Disease relevance of FCER2

• High concentrations of soluble CD23 and L-selectin are found in the serum of patients with B-chronic lymphocytic leukemia (B-CLL) [1].
• This inhibition was restricted to the MHM6 epitope of CD23 and antibodies to other epitopes [Epstein-Barr virus (EBV) CS-1, EBV CS-2, EBV CS-5 and mAb 25] or occupation of the Fc-binding site by IgE had no or a slightly enhancing effect on aggregation [2].
• In this study it was investigated whether the control of IL-4 and CD23 levels result in a decrease of the severity of allergic reactions [3].
• By contrast, the activation antigen CD23 was associated with a higher WBC, higher Rai stage, younger age group, and the presence of lymphadenopathy [4].
• Similar to its effect on peripheral B cells, Jurkat D1.1 activates B cells from lymphoid organs, as well as a B cell lymphoma clone, RAMOS 266,4CN 3F10 (RAMOS 266), to up-regulate surface CD23 [5].

Psychiatry related information on FCER2

• Multiple proteins are proteolytically shed from the membrane, including the amyloid precursor protein (APP) involved in Alzheimer's disease, the blood pressure regulating angiotensin converting enzyme (ACE), the low affinity IgE receptor CD23, and the inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) [6].

High impact information on FCER2

• IgE enhances antibody responses via the low-affinity receptor for IgE (FcepsilonRII/CD23) [7].
• CR2 also can be ligated by CD23, a lectin-like membrane protein that resides on cells that may present antigen to B cells [8].
• In both rodent and human lymphocytes, Fc epsilon RII on B cells are degraded, and their fragments are released from the cells [9].
• The R576 allele was associated with higher levels of expression of CD23 by interleukin-4 than the wild-type allele [10].
• Using this assay, we demonstrate that EBV persists, in the peripheral blood of all seropositive individuals tested, in CD19+, CD23-, and CD80 (B7)- B cells [11].

Chemical compound and disease context of FCER2

• Role of IgE immune complexes in the regulation of HIV-1 replication and increased cell death of infected U1 monocytes: involvement of CD23/Fc epsilon RII-mediated nitric oxide and cyclic AMP pathways [12].
• Only 6% of these CD19+/CD5+ patients were CD23-. Overall, CD23- patients had the worse prognostic features compared with CD23+ cases, including anemia (P = 0.03), massive splenomegaly (P = 0.000), high lactate dehydrogenase (P = 0.007), high beta2-microglobulin (P = 0.006), older age (P = 0.001), and male gender (P = 0.02) [13].
• We have previously reported that ligation of the CD23 molecule with anti-CD23 mAb, or IgE-anti-IgE complexes, leads to phosphoinositide hydrolysis and calcium mobilization through the generation of Inositol (1,4,5) trisphosphate via a process involving a Pertussis toxin insensitive GTP-binding protein [14].
• In EBV-infected Burkitt lymphoma cells, we have confirmed that high levels of expression are determined largely at the level of gene transcription by performing nuclear run-on transcription analyses and stability determinations of CD23 mRNA in actinomycin D chase experiments [15].
• The progression of uremia was associated with a gradual increase in soluble CD25, CD23, and especially neopterin levels [16].

Biological context of FCER2

• Analysis of recombinant haplotypes by microsatellites mapping to the chromosomal region 19p13.3 suggests that the disease locus maps between FCER2 and the microsatellite marker D19S424, probably close to D19S216 and D19S177 [17].
• We sequenced parts of the FCER2 gene coding for CD23 and found a restriction fragment length polymorphism (RFLP) that cosegregates with the disease [17].
• Two species of human Fc epsilon receptor II (Fc epsilon RII/CD23): tissue-specific and IL-4-specific regulation of gene expression [18].
• These Fc epsilon RII species appear to be generated utilizing different transcriptional initiation sites and alternative RNA splicing [18].
• However, the IC50 for this inhibition by Ro31-9790 was different for L-selectin and CD23 (83 v 6 micromol/L, respectively) [1].

Anatomical context of FCER2

• The Fc epsilon receptor II (Fc epsilon RII, CD23) functions in B cell growth and differentiation and in IgE-mediated immunity [18].
• These results demonstrate that CD11b and CD11c are receptors for CD23 and that this novel ligand pairing regulates important activities of monocytes [19].
• Ro 31-9790, a membrane permeant zinc chelator that inhibits the phorbol-ester-stimulated shedding of L-selectin, also inhibited shedding of CD23 from B-CLL lymphocytes [1].
• Constitutive and interleukin-4 (IL-4)-driven Fc epsilon RII/CD23 expression was markedly diminished on calcitriol-treated U937 cells and monocytes [20].
• Our results demonstrate that calcitriol, alone or in combination with cytokines, modulates Fc alpha R, Fc epsilon RII, Fc gamma RI, and Fc gamma RII expression on human mononuclear phagocytes, as well as Fc gamma R-mediated phagocytosis [20].

