FCGR2B (original) (raw)

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Antibody fragment receptor in humoral immunity

FCGR2B
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes2FCB, 3WJJ,%%s3WJL
Identifiers
Aliases FCGR2B, CD32, CD32B, FCG2, FCGR2, IGFR2, Fc fragment of IgG receptor IIb, FcRII-c, FCGR2C
External IDs OMIM: 604590; MGI: 95499; HomoloGene: 2974; GeneCards: FCGR2B; OMA:FCGR2B - orthologs
Gene location (Human)Chromosome 1 (human)Chr.Chromosome 1 (human)[1]Chromosome 1 (human)Genomic location for FCGR2BGenomic location for FCGR2BBand1q23.3Start161,663,147 bp[1]End161,678,654 bp[1]
Gene location (Mouse)Chromosome 1 (mouse)Chr.Chromosome 1 (mouse)[2]Chromosome 1 (mouse)Genomic location for FCGR2BGenomic location for FCGR2BBand1 H3|1 78.02 cMStart170,786,186 bp[2]End170,804,116 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed inplacentaright coronary arterybloodspleenmonocytelymph nodesynovial membranesynovial jointgranulocyteappendixTop expressed instroma of bone marrowtibiofemoral jointcalvariagranulocyteskin of abdomenbloodspleenright kidneymolarmotor neuronMore reference expression dataBioGPSn/a
Gene ontologyMolecular function protein binding IgG binding amyloid-beta binding low-affinity IgG receptor activity protein-containing complex binding transmembrane signaling receptor activity Cellular component integral component of membrane plasma membrane membrane integral component of plasma membrane external side of plasma membrane dendritic spine cell body cytoplasm Biological process viral process immune response signal transduction regulation of immune response negative regulation of type I hypersensitivity negative regulation of antibody-dependent cellular cytotoxicity follicular dendritic cell activation mature B cell differentiation involved in immune response follicular B cell differentiation immune complex clearance by monocytes and macrophages negative regulation of dendritic cell antigen processing and presentation regulation of B cell antigen processing and presentation negative regulation of immunoglobulin production regulation of adaptive immune response negative regulation of acute inflammatory response to antigenic stimulus positive regulation of humoral immune response negative regulation of humoral immune response mediated by circulating immunoglobulin receptor-mediated endocytosis phagocytosis, engulfment defense response inflammatory response response to bacterium regulation of signaling receptor activity immunoglobulin mediated immune response antigen processing and presentation of exogenous peptide antigen via MHC class II cerebellum development negative regulation of B cell proliferation negative regulation of interleukin-10 production Fc-gamma receptor signaling pathway involved in phagocytosis negative regulation of macrophage activation negative regulation of cytotoxic T cell degranulation regulation of innate immune response mast cell activation positive regulation of JNK cascade negative regulation of phagocytosis positive regulation of phagocytosis negative regulation of immune response negative regulation of B cell receptor signaling pathway negative regulation of B cell activation cellular response to molecule of bacterial origin regulation of immune complex clearance by monocytes and macrophages positive regulation of neuron death negative regulation of neutrophil activation regulation of dendritic spine maintenance cellular response to amyloid-beta positive regulation of response to endoplasmic reticulum stress negative regulation of dendritic cell differentiation Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez221314130EnsemblENSG00000072694ENSMUSG00000026656UniProtP31994P31995P08101RefSeq (mRNA)NM_001002273NM_001002274NM_001002275NM_001190828NM_004001NM_001077189NM_010187RefSeq (protein)NP_001002273NP_001002274NP_001002275NP_001177757NP_003992NP_963857NP_001070657NP_034317Location (UCSC)Chr 1: 161.66 – 161.68 MbChr 1: 170.79 – 170.8 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Fc fragment of IgG receptor IIb (coded by FCGR2B gene) is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.[5]

There are two major forms of FCGR2B existing (FCGR2B1 and FCGR2B2) and they are created by mRNA splicing mechanism, which results in the inclusion (FCGR2B1) or exclusion (FCGR2B2) of the C1 exon sequence. The presence of the C1 exon sequence (in FCGR2B1) results in tethering to the membrane of B cells, whereas its absence (in FCGR2B2) allows fast internalization of the receptor in myeloid cells. Both forms contain the Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) in their cytoplasmic regions. The extracellular domains are 95% identical to the domains of FCGR2A and almost completely identical to the FCGR2C (the other members of CD32 family).[6] It is the only inhibitory type I FcγR[7] in humans and mice.

