Complement (C) is a major biological effector system which augments host defense against infectious agents. Numerous studies indicate the C initiates and modulates certain cellular responses. These effects are mediated through C receptors (CR), membrane glycoproteins which bind specific C fragments. Evidence from this and other laboratories indicates that C effects on B cells are primarily mediated through CR2, the specific B cell receptor for the C3dg fragment of the third C component, C3. In particular, CR2 modulates B cell activation and growth, apparently in conjunction with membrane Ig (mig) the antigen (Ag) receptor. CR2 is also the cell surface structure by which Epstein-Barr virus (EBV), a human herpesvirus and prime candidate for a human cancer virus, infects B cells. Certain CR2 ligands, including EBV, modulate B cell activation, thereby triggering secretion of cytokines and progression through the cell cycle. During the current granting period, we have examined a number of parameters of B cell activation initiated through CR2 and analyzed CR2 structural and functional epitopes. We also isolated the first full length cDNA clone for CR2, determined its nucleotide sequence, expressed it in membrane associated form in prokaryotic and eukaryotic cells and showed that such cells acquired the ability to bind C3dg, EBV and MAb. Soluble CR2, expressed in the baculovirus system, blocked EBV infection in vitro and in vivo. Aberrant regulation of normal immunological processes is the hallmark of autoimmune diseases, including rheumatoid arthritis (RA). There are many close associations between RA and EBV including augmented responses to EBV Ags, increased numbers of EBV infected cells, and impaired T cell responses to EBV infected B cells in RA patients. Also, several EBV proteins elicit Abs reactive with normal tissues and normal IgG. An EBV protein duplicates the RA susceptibility determinant found in HLA DR4. We propose to identify, characterize and analyze the signal transducing pathway(s) utilized by CR2 and by CR2 in conjunction with mig and with CD19 with which it is closely associated. The roles of protein kinases, phosphorylation, G proteins, phospholipases, secondary mediators, etc., will be analyzed using molecular approaches. Intramembranous association of CR2 with other proteins for signal transduction and regions and residues of CR2 involved will be evaluated. The role of CR2 in the endocytic pathway which mediates entry of EBV into cells will be analyzed. Cytoskeletal involvement, fates of ligands and receptors, etc., will be assessed in molecular terms. These studies will identify the processes and underlying mechanisms which regulate B cell activation via CR2 alone and together with the Ig receptor and CD19. They will shed light on the mechanisms involved in chronic B cell activation and hyperactivity and the effects of EBV on these responses. As such, they have the prospect of contributing insights into the aberrant immunoregulatory processes in RA and the role of EBV in this disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033244-02
Application #
3148333
Study Section
Experimental Immunology Study Section (EI)
Project Start
1992-01-01
Project End
1996-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
2
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037