Associations of FCER2 with chemical compounds

• We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up [21].
• Adenosine triphosphate-induced shedding of CD23 and L-selectin (CD62L) from lymphocytes is mediated by the same receptor but different metalloproteases [1].
• A number of tumor necrosis factor (TNF) family proteins and CD23 were screened as potential substrates for ectodomain cleavage [22].
• Nitric oxide production has been shown to be induced by engagement of CD23 antigen [23].
• The effects of 1 alpha,25-dihydroxyvitamin D3/calcitriol on the expression of Fc receptors (FcR) for IgA (Fc alpha R), IgE (Fc epsilon RII), and IgG (Fc gamma R) on human peripheral blood monocytes and the cell lines U937, THP-1, and Mono Mac-6, in combination with various cytokines, was examined by flow cytometry [20].
• We also found that the addition of lumiliximab to rituximab or fludarabine results in synergistic cytotoxicity of primary CLL cells and CD23-expressing B-cell lines [24].

Physical interactions of FCER2

• The mAbs that inhibit the most CD23 binding to CD21 map in SCRs 5 to 8 [25].
• Exposure of B-CLL cells to PI led to induction of apoptosis, a time- and dose-dependent downregulation of CD23 expression and a decline in DNA binding of transcriptionally active Notch2 [26].
• However, reconstitution of these X-SCID B cells with gammac enhanced IL-4-mediated responses including STAT6 phosphorylation and DNA binding activity and resulted in increased CD23 expression [27].

Regulatory relationships of FCER2

• Induction of the CD23/nitric oxide pathway in endothelial cells downregulates ICAM-1 expression and decreases cytoadherence of Plasmodium falciparum-infected erythrocytes [23].
• In contrast to IL 4-promoted stimulation, CD72 antibody failed to up-regulate the surface expression of either IgM or the CD23 antigen [28].
• The early events triggered in interleukin-4 (IL-4)-stimulated U937 cells by ligation of CD23/Fc epsilon RII with specific monoclonal antibodies (mAb) were analysed, as a model of the action of this molecule on the differentiation of promonocytic cells [29].
• TNF-alpha alone had a weak but significant stimulating effect on the Fc epsilon RII expression on the cell lines U937 and THP-1, and very modestly on Mono-Mac-6 cells [30].
• Ligation of the CD23 antigen by a specific anti-CD23 monoclonal antibody at the cell surface of HLECs was found to induce iNOS mRNA and protein expression, NO release and P. falciparum killing [23].

Other interactions of FCER2

• The interaction was specifically inhibited by anti-CD11b or anti-CD11c, respectively, and by anti-CD23 MAbs [19].
• We conclude that ADAM8 could contribute to ectodomain shedding of CD23 and may thus be a potential target for therapeutic intervention in allergy and inflammation [22].
• We demonstrate that normal human lung endothelial cells (HLECs) are able to express the low affinity receptor for IgE (Fc in RII/CD23), following cell incubation with interleukin 4 or PRBCs [23].
• Although weaker than in monocytes, CD23 ligation evoked a small secretion of the pro-inflammatory mediators IL-6 and thromboxane B2 [29].
• We investigated the expression of the low affinity Fc IgE receptor (Fc epsilon RII/CD23) on the human monocytic cell lines U937, THP-1, Mono-Mac-6, and cultured human peripheral blood monocytes under stimulation with human tumour necrosis factor-alpha (TNF-alpha) and other cytokines [30].

Analytical, diagnostic and therapeutic context of FCER2

• Affinity-purified sCD21 was capable of binding to purified human iC3b and to human recombinant CD23, as assessed by enzyme-linked immunosorbent assay and by using the BIAcore technology [31].
• Fc epsilon R2/CD23 induction was detectable both by flow cytometry using anti-CD23 mAbs as well as soluble IgE, and by the immunoprecipitation with CD23-specific mAb or IgE of a 45-kD band from 125I-lactoperoxidase-labeled Mo [32].
• The co-expression of major histocompatibility complex class II molecules and CD23 on CD4+ T lymphocytes in allergic patients, as assessed by the three-color immunofluorescence analysis, indicates that these cells were activated [33].
• Northern blot analysis showed an increase in CD23 mRNA when activated T cells were cultured in the presence of IL-7 [34].
• CONCLUSIONS: These data indicate that CD23 negativity is rare in typical B-cell CLL, and CD23 negativity in patients with CD19+/CD5+ is suggestive of mantle cell leukemia a more aggressive disease with poor response to conventional therapy in which newer chemotherapy regimens such as hyper-CVAD may be more effective [13].

References