FCGR2B1 is highly expressed by B cells, and its mRNA has also been identified at lower levels on monocytes. FCGR2B2 is highly expressed on basophils and at low levels on monocytes. FCGR2B is co-expressed with the activating FCGRA on circulating myeloid dendritic cells in peripheral blood.[8] Cytokine regulation of the expression is positive in the case of IL-10 and IL-6 and negative in the case of TNF-α, C5a and IFN-γ.[6]

FCGR2B is co-expressed with the activating FCGRA on circulating myeloid dendritic cells.[8]

The receptor inhibits the functions of activating FcγRs, such as phagocytosis and pro-inflammatory cytokine release, mainly by clustering of FCGR2B with different activating FCGR receptors or with the BCR by immune complexes.[9][6]

The phosphorylated ITIM of FcγRIIB recruits the inositol phosphatases SHIP1 and SHIP2, which inhibit Ras activation, downregulate MAPK activity and reduce PLCγ function and lead to decreased activation of PKC. Inhibition of the MAP kinase pathway, together with the anti-apoptotic kinase Akt can negatively affect proliferation and survival of the cells.[6] However, FcγRIIB can restrict activation of cells bearing FcγRs by simply competing with them for engagement with immune complexes, as removal of the ITIM retains this activity.[10]

FCGR2B regulates B cell activation by increasing the BCR activation threshold and suppressing B cell-mediated antigen presentation to T cells through the ITIM-dependent inhibitory mechanism.[9] Ligation of FCGR2B on B cells downregulates antibody production, prevents the membrane organization of BCR and CD19 and promotes apoptosis. Co-ligation of FCGR2B on dendritic cells inhibits maturation and blocks cell activation.[6][8] The negative regulatory role of the FCGRIIB molecule is not limited to BCR-induced B-cell activation, but is also functional on other B-cell activation pathways mediated by CD40 and IL-4.[11] BCR signaling attenuates the pro-apoptotic signaling induced by aggregation of FcγRIIB through immune complexes,[12] allowing for FcγRIIB to effectively tune the affinity threshold for antigen in immune responses and selectively promote retention and survival of high-affinity B cells.[13]

The transmembrane region of FcγRIIB also appears to be functionally important.[14] Multiple epidemiological studies link polymorphisms in the transmembrane domain of FcγRIIB to autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis. Mutagenesis studies confirm that lesioning the transmembrane region impairs the ability of FcγRIIB to attenuate B cell signaling. Multiple mechanisms are proposed to account for this, relating to the ability of FcγRIIB to co-localize with the BCR, colocalize with activating FcγRs (in non-B cells), prevent its colocalization with the activating receptor CD19.

FCGR2B expression on follicular dendritic cells (FDCs) is important for capturing the antigen-containing immune complexes which are essential for the germinal centre response.[9] It has been shown that in the absence of FcγRIIB on FDCs, the germinal centers are more diverse but populated by low affinity B cells with low levels of somatic hypermutation.[15] The mechanisms underlying this are incompletely understood, but it is noted that the ability of FDCs to retain immune complexes in the absence of FcγRIIB is impaired and this may result in lower stringency in selection for entry into the germinal center reaction.

