Disease relevance of Fcgr2b

• Genetic modifiers of systemic lupus erythematosus in FcgammaRIIB(-/-) mice [1].
• FcgammaRIIB is a potent lupus susceptibility gene as demonstrated by the observation that mice deficient in this molecule develop spontaneous antinuclear antibodies (ANA) and fatal glomerulonephritis when on the C57BL/6 background [1].
• Thus, following Jo2 treatment, all FcgammaRIIB(-/-) mice survived while 80% of wild-type and all FcR-gamma(-/-) mice died from acute liver failure [2].
• FcgammaRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease [3].
• Fc gamma RIIB-deficient B6.Fas(lpr/lpr) (B6.IIB(-/-)Fas(lpr/lpr)) mice developed systemic autoimmune diseases, including anti-DNA and anti-type II collagen autoantibodies and cryoglobulin production, immune complex glomerulonephritis and arthritis [3].

Psychiatry related information on Fcgr2b

• CTC cells originating from tumors which appeared after a long latency period (late tumors) tended to express Fc gamma RII while CTC cells originating from tumors which appeared after a short latency period (early tumors) as well as the corresponding C cells tended not to express Fc gamma RII [4].
• Furthermore, by using knockout mice, we have shown that inhibition of the Id-specific memory B cells by the Id protein is largely independent of the FcgammaRIIB and, hence, independent of immune complexes [5].

High impact information on Fcgr2b

• A population of early fetal thymocytes expressing Fc gamma RII/III contains precursors of T lymphocytes and natural killer cells [6].
• Our results show that this chimeric protein is able to form complexes with both Fc epsilon RI and Fc gamma RII, and inhibit mast-cell and basophil function [7].
• Mouse monoclonal antibodies, as well as the humanized, clinically effective therapeutic agents trastuzumab (Herceptin(R)) and rituximab (Rituxan(R)), engaged both activation (FcgammaRIII) and inhibitory (FcgammaRIIB) antibody receptors on myeloid cells, thus modulating their cytotoxic potential [8].
• These results demonstrate that Fc-receptor-dependent mechanisms contribute substantially to the action of cytotoxic antibodies against tumors and indicate that an optimal antibody against tumors would bind preferentially to activation Fc receptors and minimally to the inhibitory partner FcgammaRIIB [8].
• Crosslinking Fc gamma RIIB with the surface immunoglobulin complex confers a dominant signal that prevents or aborts lymphocyte activation triggered through the ARH-1 motifs of the signal transduction subunits Ig-alpha and Ig-beta [9].

Chemical compound and disease context of Fcgr2b

• Lym-1-gelonin was very active in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium salt and sulforhodamine B in vitro cytotoxicity assays against the Raji lymphoma cell line and confirmed the fact that monoclonal antibody Lym-1 internalizes into human lymphoma cells [10].
• A type I ribosome inactivating protein, gelonin, was linked to Lym-1, a murine monoclonal antibody reactive with a polymorphic determinant of class II HLA-DR histocompatibility leukocyte antigen (HLA) on human lymphoma cells, via a disulfide linkage using the heterobifunctional cross-linking agent, N-succinimidyl-3-(2-pyridyldithio) propionate [10].
• Lipopolysaccharide-activated murine B splenocytes and B lymphoma cells transfected with intact or truncated Fc gamma RII-cDNA were used to determine the domains of Fc gamma RII implicated in the inhibition of the Ca2+ signal [11].
• PURPOSE: Lym-1, a monoclonal antibody that preferentially targets malignant lymphocytes, has induced remissions in patients with non-Hodgkin's lymphoma (NHL) when labeled with iodine 131 ((131)I) [12].
• RESULTS: Nine anti-mouse Fc gamma RII sFv molecules were isolated from two human phage display libraries (Marks et al., J Mol Biol 1991;222:581-597; Sheets et al., Proc Natl Acad Sci USA, in press) [13].

Biological context of Fcgr2b

• In addition, we identified an NZB-derived locus on chromosome 1 predisposing to the development of monocytosis, which peaked at Fcgr2b encoding FcgammaRIIB and directly overlapped with the previously identified NZB autoimmunity 2 (Nba2) locus [14].
• Transcriptional regulation of Fcgr2b gene by polymorphic promoter region and its contribution to humoral immune responses [15].
• Interestingly, FcgammaRIIB(-/-) chimeras showed a differential phenotype with impaired splenic but normal bone marrow responses [16].
• Addition to the cultures of 2.4G2, a rat monoclonal antibody (mAb) that reacts with Fc gammaRII (CD32) and Fc gammaRIII (CD16), induced granulocyte apoptosis within 24 hours [17].
• Furthermore co-clustering FcgammaRIIb with FcgammaRIIa resulted in enhanced phosphorylation of the inositol phosphatase SHIP, association of SHIP with Shc, and phosphorylation of additional proteins around 120 and 60-65 kDa, with a concomitant attenuation of Akt activation [18].

