Disease relevance of FCGR2A

• FCGR3A and FCGR2A polymorphisms may not correlate with response to alemtuzumab in chronic lymphocytic leukemia [1].
• 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].
• FCGR2A polymorphism is correlated with clinical outcome after immunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage colony-stimulating factor [2].
• Association of FCGR2A and FCGR2A-FCGR3A haplotypes with susceptibility to giant cell arteritis [3].
• Solely Fc gamma RIIa-expressing IIA1.6 cells were capable of phagocytosing opsonized Staphylococcus aureus bacteria, and cross-linking of Fc gamma RIIa triggered a rapid induction of tyrosine phosphorylation after 20 seconds [4].

High impact information on FCGR2A

• Human resting B lymphocytes entered a state of sustained proliferation when incubated with both the mouse fibroblastic Ltk- cell line that had been transfected with the human Fc receptor (Fc gamma RII/CDw32) and monoclonal antibodies to CD40 [5].
• A murine macrophage cell line, but not a fibroblast cell line, that was transfected with human Fc gamma RIIA mediated phagocytosis and an intracellular Ca2+ concentration ([Ca2+]i) flux upon cross-linking of human Fc gamma RIIA [6].
• However, only wild-type transfectants phagocytosed labeled erythrocytes and fluxed [Ca2+]i. Thus, the cytoplasmic domain of human Fc gamma RIIA contains distinct functional regions [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].
• We conclude that CD32 is an antigen uptake receptor on pDCs and that antigen presentation by pDCs is of particular relevance when circulating antibodies are present [8].

Chemical compound and disease context of FCGR2A

• Electrospray ionisation mass spectrometry (ESMS) indicate that the N-glycans of baculovirus derived Fc gamma RIIa are core mannose oligosaccharide side chains [9].
• Fc gamma RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis [10].

Biological context of FCGR2A

• The risk of GCA in HLA-DRB1*04 positive individuals homozygous for the FCGR2A-131R allele is increased almost six-fold compared with those with other FCGR2A genotypes who are HLA-DRB1*04 negative [3].
• The increased association observed with a FCGR2A-FCGR3A haplotype suggests the presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility [3].
• 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].
• CONCLUSION: The favorable outcome associated with FCGR2A (R/R) genotype is consistent with the proposed role of FCGR2A and phagocyte-mediated ADCC in 3F8 plus GM-CSF immunotherapy [2].
• FCGR2A (R/R) also correlated with marrow remission 2.5 months after treatment initiation: by histology (P = .021 and P = .036, for the entire cohort and the subset, respectively) and by qRT-PCR (P = .052 and P = .033, respectively) [2].

Anatomical context of FCGR2A

• FCGR2A was highly expressed in adipocytes in both depots and this was verified by immunohistochemistry [11].
• In this study, we analyzed the role of Fc gamma RIIa in binding of stable hIgG-subclass dimers, and in induction of T cell mitogenesis using chimeric anti-CD3 mAb [12].
• The Fc gamma R-negative B-cell line IIA1.6 was transfected with wild-type or mutant human Fc gamma RIIa and IIb molecules [4].
• Human basophils selectively express the Fc gamma RII (CDw32) subtype of IgG receptor [13].
• This work reveals a new role for CRP in modulating the immune system by inhibiting DC differentiation, maturation and functions mainly through FcgammaRIIa/CD32 [14].

Associations of FCGR2A with chemical compounds

• In contrast, Fc gamma RIIb isoforms triggered tyrosine phosphorylation on cross-linking with much slower kinetics (> 3 minutes) than Fc gamma RIIa [4].
• Conversely, both the Fc gamma RIIIa 158 valine/valine and the Fc gamma RIIa 131 histidine/histidine genotypes were found to be independently associated with the response rate and freedom from progression [15].
• Recent studies have revealed that phagocytosis initiated by Fc gamma RIIa is tightly controlled by the inositol phosphatase SHIP-1, and the protein-tyrosine phosphatase SHP-1 [16].
• In addition, anti-P-selectin glycoprotein ligand-1 antibody reduced the expression of CD11b, CD32, and CD33 in THP-1 after PMP stimulation [17].
• The FCGR3A valine (V) allele was significantly correlated with a higher complete response rate to R-CHOP compared with the phenylalanine (F) allele (88% in V/V vs 79% in V/F vs 50% in F/F; P = .002), while no difference was found between FCGR2A polymorphisms [18].

