BIOCHEMICAL AND MOLECULAR EVENTS OF B CELL ACTIVATION BY POLYSACCHARIDES

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Immune responses to polysaccharides such as those found in bacterial capsules or some bacterial vaccines involve T cell independent antibody responses by B cells activated by Ig receptor cross-linking. Mice of the xid mutant strain are unresponsive to polysaccharide antigens and can serve as a model where activation of B cells by T independent (TI-2) antigens is deficient. They can be used to delineate factors required for immune responses to polysaccharides. These mice are reported to have a mutation in a B cell associated tyrosine kinase gene, btk, causing an arrest in TI-2 but not T dependent (TD) or TI-1 activation. Other effects of xid include low serum IgG3 levels, a missing subset of B cells, the Lyb-5+ B cells, and lower numbers of B cells. To investigate the effect of the xid mutation in B cell activation, events in xid and non-xid B cells activated in vitro by Ig crosslinking are being compared. TI-2 activation sets off a series of events in B cells, which proceed in a temporal order over a time course of up to 5 days. These events range from signaling events related to progression from G0 to G1 phase to DNA synthesis and other events associated with progression into S/G2 and M phase. Earlier studies performed in other labs have revealed that the immediate signaling events such as PI turn over and tyrosine phosphorylation are intact in xid B cells. Our extensive analysis has shown that other signaling events in xid B cells such as proto-oncogene and nuclear factor induction are intact, with late events more related to entry to cell cycle such as housekeeping gene up-regulation are diminished relative to non-xid. In addition, we find that sustained viability in culture of xid B cells is diminished relative to non-xid and is not effected by TI-2 activation. Further studies examining S/G2 entry in xid B cells will be pursued including examination of cyclin and cyclin dependent kinase activity in xid B cells. A clear understanding of the events associated with TI-2 activation is required to optimize immune responses to polysaccharide vaccines. This is especially important for vaccination of very young and elderly populations which respond poorly to polysaccharides.