This grant examines the interaction of immunoglobulin and complement and explores the hypothesis that an important function of immunoglobulin is to regulate the binding of activated complement proteins with host tissues. The hypothesis arises from studies of the effect of intravenous immunoglobulin. Intravenous immunoglobulin (IVIG) is used in treatment of patients with a variety of autoimmune disease, including idiopathic thrombocytopenic purpura and Kawasaki's disease. The mechanism of action is unknown. In many autoimmune disease, humoral antibody binds to target tissues, and activates complement, causing tissue destruction. Here we suggest that the Ig molecule acts as a preferred acceptor for activated complement peptides and that one mechanism of action of IVIG is to prevent complement binding to antibody sensitized targets. The mechanism by which IVIG acts is dissected in detail. The goal is to provide a more effective, less expensive and more convenient substitute for IVIG. Subclasses of IgG are examined for efficacy in this model as are fragments of IgG and IgM immunoglobulin and reduced and alkylated antibodies. Studies determine whether IVIG acts with both IgG and IgM sensitized targets. The activity of antibodies with covalently bound polyethylene glycol to improve acceptor status of complement peptides is examined. Myeloma proteins are studied to determine which structural characteristics of Ig allow it to act as an effective acceptor. The question of whether IVIG is capable of decreasing complement binding to microbes is examined. A second related hypothesis is explored. Are all IVIG molecules equal or is a fraction of IVIG responsible for most of its effect? Polyspecific, low affinity natural antibody with the variable region in the germ line gene configuration is secreted by a defined set of B lymphocytes CD5 positive cells. This antibody constitutes 20-30% of all serum immunoglobulin but its function is unknown. This antibody binds with low affinity to many normal tissue antigens. We suggest that natural antibody coats many body surfaces with immunoglobulin. This antibody acts as an acceptor for activated complement peptides, preventing their binding to normal tissue components to which antibody has been formed as a result of immune dysregulation. Such low affinity antibody with bound complement peptides can disassociate from tissue surfaces and normal tissues are not damaged. We will compare the activity of polyspecific low affinity antibody to IVIG and antibody with high affinity in blocking complement binding to targets. Myeloma protein sets and isolated antibodies with these characteristics will be studied. We will perform these experiments using targets to which the polyspecific antibody does or does not bind. In addition, we will determine whether patients with autoimmune disease have polyspecific Ig that acts normally in this respect.
| Wagner, E; Platt, J L; Howell, D N et al. (1999) IgG and complement-mediated tissue damage in the absence of C2: evidence of a functionally active C2-bypass pathway in a guinea pig model. J Immunol 163:3549-58 |
| Wagner, E; Platt, J L; Frank, M M (1998) High dose intravenous immunoglobulin does not affect complement-bacteria interactions. J Immunol 160:1936-43 |
| Miletic, V D; Hester, C G; Frank, M M (1996) Regulation of complement activity by immunoglobulin. I. Effect of immunoglobulin isotype on C4 uptake on antibody-sensitized sheep erythrocytes and solid phase immune complexes. J Immunol 156:749-57 |
| Miletic, V D; Frank, M M (1995) Complement-immunoglobulin interactions. Curr Opin Immunol 7:41-7 |
