FCGR2B explained

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.[1]

Structure

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).[2] It is the only inhibitory type I FcγR[3] in humans and mice.

Expression

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.[4] 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.

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

Function

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.[5]

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. 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.[6]

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. 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. 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.[7] BCR signaling attenuates the pro-apoptotic signaling induced by aggregation of FcγRIIB through immune complexes,[8] 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.[9]

The transmembrane region of FcγRIIB also appears to be functionally important.[10] 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. 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.[11] 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.

Autoimmunity

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.

FCGR2B may be a target for monoclonal antibody therapy for autoimmune diseases as well as malignancies.[12] [13]

See also

Further reading

Notes and References

  1. Web site: FCGR2B Fc fragment of IgG receptor IIb [Homo sapiens (human)] - Gene - NCBI]. www.ncbi.nlm.nih.gov. 2019-06-14.
  2. Anania JC, Chenoweth AM, Wines BD, Hogarth PM . The Human FcγRII (CD32) Family of Leukocyte FcR in Health and Disease . Frontiers in Immunology . 10 . 464 . 2019-03-19 . 30941127 . 6433993 . 10.3389/fimmu.2019.00464 . free .
  3. Pincetic A, Bournazos S, DiLillo DJ, Maamary J, Wang TT, Dahan R, Fiebiger BM, Ravetch JV . 6 . Type I and type II Fc receptors regulate innate and adaptive immunity . Nature Immunology . 15 . 8 . 707–716 . August 2014 . 25045879 . 10.1038/ni.2939 . 7430760 .
  4. Boruchov AM, Heller G, Veri MC, Bonvini E, Ravetch JV, Young JW . Activating and inhibitory IgG Fc receptors on human DCs mediate opposing functions . The Journal of Clinical Investigation . 115 . 10 . 2914–2923 . October 2005 . 16167082 . 10.1172/JCI24772 . 1201664 .
  5. Smith KG, Clatworthy MR . FcgammaRIIB in autoimmunity and infection: evolutionary and therapeutic implications . Nature Reviews. Immunology . 10 . 5 . 328–343 . May 2010 . 20414206 . 10.1038/nri2821 . 4148599 . free . Menna Clatworthy .
  6. Simpson AP, Roghanian A, Oldham RJ, Chan HT, Penfold CA, Kim HJ, Inzhelevskaya T, Mockridge CI, Cox KL, Bogdanov YD, James S, Tutt AL, Rycroft D, Morley P, Dahal LN, Teige I, Frendeus B, Beers SA, Cragg MS . 6 . FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms . Cell Reports . 40 . 3 . 111099 . July 2022 . 35858562 . 9638011 . 10.1016/j.celrep.2022.111099 .
  7. Horejs-Hoeck J, Hren A, Mudde GC, Woisetschläger M . 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 . July 2005 . 15946258 . 1782155 . 10.1111/j.1365-2567.2005.02162.x .
  8. Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV . SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis . Immunity . 10 . 6 . 753–760 . June 1999 . 10403650 . 10.1016/s1074-7613(00)80074-6 . free .
  9. Wang TT, Ravetch JV . Functional diversification of IgGs through Fc glycosylation . The Journal of Clinical Investigation . 129 . 9 . 3492–3498 . September 2019 . 31478910 . 10.1172/JCI130029 . 6715372 .
  10. Wang J, Li Z, Xu L, Yang H, Liu W . Transmembrane domain dependent inhibitory function of FcγRIIB . Protein & Cell . 9 . 12 . 1004–1012 . December 2018 . 29497990 . 10.1007/s13238-018-0509-8 . 6251803 .
  11. van der Poel CE, Bajic G, Macaulay CW, van den Broek T, Ellson CD, Bouma G, Victora GD, Degn SE, Carroll MC . 6 . Follicular Dendritic Cells Modulate Germinal Center B Cell Diversity through FcγRIIB . Cell Reports . 29 . 9 . 2745–2755.e4 . November 2019 . 31775042 . 7015177 . 10.1016/j.celrep.2019.10.086 .
  12. Rankin CT, Veri MC, Gorlatov S, Tuaillon N, Burke S, Huang L, Inzunza HD, Li H, Thomas S, Johnson S, Stavenhagen J, Koenig S, Bonvini E . 6 . CD32B, the human inhibitory Fc-gamma receptor IIB, as a target for monoclonal antibody therapy of B-cell lymphoma . Blood . 108 . 7 . 2384–2391 . October 2006 . 16757681 . 10.1182/blood-2006-05-020602 . free .
  13. Zhou P, Comenzo RL, Olshen AB, Bonvini E, Koenig S, Maslak PG, Fleisher M, Hoffman J, Jhanwar S, Young JW, Nimer SD, Boruchov AM . 6 . 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 . April 2008 . 18216299 . 2275009 . 10.1182/blood-2007-11-125526 . free .

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