Our work focuses on one of the most basic questions in immunology--what happens to the immunogen during the induction of a secondary response? In immune animals Ag encounters Ab and is almost instantaneously converted into Ab-Ab complexes. These complexes are quickly trapped, endocytosed, and catabolized by macrophages. This process occurs quickly and by 48 hours after immunization very little Ag persists in or on these macrophages. However, some immune complexes enter an """"""""alternative"""""""" follicular dendritic cell (FDC) dependent pathway which serves to utilize Ag efficiently and preserves some Ag for months and perhaps years. For several days after secondary challenge, the dendritic processes of FDC form and release immune complex coated bodies or """"""""iccosomes"""""""" which are endocytosed by germinal center B cells. Major tenets of the basic hypothesis are FDC present Ag to specific follicular B cells and that follicular B cells endocytose the iccosomes then process and present Ag to follicular T cells. The T cells provide factors needed for formation of the germinal center, production of Ab, and B memory cells. Although FDC release iccosomal Ag for a few days after challenge, most Ag persists on the FDC and functions in conjunction with an Ab feedback system to maintain immune responses. The feedback system determines when and how much is released from the FDC for processing. In this application we propose to study both the induction maintenance of anamnestic responses in mice lacking FDC. If our hypotheses are correct, anamnestic responses should be grossly aberrant. Iccosomal Ag appears to be highly immunogenic. We propose to establish the relative immunogenicity of iccosomal Ag, Ag-Ab complexes and free Ag and determine the role of the sIg B cell receptor in the uptake of iccosomes. Finally, we propose to study regulation of the germinal center reaction by T cells. The immunological significance of FDC and iccosomes is only beginning to be understood. Clearly more information is needed but only a few groups around the world are focusing on FDC and their products.
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