Regulation of production of soluble Fc gamma receptors type III in normal and pathological conditions

CD16 (Fc gamma R type III), a low affinity IgG Fc receptor, is found in two forms, a transmembrane Fc gamma RIIIa expressed by NK cells and monocytes and a phosphatidylinositol-linked Fc gamma RIIIb present on neutrophils. Ex posure of neutrophils to inflammatory signals induces a rapid loss of CD16 expression and release of a soluble form of CD16 (sCD16). Soluble CD16 circ ulates in plasma, levels being reduced in sera from patients with multiple myeloma. In the present manuscript the authors summarize work that aimed to better understand: (i) the role of proteinases in sCD16 production and CD1 6 membrane shedding; and (ii) the regulation of sCD16 levels in multiple my eloma patients and the possible biological consequences of its decrease in this disease. Soluble CD16 was purified from human serum. Its N-terminal se quencing demonstrated that it originates from neutrophil CD16 and its C-ter minal sequencing showed that the cleavage site was between Val 196 and Ser 197, close to the membrane anchor. Analysis of the effect of protease inhib itors revealed that the cleavage leading to sCD16 production by PMA-activat ed neutrophils was metalloproteinase-dependent. In addition, membrane and s CD16 were sensitive to serine proteinases released by azurophil granules or added under purified form. The reduction of sCD16 levels that occurs in pa tients with multiple myeloma was associated with a slight decrease in circu lating neutrophils, but not with a significant defect in sCD16 production b y neutrophils, as detected in vitro. Moreover, addition of a recombinant sC D16 to plasmocytoma lines did not significantly modify their proliferation and Ig secretion. (C) 1999 Elsevier Science B.V. All rights reserved.