Physical interactions of FCGR2A

• We observed that binding of the Fab parts of 3G8 mAb to two Fc gamma RIIIb molecules and binding of the Fc part to one Fc gamma RIIa molecule is required, because a bispecific antibody, 2B1, in which only one 3G8 Fab is present, did not induce neutrophil activation [19].
• The cross-linking of Fc gamma RIIa by complexed IgG triggers activation of protein tyrosine kinase and internalization of immune complexes [20].

Enzymatic interactions of FCGR2A

• Functional analysis of this molecule determined that activated Fc gamma RIIA is tyrosine phosphorylated and that activation induced the physical association with the protein tyrosine kinase p72syk [21].

Regulatory relationships of FCGR2A

• Here we report that Fc gamma RIIa clustering induces SHP-1 phosphatase activity in THP-1 cells [16].
• Fc gamma RIIa is expressed on natural IFN-alpha-producing cells (plasmacytoid dendritic cells) and is required for the IFN-alpha production induced by apoptotic cells combined with lupus IgG [22].
• Molecular characterization of FcgammaRIIc isoforms expressed by the CD32+ donors revealed that the majority of donors expressed the FcgammaRIIc1 isoform [23].
• T cell-independent differentiation of sIgD+ and sIgD- B cells could be achieved by simultaneous crosslinking of sIgs and CD40 in the presence of a mouse Ltk- cell line stably expressing human CDw32/Fc gamma RII (CDw32 L cells) [24].
• Mechanistic studies into the IgE class switch process demonstrated that IL-4/anti-CD40-induced IgE germline gene transcription and B-cell proliferation were not affected by CD32 ligation [25].

Other interactions of FCGR2A

• 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].
• In addition, the same groups of patients and controls were genotyped for the previously known polymorphisms of FCGR2A, FCGR3A, and FCGR3B [26].
• Although Fc gamma RIIA utilizes tyrosines within its own cytoplasmic domain for signaling while Fc gamma RI utilizes the cytoplasmic tyrosines of its associated gamma subunit, our results indicate sharing of several proteins for signaling in monocytes by these Fc receptors [27].
• Although some details remain to be elucidated, signaling following crosslinking of Fc gamma RIIA requires the activation of tyrosine kinases of both Src-family kinases and Syk, resulting in tyrosine phosphorylation of Shc, phospholipase C gamma isozymes, and a [Ca2+]i transient [28].
• The protein-tyrosine phosphatase SHP-1 associates with the phosphorylated immunoreceptor tyrosine-based activation motif of Fc gamma RIIa to modulate signaling events in myeloid cells [16].

Analytical, diagnostic and therapeutic context of FCGR2A

• Polymorphic alleles of FCGR2A and FCGR3A were determined by PCR plus direct sequencing using genomic DNA samples obtained from marrow or blood of patients [2].
• RESULTS: FCGR2A (R/R) genotype correlated with progression-free survival for the entire cohort (P = .049) and for the subset of patients with no history of prior relapse (P = .023) [2].
• Furthermore, Fc gamma RIIA and Fc gamma RIIIB genotype results were confirmed by quantitative flow cytometry using specific monoclonal antibodies [29].
• The specificity of N55 IgG for Fc gamma RIII was confirmed by ELISA using secreted recombinant Fc gamma RIIA and Fc gamma RIIIB protein to coat microtiter wells [30].
• Fc gamma RIIa allotypes were determined by immunophenotyping of blood monocytes [31].

References