Disease relevance of FCGR3A

• With rituximab, FCGR3A and FCGR2A high-affinity polymorphisms have been associated with clinical response in lymphoma but not in CLL, suggesting potential divergent mechanisms of action between these 2 diseases [1].
• FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia [1].
• There was no LD between CRP and FCGR3A in healthy donors or Crohn's disease patients [2].
• Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis [3].
• Functional reconstitution studies with a mastocytoma cell line indicate that Fc gamma RIIIA composed of alpha, beta, and gamma subunits has the capacity for signal transduction [4].

Psychiatry related information on FCGR3A

• Means (SD) for CD14/CD16 in HIV-negative controls and in AIDS non-dementia and AIDS dementia patients were 6.5% (4), 16% (13), and 37% (21), respectively (p = 0.008 between the two groups of patients) [5].
• Eight clinical scales (hypochondriasis, depression, hysteria, psychopathic deviate, paranoia, psychasthenia, schizophrenia, and hypomania) as well as cortisol level, CD3, CD4, CD8, and CD16 markers by group were compared [6].

High impact information on FCGR3A

• The results indicate that the FcRIII receptor on human macrophages and possibly another Fc receptor on human CD4+ lymphocytes mediate antibody-dependent enhancement of HIV infectivity and that this phenomenon proceeds through a mechanism independent of the CD4 protein [7].
• We found that receptor complexes containing a conserved tyrosine activation motif (ITAM), as found in the cytoplasmic domain of Fc gamma RIIA and in the gamma chain associated with Fc gamma RIA and Fc gamma RIIIA, readily internalized target particles [8].
• These studies define the elements conferring the cell type-specific expression of the human Fc gamma RIII genes within the 5' flanking sequences and first intron of the human Fc gamma RIIIA and Fc gamma RIIIB genes [9].
• Greater than 75% of inflammatory SFs tested (a total of 22 fluids to date) increased cell surface expression and dramatically increased mRNA levels of monocyte activation markers Fc gamma RI, Fc gamma RIII, and HLA-DRA [10].
• Induced activation of protein tyrosine kinase(s) is a central event in signal transduction mediated via the low affinity receptor for IgG (Fc gamma RIIIA, CD16) in natural killer (NK) cells [11].

Chemical compound and disease context of FCGR3A

• FCGR3A (V/F) polymorphism and three CRP polymorphisms (-717G/A, 1444C/T, CRP 4A/G) were determined in 206 healthy blood donors and 189 Crohn's disease patients who had received infliximab for either refractory luminal or fistulizing Crohn's disease [2].
• In follicular lymphoma (FL), genomic polymorphisms corresponding to the expression of valine (V) or phenylalanine (F) at amino acid 158 of Fc gamma RIIIa alter the binding affinity of immunoglobulin G1 (IgG1) to the receptor and have been associated with varied responses to rituximab [12].
• O2- formation occurred in neutrophils incubated with Staphylococcus aureus cell walls bearing antibodies to Fc gamma RII or Fc gamma RIII [13].
• 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 [14].

Biological context of FCGR3A

• When the present results were combined with our previous data on the Japanese and the Thais using meta-analytic methods, highly significant and independent association was observed for FCGR2B and FCGR3A genotypes [15].
• 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 [16].
• 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 [17].
• The haplotype showing the strongest association with GCA susceptibility was the FCGR2A-FCGR3A 131R-158F haplotype (OR 2.84, P = 0.01 for homozygotes compared with all others) [3].
• Stimulation of Fc gamma RIIIA results in phospholipase C-gamma 1 tyrosine phosphorylation and p56lck activation [18].

Anatomical context of FCGR3A

• Urinary tract infection (UTI) was associated with the TNF -238 A (odds ratio(OR) 2.56, 95% confidence interval (CI) 1.05-6.25) and LTA +365 C (OR 1.73, 95% CI 1.07-2.79) alleles, and marginally with the FCGR3A F allele (OR 1.72, 95% CI 0.99-3.00) [19].
• FCGR3B is highly homologous to FCGR3A, which is expressed as a transmembrane receptor on natural killer cells and monocytes/macrophages [20].
• Physical and functional association of p56lck with Fc gamma RIIIA (CD16) in natural killer cells [21].
• Our studies show that the zeta chain, the signal transducing subunit of Fc gamma RIIIA and of T cell receptor, associates with p56lck and, in NK cells, is a substrate for this kinase [21].
• Here we show that in mast cells, in addition to the dimeric gamma chains, the beta subunit is associated not only with Fc epsilon RI, but also with Fc gamma RIIIA [4].

