We have continued our studies on the mechanisms of activation, proliferation, and differentiation of human lymphocytes, particulary B cells, at the cellular and molecular levels. By examinimg intracellular, second messenger events following triggering of B cells with anti-mu, Staphylococcus aureus Cowan I (SAC), or a B cell activating factor (BCAF), we have demonstrated divergent pathways of activation associated with expression of different cellular function. We have extended our studies on the B cell specific growth factors (BCGF): high molecular weight (HMW) and low molecular weight BCGFs. We have demonstrated that these factors expand different functional subset of B cells. In addition, we have shown that B cells from patients with diseases such as common variable hypogammablogulinemia (CVH) or a variety of B cell leukemias express receptors to these factors to variable levels and are responsive to the factors in a manner discordant with the expression of receptors for the factors. We have delineated the intracellular signals involllved in B cell proliferation to our BCGFs and have demonstrated that the receptor for HMW-BCGF is phosphorylated upon binding of factor to its cellular binding site. Attempts at cloning the genes for the HMV- BCGF and receptor continue. In parallel, we have continued studies on BCGFs that are potent inducers of B cell function, but which are not entirely B cell specific. We have demonstrated that transforming growth factor Beta (TGF-beta) is an inhibitory autocrine lymphokine that may play a role in physiologic downregulaltion of B cell function. In addition, we have characterized the TGF-beta receptor on human B cell. We have demonstrated that lymphotoxin and tumor necrosis factor alpha (TNF- alpha) are important B cell regulatory factors and have show the upregulation of TNF-alpha receptors following B cell activation. Additional studies suggest that the TNF-alpha receptor on human B cell is a multichain complex. We have recently initiated studies aimed at analyzing B cell specific gene products. A cDNA library has been constructed from activated B cell mRNA and screened with B minus T cell mRNA probes.
