Disease relevance of FCAR

• These results suggest that the FCAR promoter SNPs may be related to chronic HCV infection and disease progression in Japanese CHC, which might be explained by altered FcalphaR expression affecting IgA-mediated immune responses and/or IgA catabolism [1].
• Because inheritable variations modifying individual immune responses or immunoglobulin catabolism may affect the chronicity of viral infection, we investigated whether promoter polymorphisms of the FcalphaR gene (FCAR) affect chronic hepatitis C virus (HCV) infection and its disease progression [1].
• Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice [2].
• The data show that phage display-derived fully human IgA1 antibodies efficiently recruit immune effector cells that express the Fc receptor for IgA, FcalphaRI (CD89) [3].
• Effective in vitro clearance of Porphyromonas gingivalis by Fc alpha receptor I (CD89) on gingival crevicular neutrophils [4].

High impact information on FCAR

• Immunoglobulin-alpha (IgA)-bound antigens induce immune effector responses by activating the IgA-specific receptor FcalphaRI (CD89) on immune cells [5].
• Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, FcalphaRI (CD89), is poorly understood [6].
• GM-CSF induces human neutrophil IgA-mediated phagocytosis by an IgA Fc receptor activation mechanism [7].
• To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice [2].
• Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains [2].

Biological context of FCAR

• A 259-base pair fragment of the FCAR promoter is sufficient to direct myeloid expression of a reporter gene and contains functionally important binding sites for CCAAT/enhancer-binding protein alpha (C/EBPalpha) (CE1, CE2, and CE3) and an unidentified Ets-like nuclear protein [8].
• Localization of the binding site for the monocyte immunoglobulin (Ig) A-Fc receptor (CD89) to the domain boundary between Calpha2 and Calpha3 in human IgA1 [9].
• Identification of Fc alpha receptor (CD89) isoforms generated by alternative splicing that are differentially expressed between blood monocytes and alveolar macrophages [10].
• Cross-linking of CD89 on DC triggered endocytosis in time-dependent manner [11].
• Effective phagocytosis and killing of Candida albicans via targeting FcgammaRI (CD64) or FcalphaRI (CD89) on neutrophils [12].

Anatomical context of FCAR

• The FcalphaRI (CD89) expressed by myeloid cells selectively binds IgA1 and IgA2 antibodies, whereas the poly-IgR, Fcalpha/muR, and asialoglycoprotein receptors bind other ligands in addition to IgA [13].
• Differential expression and function of IgA receptors (CD89 and CD71) during maturation of dendritic cells [14].
• The immunoglobulin A (IgA) Fc receptor (FcalphaRI), encoded by the FCAR gene, is a possible candidate for eosinophil activation at mucosal surfaces, where IgA is abundant [15].
• Cloning and characterization of Fc alpha Rb, a novel Fc alpha receptor (CD89) isoform expressed in eosinophils and neutrophils [16].
• In this report, we show that the Src family nonreceptor protein tyrosine kinase (PTK) Lyn associates with aggregated IgA Fc receptor (Fc alpha R) in the monocytic cell line THP-1 [17].

Associations of FCAR with chemical compounds

• Because the myeloid IgA Fc receptor encoded by FCAR mediates inflammation, we hypothesized that the FCAR Asp92Asn polymorphism is associated with risk of MI and that this risk would be modified by pravastatin [18].
• On both monocyte-derived macrophages and the myelomonocytic cell lines, Fc alpha R/CD89 expression was induced by calcitriol alone and additively in combination with tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and granulocyte-macrophage colony-stimulating factor [19].
• Tumor necrosis factor-alpha was found to specifically increase the ratio of Delta EC2 to the wild type CD89 in neutrophils and conversely decrease the Delta EC2 ratio in monocytes [20].
• Cytokine-induced inside-out activation of FcalphaR (CD89) is mediated by a single serine residue (S263) in the intracellular domain of the receptor [21].
• These data indicate that SIgA can interact with DC not via CD89, but via carbohydrate-recognizing receptors like mannose receptor and suggest that uptake of SIgA-containing immune complexes by immature DC may be a mechanism to modulate mucosal immune responses [22].

Regulatory relationships of FCAR

• Transforming growth factor-beta 1 (TGF-beta 1) down-regulates IgA Fc-receptor (CD89) expression on human monocytes [23].

Other interactions of FCAR

• Interstitial-type DC expressed CD89 as a 50- to 75-kDa glycoprotein with a 32-kDa protein core, which was down-regulated upon addition of TGF-beta 1 [11].
• In addition, the H22xKi-4 and A77xKi-4 BSMs were shown to bind cells expressing CD64 and CD89, respectively [24].
• Furthermore, the NK cell-expressed NKp46 gene was localized 20 kb telomeric of FCAR; and 14 novel genes mapping within the LRC were identified by cDNA selection [25].
• Investigation of human Fc alpha R (CD89) transcripts in neutrophils, eosinophils and a monocyte-like cell line, THP-1, with the use of reverse transcriptase PCR, Northern blotting and RNase protection analysis, has provided evidence in these cell types for at least two distinct transcripts generated by alternative splicing [26].
• IgA nephropathy-specific expression of the IgA Fc receptors (CD89) on blood phagocytic cells [27].

Analytical, diagnostic and therapeutic context of FCAR

• Using specific and sensitive ELISA techniques (detection limit 50 pg/ml), we were not able to detect circulating CD89 in human sera [28].
• Size fractionation of human serum using gel filtration chromatography showed that the CD89 molecule was predominantly present in larger molecular mass fractions [28].
• However, using Western blotting, a 30-kDa soluble CD89 molecule was demonstrated in both serum and plasma [28].
• No message for CD 89 was detectable in quiescent or AIgA1 stimulated HMC by Northern analysis or RT-PCR using several primer sequences based on the sequence of U937 FcalphaR cDNA [29].
• Flow cytometry on the mesangial cells, using My 43, a monoclonal antibody to FcalphaR1 confirmed that CD 89 was not present on the cell [29].

References