Disease relevance of FCGR3B

• In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus [1].
• Sera from patients with progressive systemic sclerosis showed both IgG and IgM Fc gamma RII and Fc gamma RIII reactivity [2].
• Many patients diagnosed with degenerative osteoarthritis also had IgG autoantibodies, directed primarily against Fc gamma RII with lesser reactivity toward Fc gamma RIII [2].
• Only in Fc gamma RIII-deficient PMN from paroxysmal nocturnal hemoglobinuria patients could a decreased H2O2 production be demonstrated to be Fc gamma RII dependent [3].
• The modulation of soluble CD16 titers in human immunodeficiency virus (HIV)-infected patients' serum, with an initial increase in Centers for Disease Control (CDC) clinical stage II and III patients followed by a dramatic drop in patients with AIDS (CDC clinical stage IV), is reported [4].

Psychiatry related information on FCGR3B

• RESULTS: Both patients with panic disorder and patients with social phobia had increased CD16 (natural killer) cell numbers [5].
• Response times were significantly faster for Fc gamma RII than for Fc gamma RIII [6].

High impact information on FCGR3B

• Mac bound to CD16 (FcgammaRIIIB) on the surface of human polymorphonuclear leukocytes and inhibited opsonophagocytosis and production of reactive oxygen species, which resulted in significantly decreased pathogen killing [7].
• Efficient internalization and antigen presentation via Fc gamma RIII did not require the cytoplasmic domain of the ligand-binding alpha-chain, but did require the gamma-subunit [8].
• The structural relatedness of zeta and gamma is emphasized by the recent demonstration of zeta zeta in association with CD16 in TCR-negative natural killer cells [9].
• Analysis of FcRIII expression in cells of PNH patients, known to be deficient in PI-linked proteins, suggests FcRIII is not PI-linked in monocytes [10].
• Neutrophils carry Fc receptor II (FcRII; CDw32) and FcRIII (CD16) which both bind IgG-containing immune complexes, leading to phagocytosis of the complex and activation of the neutrophil [10].

Chemical compound and disease context of FCGR3B

• Neutrophil FcRIII is a glycosyl-phosphatidylinositol anchored membrane GP as is decay accelerating factor and both are absent from neutrophils of patients with paroxysmal nocturnal hemoglobinuria (PNH) [11].
• In this study, we produced in vitro infectious recombinant AAV virions containing the neomycin resistance (NeoR) and the human CD-16 (FC gamma RIIIa) gene [12].
• The production of interleukin-6 (IL-6) by CD16+ and CD16- monocytes stimulated with LPS from Escherichia coli and Actinobacillus actinomycetemcomitans was also examined using flow cytometry [13].
• The effect of H/R plus FMLP on CD32 and CD16 expression was blocked by pertussis toxin, whereas staurosporine, H-7, H-9, and genistein had no effect [14].
• Modulation of human leukocyte antigen-DR on monocytes and CD16 on granulocytes in patients with septic shock using hemoperfusion with polymyxin B-immobilized fiber [15].

Biological context of FCGR3B

• At least one URI was noted in 52% of subjects (99/191) with the NA2/NA2 genotype of the neutrophil-specific FCGR3B gene, compared to 42% (77/181) of those with the NA1/NA2 genotype and 39% (23/59) of those with the NA1/NA1 genotype (P = 0.038) [16].
• We characterized two FCGR3B cDNAs of different lengths corresponding to two polyadenylation sites [17].
• This study investigated the FCGR3B gene frequencies and FCGR3 variants in a Chinese population compared with the results of Northern Germans and African Blacks (Uganda) [18].
• Common polymorphisms have been described in three low-affinity receptors: FCGR2A, FCGR3A, and FCGR3B; each has been shown to alter biological function, and each has also been associated with disease susceptibility [19].
• The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis [20].

Anatomical context of FCGR3B

• The FCGR3B chain bears allotypes that define the human neutrophil antigen-1 (HNA-1 and NA) system involved in major post-transfusional reactions [17].
• FCGR3B is highly homologous to FCGR3A, which is expressed as a transmembrane receptor on natural killer cells and monocytes/macrophages [17].
• In the present work, we sequenced FCGR3B cDNAs with complete 3' untranslated region from purified granulocytes of HNA-1b/HNA-1b (NA2/NA2) genotyped donors [17].
• Here, we report that Fc gamma RIII stimulation induces activation of phosphatidylinositol (PI)-3 kinase in NK cells [21].
• To determine the functional role of the two isoforms of Fc gamma RIII (CD16) (IIIA, IIIB), the signal transduction capabilities of wild-type and mutant forms of these receptors were analyzed in transfected lymphoid, myeloid, and fibroblastic cell lines [22].

