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]
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).[6] It is the only inhibitory type I FcγR[7] 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.[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]
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.[9][6]
The phosphorylated ITIM of FcγRIIB recruits the inositol
phosphatasesSHIP1 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]
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.[9]
Tsuchiya N, Kyogoku C (August 2005). "Role of Fc gamma receptor IIb polymorphism in the genetic background of systemic lupus erythematosus: insights from Asia". Autoimmunity. 38 (5): 347–352.
doi:
10.1080/08916930500123926.
PMID16227149.
S2CID37295376.
Engelhardt W, Geerds C, Frey J (June 1990). "Distribution, inducibility and biological function of the cloned and expressed human beta Fc receptor II". European Journal of Immunology. 20 (6): 1367–1377.
doi:
10.1002/eji.1830200624.
PMID2142460.
S2CID13498051.
Engelhardt W, Matzke J, Schmidt RE (April 1995). "Activation-dependent expression of low affinity IgG receptors Fc gamma RII(CD32) and Fc gamma RIII(CD16) in subpopulations of human T lymphocytes". Immunobiology. 192 (5): 297–320.
doi:
10.1016/s0171-2985(11)80172-5.
PMID7649565.
D'Ambrosio D, Hippen KL, Minskoff SA, Mellman I, Pani G, Siminovitch KA, Cambier JC (April 1995). "Recruitment and activation of PTP1C in negative regulation of antigen receptor signaling by Fc gamma RIIB1". Science. 268 (5208): 293–297.
Bibcode:
1995Sci...268..293D.
doi:
10.1126/science.7716523.
PMID7716523.
Warmerdam PA, van den Herik-Oudijk IE, Parren PW, Westerdaal NA, van de Winkel JG, Capel PJ (March 1993). "Interaction of a human Fc gamma RIIb1 (CD32) isoform with murine and human IgG subclasses". International Immunology. 5 (3): 239–247.
doi:
10.1093/intimm/5.3.239.
PMID8466861.
Muraille E, Bruhns P, Pesesse X, Daëron M, Erneux C (April 2000). "The SH2 domain containing inositol 5-phosphatase SHIP2 associates to the immunoreceptor tyrosine-based inhibition motif of Fc gammaRIIB in B cells under negative signaling". Immunology Letters. 72 (1): 7–15.
doi:
10.1016/S0165-2478(00)00162-0.
PMID10789675.
Jessup CF, Ridings J, Ho A, Nobbs S, Roberton DM, Macardle P, Zola H (July 2001). "The Fc receptor for IgG (Fc gamma RII; CD32) on human neonatal B lymphocytes". Human Immunology. 62 (7): 679–685.
doi:
10.1016/S0198-8859(01)00257-9.
PMID11423173.