Signals involved in germinal center reactions.

Many of the features observed in the in vitro cultures discussed in this review coincide with characteristics described for an in vivo germinal center response. FDC and T cells are required to maintain B-cell proliferation which is confined to a finite amount of time (i.e. less than 2 wk). Large cellular aggregated form which contain many blasting cells undergoing DNA synthesis. In addition to proliferation, apoptosis is also occurring in the cultures but appears to be limited to the population which is not in contact with the FDC. The system can be driven by specific antigen, suggesting that clonal expansion is occurring. As in other immunological systems, there is an important role for adhesion molecules both for cluster formation and DNA synthesis. Antigen processing and presentation is a major event since blocking this through several mechanisms ends the stimulation. The role of T cells is essential both in vivo and in vitro; however, their exact contribution is still not well understood. It is interesting that blocking IL4 usage either by neutralizing the molecule or its receptor by monoclonal antibodies has no effect on the system. Which interleukins are important for germinal centers remains on open question. Evidence continues to accumulate on the important role of FDC and the molecules they express. Not only are the immune complexes an essential part, but it seems that molecules yet to be defined have an effect. For many practical reasons these have remained a mystery, but using our various systems we are attempting to reveal them. Two intriguing questions which remain include: 1. the molecular nature of the signalling between the FDC and B cell; and 2. how does the FDC retain the antigen in a native form for such long periods of time? An understanding of both mechanisms will provide us with a better appreciation for the events leading to a germinal center response and the immunological phenomenon referred to as memory.