Two polymorphic forms of Fc receptor III (FcR III) are expressed on human neutrophils. These differ with respect to their apparent molecular masses after digestion with N-glycanase, and with respect to their reactivity with MAb Gran 11 and alloantisera which recognize determinants (NA1 and NA2) of the biallelic neutrophil antigen (NA) system. To determine the molecular basis for this polymorphism we isolated RNA from neutrophils of NAlNAl and NA2NA2 homozygotes and synthesized corresponding cDNAs. cDNAs encoding FcR III were then amplified using the polymerase chain reaction, cloned, and sequenced. The cDNA that encodes FcR III on NAlNAl neutrophils differed from the cDNA that encodes FcR III on NA2NA2 neutrophils at five nucleotides, predicting four amino acid substitutions. As a result, NA1 FcR III has only four potential N-linked glycosylation sites as compared with six in NA2 FcR III. The amino acid substitutions and differences in the number of potential N-linked glycosylation sites probably account for the different forms of neutrophil FcR III observed after digestion with N-glycanase and for the antigenic heterogeneity of this receptor.

Clearance of immune complexes by the mononuclear phagocyte system is important for maintaining normal host defenses against bacterial and viral assault (1), but also contributes to the pathogenesis of a variety of immune-mediated diseases . For example, removal from the circulation of IgG-coated erythrocytes and platelets by the MPS is the sine qua non of immune-mediated cytopenias (2, 3). On the other hand, abnormally decreased removal by the MPS of smaller, soluble immune complexes may play a role in the pathogenesis of immune complex-mediated tissue damage found in such autoimmune diseases as SLE (4).Although the physicochemical nature and the size of immune complexes can influence rates of clearance and sites of deposition (reviewed in 5), interactions between immune complexes and the MPS in vivo are poorly understood . The inability to directly measure binding or internalization of immune complexes by cells in the liver and spleen has made the analysis of the molecular basis of immune complex clearance very difficult . Receptors for the Fc portion of IgG (FcyR) and for complement (CR) undoubtedly play a role in the removal of immune complexes, but the relative importance of these receptors is not known.There are three types of FcyRs on human leukocytes . A 72 kD receptor with high affinity for monomeric IgG is found on monocytes (6) and some resident macrophages (7). Two receptors exist with low affinity for monomeric IgG, one with broad electrophoretic mobility (51-73 kD) on neutrophils (8), natural killer cells (9), and macrophages (8); the other recently described (40 kD) on platelets (10), monocytes (10), and several tumor cell lines (11). All three bind immunoglobulin that is aggregated or complexed to antigen . The 51-73 kD receptor is recognized by mAb 3G8, which blocks ligand binding and has been very useful in the partial biochemical characterization of this receptor (8).In vitro analysis of the role played by FcyRs in individuals with abnormally prolonged clearance of opsonized red cells (model particulate immune complexes) generally has been limited to studies of high-affinity FcyRs on monocytes.

We characterized Fc receptor III (FcR III) on human neutrophils and found it to be heavily glycosylated and polymorphic. In some individuals, FcR III that had been digested with Nglycanase appeared after SDS-PAGE under

We previously isolated cDNA clones from a human monocyte library that encoded one member of a family of low‐affinity surface receptors for the Fc domain of IgG (hFcRII‐A). To investigate possible structural and functional heterogeneity among these receptors, we have now isolated two additional cDNAs (hFcRII‐B and hFcRII‐C) from a human placental library, placenta being a good source of FcR‐bearing macrophages and epithelial cells. Three cDNAs encoded related but distinct transmembrane glycoproteins containing two immunoglobulin‐like domains; however, transfected cells produced receptors that were indistinguishable on the basis of ligand binding or reactivity with anti‐hFcRII monoclonal antibodies. The sequences of hFcRII‐A and ‐B were most closely related and were identical except for several amino acid substitutions and one small internal deletion. While the ectodomain of hFcRII‐C was identical to hFcRII‐B, its cytoplasmic tail was unrelated but highly homologous to the corresponding domain of the receptor isoform (mFcRII‐B2) found in murine macrophages. Thus, human FcRII may be derived from at least two alternatively spliced genes. Northern blots revealed little difference in the pattern of expression of hFcRII isoforms among various myeloid and lymphoid cells or cell lines. However, the blots‐‐as well as in situ hybridization and immunohistochemistry‐‐demonstrated that hFcRII‐C (along with a second monocyte marker, the c‐fms encoded CSF‐1 receptor) was expressed in placental syncytiotrophoblasts. Since syncytiotrophoblasts comprise the IgG‐transporting epithelium of the placental villus, these findings suggest that FcR found in the immune system and in certain epithelia may be structurally or functionally related.

In the course of examining the structure