Anatomical context of Fcgr2b

• In this study, we established congenic C57BL/6 mice for NZB-type Fcgr2b allele and found that NZB-type allele down-regulates FcgammaRIIB1 expression levels in germinal center B cells and up-regulates IgG Ab responses [15].
• Finally, we observed a very low-level expression of FcgammaRIIB on macrophages bearing the NZB-type Fcgr2b allele, compared with those bearing the B6-type allele, and the development of monocytosis in FcgammaRIIB haploinsufficient B6 mice carrying the Yaa mutation [14].
• In contrast, inhibitory FcgammaRIIB deficiency significantly increased CD20 mAb-induced B cell depletion by enhancing monocyte function [19].
• B lymphocyte memory: role of stromal cell complement and FcgammaRIIB receptors [16].
• Fc gammaRII (CD32) is linked to apoptotic pathways in murine granulocyte precursors and mature eosinophils [17].

Associations of Fcgr2b with chemical compounds

• In addition to facilitating the recruitment of SHIPs, the second tyrosine-based motif may confer upon FcgammaRIIB the properties of scaffold proteins capable of altering the composition and stability of the signaling complexes generated following receptor engagement [20].
• When coaggregated with ITAM-bearing receptors, FcgammaRIIB become tyrosyl-phosphorylated and recruit the Src homology 2 (SH2) domain-containing inositol 5'-phosphatases SHIP1 and SHIP2, which mediate inhibition [20].
• To test this possibility, we determined the development of RF in C57BL/6 (B6) mice lacking FcgammaRIIB, in relation to the H2 haplotype, complement C3, and the Y-linked autoimmune acceleration (Yaa) mutation [21].
• Tumor necrosis factor induces a block in the cotranslation of Fc gamma RIIb mRNA in mouse peritoneal macrophages [22].
• In contrast to the lymphoid precursors, myeloid precursors able to generate colonies in methyl cellulose cultures were found in all four fractions including the one which expressed Fc gamma RII/III but no AA4.1 (FcR+) and the one which expressed neither marker (AA4.1-/FcR-) [23].

Physical interactions of Fcgr2b

• Sequence analysis of cDNA clones indicates that mouse Fc gamma RI is a transmembrane glycoprotein that is composed of three disulfide bonded extracellular Ig binding domains unlike Fc gamma RII of man and mouse [24].
• This conclusion is supported by the observation that after proteolysis, the Fc gamma RII-mediated binding of EA-mouse IgG1 becomes susceptible to inhibition by (monomeric) human IgG [25].
• After coaggregation, FcgammaRIIB and FcepsilonRI rapidly interact with the F-actin skeleton and engage SHIP1 and filamin-1 [26].
• Unique features of SHIP, SHP-1 and SHP-2 binding to FcgammaRIIb revealed by surface plasmon resonance analysis [27].
• In mice, the beta Fc gamma R gene codes for Fc gamma RII and the alpha Fc gamma R gene codes for the ligand-binding Fc gamma RIII alpha-chain [28].

Regulatory relationships of Fcgr2b

• Chondrocyte death was reduced in Fc gamma RIII(-/-) mice (68% lower) and enhanced in Fc gamma RII(-/-) mice (6-12-fold higher) [29].
• Crosslinking of Fc gamma RII induced a rapid increase in the tyrosine kinase activity and comodulation of Fgr [30].
• Alternatively, homoaggregation of FcgammaRIIB can induce a proapoptotic state in B cells that is dependent on the presence of Bruton tyrosine kinase (Btk), a kinase also expressed in monocytes [31].
• In contrast, absence of the inhibiting FcgammaRIIB augmented the Hg-induced increase of both serum IgG1 and IgE [32].
• Previous studies by our lab and others established that co-crosslinking sIg and IgG receptor FcgammaRIIb in B cells in a feedback suppression model (negative signaling) promoted tyrosine phosphorylation of the inositol 5-phosphatase SHIP and its interaction with Shc and that these events were associated with inhibition of the Ras pathway [33].

Other interactions of Fcgr2b

• To determine the mechanisms underlying the epistasis displayed by this gene we have constructed hybrids between FcgammaRIIB(-/-) and the systemic lupus erythematosus (SLE) modifiers yaa and lpr and the susceptibility locus Sle1 [1].
• Mice lacking Fc gamma RIII showed almost no PG depletion, whereas in Fc gamma RII(-/-) mice, PG depletion was increased 3-7-fold in various cartilage areas [29].
• Induction of intracellular Ca2+ mobilization and cytotoxicity by hybrid mouse monoclonal antibodies. Fc gamma RII regulation of Fc gamma RI-triggered functions or signaling [34]?
• Src homology 2 domain-containing inositol 5-phosphatase 1 mediates cell cycle arrest by FcgammaRIIB [35].
• IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain-deficient mice and increased in Fc gamma RII-deficient mice [36].

Analytical, diagnostic and therapeutic context of Fcgr2b

• Adoptive transfer of CD4(+) T cells from the spleen of FcgammaRIIB(-/-) mice to naive acceptor mice demonstrated that OVA-responding T cells failed to differentiate into regulatory T cells, explaining the lack of tolerance in these mice [37].
• The fourth anti Fc gamma RII MAb, 93.4, directed against the intracellular region of Fc gamma RIIa1/2, allows its detection by Western blotting only when it is not phosphorylated [38].
• Using multicolor flow cytometry, spleens from neonatal mice of increasing age and adult bone marrow were analyzed for expression of the Fc gamma RII [39].
• In the case of LyM-1, sequential immunoprecipitation provided evidence that Ly-m20.2 and LyM-1 are identical [40].
• Analyses of surface expression of FcgammaRIIB by flow cytometry and FcgammaRIIB mRNA levels by RT-PCR analysis confirmed that this FcR is down-regulated in GC B cells [41].

References