Disease relevance of FCGR2B

• CONCLUSION: The differential activity of FCGR2B alleles suggests a novel mechanism of FcgammaRIIb regulation that may influence the risk of autoimmune disease [1].
• This mechanism could be responsible for the decreased expression of FcgammaRIIb associated with the -343 C/C homozygous FCGR2B genotype in lupus patients [2].
• Screening of a panel of 76 B-cell lymphomas with 1q21-23 cytogenetic aberrations by Southern blot analysis using breakpoint probes identified an additional FL with a t(14;18)(q32;q21) and a breakpoint in the FCGR2B region [3].
• Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas [3].
• Platelet count, previous infection and FCGR2B genotype predict development of chronic disease in newly diagnosed idiopathic thrombocytopenia in childhood: results of a prospective study [4].

High impact information on FCGR2B

• Mast cells and basophils co-express Fc gamma RIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with Fc epsilon RI can block Fc epsilon RI-mediated reactivity [5].
• 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 [6].
• We show here that, when coaggregated to these receptors, Fc gamma RIIB inhibit Fc epsilon RI-, Fc gamma RIIA-, and TCR-dependent cell activation [7].
• The same tyrosine-based inhibitory motif (ITIM), which is highly conserved in murine and human Fc gamma RIIB and that was previously shown to inhibit BCR-dependent B cell activation, was required to regulate TCR- and FcR-dependent cell activation [7].
• The same tyrosine-based inhibition motif, in the intracytoplasmic domain of Fc gamma RIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation [7].

Chemical compound and disease context of FCGR2B

• The biotinylated peptides R(255)-P(271) and T(256)-P(271) complexed by avidin exhibited functional activity; they induced Fc gamma RIIb-mediated inhibition of the BCR-triggered Ca(2+) response of human Burkitt lymphoma cells, and inflammatory cytokine production (TNF-alpha and IL-6) by the human monocyte cell line MonoMac [8].
• K1m also expresses Fc receptors for immunoglobulin G (IgG) (CD64, CD32, and CD16) and can be shown to phagocytose polystyrene latex beads, as well as neuroblastoma cells in the presence of tumour-specific monoclonal antibody (mAb) [9].
• The functions were the following: respiratory burst; secretion of glutamate, interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha); toxicity of culture supernatants towards SH-SY5Y human neuroblastoma cells; and expression of the inflammatory surface markers HLA-DR and Fcgamma RII (CDw32) [10].

Biological context of FCGR2B

• We found a strong association between the 2B.4 haplotype of the FCGR2B promoter with increased transcriptional activity in individuals with 1:1 ratios and the more common low-expression 2B.1 haplotype in individuals with FcgammaRIIa/FcgammaRIIb2 mRNA ratios of 2:1, 3:1, or 4:1 [11].
• CD72 polymorphisms associated with alternative splicing modify susceptibility to human systemic lupus erythematosus through epistatic interaction with FCGR2B [12].
• Phosphorylation of c-Jun was accompanied by transactivation of both FCGR2B promoter variants, whereas dephosphorylation of c-Jun by an inhibitor of c-Jun N-terminal kinase, markedly decreased the promoter activities [2].
• Our case-control study in 600 Caucasians indicates a significant association of the less frequent FCGR2B promoter haplotype with the SLE phenotype (odds ratio = 1.65; p = 0.0054) [13].
• RESULTS: We detected a single-nucleotide polymorphism in FCGR2B, (c.695T>C), coding for a nonsynonymous substitution, Ile232Thr (I232T), within the transmembrane domain [14].

Anatomical context of FCGR2B

• In this study, we examined the impact of FCGR2B c.695T>C on the functional properties of FcgammaRIIB by expressing each allele product in a human B cell line ST486 lacking endogenous FcgammaRIIB [15].
• Three different classes of Fc receptors for IgG (Fc gamma R) are currently distinguished in humans, of which polymorphonuclear phagocytes (PMN) normally express both low-affinity receptor classes--Fc gamma RII (CD32) and Fc gamma RIII (CD16) [16].
• Dermal microvascular endothelial cells express CD32 receptors in vivo and in vitro [17].
• The highest percentage of CD32 expressing T lymphocytes could be detected after three days of activation [18].
• Two proteins have been identified on resting human granulocytes which function as Fc gamma receptors, Fc gamma RII (CD32) and Fc gamma RIII (CD16) [19].

Associations of FCGR2B with chemical compounds

• A promoter haplotype of the immunoreceptor tyrosine-based inhibitory motif-bearing FcgammaRIIb alters receptor expression and associates with autoimmunity. I. Regulatory FCGR2B polymorphisms and their association with systemic lupus erythematosus [13].
• In cryostat sections of normal human skin, mAb IV.3 or AT10, both recognizing CD32 (Fc gamma RII), localizes to the luminal surface of DMEC of the superficial but not of the deep vascular plexus [17].
• The expression of Fc gamma RII/CD32 on monocytes was strongly suppressed by calcitriol [20].
• Fluorescein-or rhodamine-conjugated monoclonal IgG or Fab fragments directed against FcRII (CDw32) and FcRIII (CD16) were employed to label receptors [21].
• In contrast, the 2.5-kb CDw32 transcript is strongly induced in HL-60 cells which have been induced to differentiate into granulocytes by exposure to dimethylsulfoxide [22].

Regulatory relationships of FCGR2B

• 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 [23].
• Co-clustering B cell receptors (BCR) and type II receptors binding the Fc part of IgG (Fc gamma RIIb) inhibits B cell activation and antibody production [24].

Other interactions of FCGR2B

• HUVEC do not contain Fc gamma RIIa or Fc gamma RIIb mRNA [17].
• These results suggest that FCGR2B may be deregulated by 1q21 aberration in BCL2 rearranged FLs and possibly play a role in their progression [3].
• 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 [25].
• Yin-Yang 1 competed with activating protein 1 for binding at the -343 site, and contributed to the repression of the mutant FCGR2B promoter activity [2].
• The translocation brought the Sgamma2 region of a productive IGH allele 20 approximately 30 kbp upstream of FCGR2B [3].

Analytical, diagnostic and therapeutic context of FCGR2B

• METHODS: Discovery of SNPs in FCGR2B was performed by direct cycle sequencing of complementary DNA samples derived by reverse transcriptase-polymerase chain reaction [1].
• METHODS: Variation screening of FCGR2B was performed by direct sequencing and polymerase chain reaction (PCR)-single-strand conformation polymorphism methods using complementary DNA samples [14].
• Promoter pulldown and chromatin immunoprecipitation assays demonstrated binding of c-Jun to the FCGR2B promoter [2].
• Molecular cloning of the CD32 antigen by reverse transcription and polymerase chain reaction demonstrates that activated human T lymphocytes express the Fc gamma RIIIb2 isoform [18].
• Our inference, that Fc gamma RIIb was the likely receptor, we confirmed by analyzing purified placental villi, enriched in endothelium, by immunoblotting with a new Ab specific for the cytoplasmic tail of Fc gamma RIIb [26].

References