Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19. J Exp Med 173:55-64
Kalli, K R; Hsu, P H; Bartow, T J et al. (1991) Mapping of the C3b-binding site of CR1 and construction of a (CR1)2-F(ab')2 chimeric complement inhibitor. J Exp Med 174:1451-60
Hebell, T; Ahearn, J M; Fearon, D T (1991) Suppression of the immune response by a soluble complement receptor of B lymphocytes. Science 254:102-5
Kalli, K R; Ahearn, J M; Fearon, D T (1991) Interaction of iC3b with recombinant isotypic and chimeric forms of CR2. J Immunol 147:590-4

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