FCGR2B is present on non-leukocyte cells including airway smooth muscle and liver sinusoidal endothelial cells, where small immune complexes are internalized inhibiting the pro-inflammatory signalling.[6]

FCGR2B is one of the genes thought to influence susceptibility to several autoimmune diseases in humans. Its decreased function is associated with systemic lupus erythematosus, rheumatoid arthritis, Goodpasture's disease, multiple sclerosis and others.[9]

FCGR2B may be a target for monoclonal antibody therapy for autoimmune diseases as well as malignancies.[9][16][17]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000072694 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026656 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "FCGR2B Fc fragment of IgG receptor IIb [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2019-06-14.
  6. ^ a b c d e f Anania JC, Chenoweth AM, Wines BD, Hogarth PM (2019-03-19). "The Human FcγRII (CD32) Family of Leukocyte FcR in Health and Disease". Frontiers in Immunology. 10: 464. doi:10.3389/fimmu.2019.00464. PMC 6433993. PMID 30941127.
  7. ^ Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, et al. (August 2014). "Type I and type II Fc receptors regulate innate and adaptive immunity". Nature Immunology. 15 (8): 707–716. doi:10.1038/ni.2939. PMC 7430760. PMID 25045879.
  8. ^ a b c Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW (October 2005). "Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions". The Journal of Clinical Investigation. 115 (10): 2914–2923. doi:10.1172/JCI24772. PMC 1201664. PMID 16167082.
  9. ^ a b c d e Smith KG, Clatworthy MR (May 2010). "FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications". Nature Reviews. Immunology. 10 (5): 328–343. doi:10.1038/nri2821. PMC 4148599. PMID 20414206.
  10. ^ Simpson AP, Roghanian A, Oldham RJ, Chan HT, Penfold CA, Kim HJ, et al. (July 2022). "FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms". Cell Reports. 40 (3): 111099. doi:10.1016/j.celrep.2022.111099. PMC 9638011. PMID 35858562.
  11. ^ Horejs-Hoeck J, Hren A, Mudde GC, Woisetschläger M (July 2005). "Inhibition of immunoglobulin E synthesis through Fc gammaRII (CD32) by a mechanism independent of B-cell receptor co-cross-linking". Immunology. 115 (3): 407–415. doi:10.1111/j.1365-2567.2005.02162.x. PMC 1782155. PMID 15946258.
  12. ^ Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV (June 1999). "SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis". Immunity. 10 (6): 753–760. doi:10.1016/s1074-7613(00)80074-6. PMID 10403650.
  13. ^ Wang TT, Ravetch JV (September 2019). "Functional diversification of IgGs through Fc glycosylation". The Journal of Clinical Investigation. 129 (9): 3492–3498. doi:10.1172/JCI130029. PMC 6715372. PMID 31478910.
  14. ^ Wang J, Li Z, Xu L, Yang H, Liu W (December 2018). "Transmembrane domain dependent inhibitory function of FcγRIIB". Protein & Cell. 9 (12): 1004–1012. doi:10.1007/s13238-018-0509-8. PMC 6251803. PMID 29497990.
  15. ^ van der Poel CE, Bajic G, Macaulay CW, van den Broek T, Ellson CD, Bouma G, et al. (November 2019). "Follicular Dendritic Cells Modulate Germinal Center B Cell Diversity through FcγRIIB". Cell Reports. 29 (9): 2745–2755.e4. doi:10.1016/j.celrep.2019.10.086. PMC 7015177. PMID 31775042.
  16. ^ Rankin CT, Veri MC, Gorlatov S, Tuaillon N, Burke S, Huang L, et al. (October 2006). "CD32B, the human inhibitory Fc-gamma receptor IIB, as a target for monoclonal antibody therapy of B-cell lymphoma". Blood. 108 (7): 2384–2391. doi:10.1182/blood-2006-05-020602. PMID 16757681.
  17. ^ Zhou P, Comenzo RL, Olshen AB, Bonvini E, Koenig S, Maslak PG, et al. (April 2008). "CD32B is highly expressed on clonal plasma cells from patients with systemic light-chain amyloidosis and provides a target for monoclonal antibody-based therapy". Blood. 111 (7): 3403–3406. doi:10.1182/blood-2007-11-125526. PMC 2275009. PMID 18216299.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.