Associations of FCGR3B with chemical compounds

• The transmembrane receptor for immunoglobulin G immune complexes on natural killer (NK) cells and macrophages, Fc gamma RIIIA (CD16), mediates cellular activation through a tyrosine kinase-dependent pathway [23].
• Phosphotyrosine immunoprecipitates from Fc gamma RIII-stimulated NK cells contain PI-kinase activity and PI-3 kinase can be directly precipitated from them [21].
• However, CD16 mAb, directed against different epitopes of Fc gamma RIII, precipitated a glycoprotein from plasma of homozygous Fc gamma RIIIB gene-deficient donors [24].
• Large granular lymphocyte/NK cells (LGL/NK cells) express the transmembrane form of Fc gamma RIII (Fc gamma RIIIa) on their surface, whereas polymorphonuclear neutrophils (PMN) express the glycosyl phosphatidyl inositol-linked receptor that is the product of the Fc gamma RIIIB gene [25].
• Human neutrophil Fc gamma RIIIB and formyl peptide receptors are functionally linked during formyl-methionyl-leucyl-phenylalanine-induced chemotaxis [26].

Physical interactions of FCGR3B

• We observed that binding of the Fab parts of 3G8 mAb to two Fc gamma RIIIb molecules and binding of the Fc part to one Fc gamma RIIa molecule is required, because a bispecific antibody, 2B1, in which only one 3G8 Fab is present, did not induce neutrophil activation [27].
• Granulocyte activation via a binding site near the C-terminal region of complement receptor type 3 alpha-chain (CD11b) potentially involved in intramembrane complex formation with glycosylphosphatidylinositol-anchored Fc gamma RIIIB (CD16) molecules [28].

Regulatory relationships of FCGR3B

• 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 [29].
• Because IFN-gamma and chemotactic factors induce eosinophil CD16 expression in vitro, we postulated that blood eosinophils could express CD16 [30].
• Generation of endogenous oxidants in PMN by cross-linking Fc gamma RIIIb similarly enhanced phosphorylation of Fc gamma RIIa and Syk, a tyrosine kinase required for phagocytic function, in a catalase-sensitive manner [31].
• GM-CSF antagonized TGF-beta-induced expression of Fc gamma RIII on monocytes in vitro in a dose-dependent way [32].
• These results indicate that during priming Fc gamma RIIIb becomes functionally activated and thence its ligation leads to stimulated Ca2+ influx and the generation of intracellular signals that lead to NADPH oxidase activation [33].

Other interactions of FCGR3B

• In addition, the same groups of patients and controls were genotyped for the previously known polymorphisms of FCGR2A, FCGR3A, and FCGR3B [34].
• Most of the mAbs recognize both the receptor isoforms, transmembranous Fc gamma RIIIA, and glycosylphosphatidylinositol-linked Fc gamma RIIIB [35].
• Binding epitopes of some of the mAbs that differentiate between the two neutrophil Ag (NA) alleles of Fc gamma RIIIB (CLB-Gran11 against NA1; GRM1, BL-LGL/1 against NA2 allele) have been mapped on the first, membrane-distal domain of CD16 [35].
• Analysis of Fcgamma receptor haplotypes in rheumatoid arthritis: FCGR3A remains a major susceptibility gene at this locus, with an additional contribution from FCGR3B [20].
• Moreover, the expression of HLA-DR molecules by SF macrophages was increased, and the expression of CD16 was decreased by anti-IL-10 MAbs [36].

Analytical, diagnostic and therapeutic context of FCGR3B

• By two-color flow cytometry, we showed that 6.5+/-0.3% of nonpurified eosinophils expressed surface CD16 [37].
• Ligation of the Fc binding site of Fc gamma RIIIB appears to be essential for altering the FMLP-induced response, since soluble aggregated IgG and other anti-Fc gamma RIII antibodies, all of which recognize the ligand binding site, mimic the inhibitory effect of the 3G8 Fab on FMLP-induced chemotaxis [26].
• Western blot analysis performed with 3G8 or DJ130c mAb showed a broad band at approximately 65 to 80 kDa, which was the same as neutrophil CD16 from the same NA2/NA2 donors [37].
• We observed that pretreatment of normal human neutrophils with Fab fragments of a mAb to the Fc gamma RIII (3G8) specifically inhibited their chemotaxis into micropore filters in response to the formylated peptides FMLP or formyl-norleucyl-leucyl-phenylalanine [26].
• Abnormal neutrophil phenotype and neutrophil FcRIII deficiency corrected by bone marrow transplantation [38].

References