Associations of FCGR3A with chemical compounds

• Accumulation of phosphoinositide D3 phosphorylated products in stimulated cells confirms PI-3 kinase activation, indicating the participation of this enzyme in Fc gamma RIIIA-mediated signal transduction [11].
• Sequence analysis of the Fc gamma RIIIA gene, encoding CD16 on NK cells and macrophages, showed a T to A nucleotide substitution at position 230 on both alleles, predicting a leucine (L) to histidine (H) amino acid change position 48 in the first extracellular lg-like domain of Fc gamma RIIIa, which contains the Leu11c/B73.1 epitope [22].
• This glycoprotein migrated in a similar way as did released Fc gamma RIIIa derived from NK cells, whereas Fc gamma RIIIa released by cultured monocytes migrated differently and appeared to be more heavily glycosylated on SDS-PAGE [23].
• Identity of this co-associated structure of Fc gamma RIIIa as the gamma-chain dimer was confirmed by elution of the protein from the anti-Fc gamma RIII immunoabsorbent with 1% Nonidet P-40 detergent and reimmunoprecipitation with anti-gamma-chain antibody [24].
• Cytokine release from 17 beta-estradiol-treated or untreated monocytes was then quantitated by enzyme-linked immunosorbent assay and FACS after crosslinking the receptor with anti-CD16 antibodies [25].
• These results suggest that individuals expressing at least one valine at FcgammaRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated ADCC [26].

Physical interactions of FCGR3A

• Three types of FcR react with IgG: Fc gamma RI is a high-affinity receptor binding IgG monomers whereas Fc gamma RII and Fc gamma RIII are low-affinity receptors binding IgG immune complexes; the three types of Fc gamma R are members of the Ig superfamily [27].
• A consistent proportion of CD16 marker-positive LGL bound VIP-coated spheres (24%, and approximately 15% of B cells also showed this ability [28].

Enzymatic interactions of FCGR3A

• We found that both Syk and ZAP-70 become ubiquitinated in response to aggregation of the low affinity Fc receptor for IgG (CD16) on human natural killer cells [29].

Regulatory relationships of FCGR3A

• 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 [30].
• Recent studies in gene knockout mice have demonstrated that the negative signaling by CD32B plays a critical role in preventing immune complex (IC)-mediated autoimmune diseases by regulating the activation signal delivered by CD16A [31].
• Under these conditions, accumulation and transcription of both IFN-gamma and TNF mRNA induced by CD16 ligands, but not that induced by rIL-2, is completely abolished and neither cytokine can be detected at significant levels in the supernatant fluids of cells so treated [32].
• In this study TGF-beta is shown to induce expression of the gp50-65 receptor for Fc gamma RIII on otherwise negative peripheral blood monocytes [33].
• The ability of CD45 mAbs to stimulate NK cells appears not to be dependent on CD16, as CD45 mAbs of both IgG1 and IgG2a isotypes were equally stimulatory, as were F(ab')2 compared with whole anti-CD45 mAbs [34].

Other interactions of FCGR3A

• Response to alemtuzumab was similar regardless of FCGR3A polymorphism (V/V, 25%; V/F, 40%; F/F, 32%) or FCGR2A polymorphism (A/A, 40%; H/A, 32%; H/H, 33%) [1].
• CD38 ligation by agonistic monoclonal antibodies induced signals leading to activation of the lytic machinery of natural killer (NK) cells from adults; similar signals could not be reproduced in YT and NKL, 2 CD16(-) human NK-like lines [35].
• Production of TNF-alpha by human V gamma 9V delta 2 T cells via engagement of Fc gamma RIIIA, the low affinity type 3 receptor for the Fc portion of IgG, expressed upon TCR activation by nonpeptidic antigen [36].
• Fc gamma receptor type IIIA (CD16a) is a receptor expressed on macrophages that selectively binds IgG molecules, an important rheumatoid factor in RA [25].
• Binding of mIgG or 3G8 to Fc gamma RIIIA induced divergent effects of functions of cultured NK cells: 3G8 mAb + IL-2 induced dose-dependent inhibition of proliferation attributable to apoptosis; in contrast, mIgG + IL-2 significantly increased NK cell proliferation [37].

Analytical, diagnostic and therapeutic context of FCGR3A

• Polymorphic alleles of FCGR2A and FCGR3A were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients [38].
• Our findings demonstrate both functional and physical association of p56lck with Fc gamma RIIIA, through direct interaction of the kinase with the zeta and/or the gamma signal transducer subunits of the receptor [21].
• The 7.5.4 MAb binds both Fc gamma RIIIa and Fc gamma RIIIb, can be used in Western blotting and does not inhibit aggregated IgG binding [39].
• In terms of overall or event-free survival, no difference was found according to FCGR3A or FCGR2A alleles [40].
• CD16, a low affinity receptor for IgG, was found on cultured human glomerular mesangial cells (GMC) by Western blot analysis, cell ELISA and in situ hybridization [41].

References