This proposal focuses on one of the most basic questions in immunology: i.e., what happens to the immunogen during the induction of a secondary response? Immunogens encounter antibody in immune animals and are almost instantaneously converted into immune complexes. These complexes are quickly trapped, endocytosed, and catabolized by macrophages. Certain antigen fragments may be expressed on macrophage membranes in a conformation that is recognizable by T cells. Our data indicates this process occurs quickly and by 48 hours after immunization very little antigen persists in or on these macrophages. However, an alternative antigen pathway exists which tends to preserve the immunogen. Initially the immune complexes are trapped on the surface of non-phagocytic cells which transport these complexes to follicular dendritic cells (FDCs) deep in the lymph node outer cortex. Recently, we observed that after encounter with immune complexes the dendrites of many FDCs appear """"""""beaded"""""""". These beads represent antigen coated spherical structures we call microspheres and these microspheres are released into the surrounding microenvironment. We have documented that these antigen coated microspheres are endocytosed by germinal center B cells and tingible body macrophages (TBMs) which accumulate in the follicles. We believe these cells are processing this antigen for presentation to appropriate T cells. This process continues for at least 8 days. We hypothesize that Ag in this alternative pathway may help initiate the secondary response, and more importantly, we propose that it serves to amplify the response and helps explain the induction of the high levels of specific antibody associated with anamnestic responses. In addition we propose that it serves to maintain and regulate serum antibody levels by initiating a new round of antibody production each time the level of specific antibody in the animal declines. Major tenants of this hypothesis are that FDCs present Ag to B cells and that germinal center B cells or TBMs present Ag to T cells. The major thrust of the proposed work is to determine if FDCs can present Ag to B cells and if germinal center B cells and TBMs can present Ag to T cells. Finally we propose to examine how Ab feedback regulation interacts in this process.
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