Regulation of antibody responses: the role of complement and adhesion molecules

To analyze the importance of cell surface-associated molecules in modulating the immune response by facilitating T/B cell interaction, we used the T cell-dependent antigen, bacteriophage phi X174. Taking advantage of "experiments of nature", we studied specific antibody synthesis in patients with deficiencies of complement components or of the adhesion molecule CD11/CD18 (leukocyte adhesion defect, LAD) and guinea pigs and dogs with early complement component deficiency. Following intravenous injection of bacteriophage phi X174 into normal subjects or animals, a primary response consisting of IgM, a secondary response consisting of IgM and IgG, and a tertiary, predominantly IgG response can be distinguished. Patients and guinea pigs deficient of early complement component and LAD patients responded to repeated phage immunization with depressed antibody titers, lack of or inadequate amplification, and failure to switch from IgM to IgG, suggesting a defect in generating antigen-specific memory cells. Several mechanisms have to be considered: (i) The complement portion of the antigen-antibody complement complex facilitates the accumulation and trapping of antigen in lymphoid organs, thus improving the response to Ag at low concentrations. (ii) Immune complexes preferentially bind to antigen-specific B cells, cells expressing Fc receptors, or CR2 and CR3, the receptors for C3bi. (iii) The weak binding established between the MHC-II/Ag complex and the TCR complex is strengthened through the binding of several adhesion molecule pairs. (iv) Receptor-ligand binding initiates activation signals. The concept of binding/signaling via interacting molecules is further supported by the observation that mAb 60.3, recognizing the beta chain of CD11/CD18, blocks in vitro synthesis of antibody to bacteriophage by primed PBMC.