Studies on positive and negative regulatory events in the activation of lymphocytes by the Fc portion of immunoglobulin will be extended by approaches which will investigate the cellular and subcellular mechanisms by which Fc fragments, their subfragments, and related synthetic peptides modulate lymphocytes and regulate immune responses. A B cell growth factor (BCAF) released from Fc fragment activated T cells, will be isolated and purified. The contrasting roles that BCAF and metabolites of arachidonic acid play in the cellular and subcellular events initiated by these Fc fragments will be firmly established and precisely defined. BCAF purified from EL-4 cells and spleen cells will be compared and its mode of action determined for both the polyclonal antibody response and adjuvant properties of the Fc fragment and its related peptides. Since preliminary data have demonstrated that Fc fragments and their subfragments produce prostaglandins which are involved in the down regulation of their activities, a comprehensive study will be conducted to determine the overall influence of arachidonic acid metabolites on Fc fragment-mediated regulation of immune responses. In addition, the pathway by which rheumatoid factor modulates immunoreactivity and its possible role in regulation of immune responses will be investigated at both cellular and subcellular levels. The proposed studies will determine whether the pathway involved in modulation of immune responses by RF complexes and monoclonal RF are similar to the pathways involved in regulation of immune responses by Fc fragments and immune complexes. In order to investigate the mechanisms of Fc fragment-mediated immune modulation, studies will be designed to determine the target cells and the cellular binding properties of Fc fragments, subfragments and their related peptides. In addition, the subcellular events involved in Fc-mediated T and B cell activation will be investigated by analyzing changes in membrane protein associations induced in target cells by Fc activation. Other studies will be carried out to establish the minimal size of Fc-derived peptide that is capable of inducing Fc fragmente-mediated immunoreactivity and to differentiate between peptides responsible for B cell proliferation and B cell differentiation.
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