The neonatal Fc receptor (FcRn) is a ubiquitously expressed protein historically involved in IgG and albumin recycling. Recent data suggest an involvement in the pathophysiology of antibody-mediated autoimmune diseases. Among them, systemic lupus erythematosus (SLE) implies clinical and biological abnormalities of innate and adaptive circulating immune cells, potentially involving newly described functions of FcRn. In this study, FcRn expression was assessed by flow cytometry in peripheral blood leukocytes of 41 SLE patients with either active or inactive disease and 32 healthy donors. FcRn expression in B cells, natural killer cells, and T cells of SLE patients was statistically lower as compared to healthy donors. Conversely, FcRn level was statistically higher in non-classical monocyte subpopulations (CD14+CD16+ monocytes) of SLE patients versus healthy donors providing an interesting perspective to further explore its role in SLE pathophysiology.
SimisterNEMostovKE. An Fc receptor structurally related to MHC class I antigens. Nature1989; 337: 184–187.
2.
IsraelEJTaylorSWuZ, et al.Expression of the neonatal Fc receptor, FcRn, on human intestinal epithelial cells. Immunology1997; 92: 69–74.
3.
ZhuXMengGDickinsonBL, et al.MHC class I-related neonatal Fc receptor for IgG is functionally expressed in monocytes, intestinal macrophages, and dendritic cells. J Immunol2001; 166: 3266–3276.
4.
StapletonNMEinarsdóttirHKStemerdingAM, et al.The multiple facets of FcRn in immunity. Immunol Rev2015; 268: 253–268.
5.
JunkerFGordonJQureshiO. Fc gamma receptors and their role in antigen uptake, presentation, and T cell activation. Front Immunol2020; 11: 1393.
6.
VéghAFarkasAKövesdiD, et al.FcRn overexpression in transgenic mice results in augmented APC activity and robust immune response with increased diversity of induced antibodies. PLoS One2012; 7: e36286.
7.
VidarssonGStemerdingAMStapletonNM, et al.FcRn: An IgG receptor on phagocytes with a novel role in phagocytosis. Blood2006; 108: 3573–3579.
8.
BakerKRathTFlakMB, et al.Neonatal Fc receptor expression in dendritic cells mediates protective immunity against colorectal cancer. Immunity2013; 39: 1095–1107.
9.
DalloneauEBaroukhNMavridisK, et al.Downregulation of the neonatal Fc receptor expression in non-small cell lung cancer tissue is associated with a poor prognosis. Oncotarget2016; 7: 54415–54429.
10.
Cadena CastanedaDBrachetGGoupilleC, et al.The neonatal Fc receptor in cancer FcRn in cancer. Cancer Med2020; 9: 4736–4742.
11.
OlaruFLuoWSuleimanH, et al.Neonatal Fc receptor promotes immune complex-mediated glomerular disease. J Am Soc Nephrol2014; 25: 918–925.
12.
FengSGanHSunJ, et al.[Expression of neonatal Fc receptor on human nephritis and rat nephritis models]. Zhonghua Bing Li Xue Za Zhi2012; 41: 81–85.
13.
KouskoffVKorganowASDuchatelleV, et al.Organ-specific disease provoked by systemic autoimmunity. Cell1996; 87: 811–822.
14.
PatelDAPuig-CantoAChallaDK, et al.Neonatal Fc receptor blockade by Fc engineering ameliorates arthritis in a murine model. J Immunol2011; 187: 1015–1022.
15.
AkileshSPetkovaSSprouleTJ, et al.The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J Clin Invest2004; 113: 1328–1333.
16.
KanekoYNimmerjahnFRavetchJV. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science2006; 313: 670–673.
17.
SamuelssonATowersTLRavetchJV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science2001; 291: 484–486.
18.
ShererYGorsteinAFritzlerMJ, et al.Autoantibody explosion in systemic lupus erythematosus: More than 100 different antibodies found in SLE patients. Semin Arthritis Rheum2004; 34: 501–537.
19.
DörnerTFurieR. Novel paradigms in systemic lupus erythematosus. Lancet2019; 393: 2344–2358.
20.
YapDYHChanTM. B cell abnormalities in systemic lupus erythematosus and lupus nephritis-role in pathogenesis and Effect of Immunosuppressive Treatments. Int J Mol Sci2019, Epub ahead of print 10 December 2019. DOI: 10.3390/ijms20246231
21.
TanakaYShirakawaFOtaT, et al.Mechanism of spontaneous activation of B cells in patients with systemic lupus erythematosus. Analysis with anti-class II antibody. J Immunol1988; 140: 761–767.
22.
Salazar-CamarenaDCOrtiz-LazarenoPCCruzA, et al.Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus2016; 25: 582–592.
23.
FanouriakisAKostopoulouMAlunnoA, et al.2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis2019, Epub ahead of print 29 March 2019. DOI: 10.1136/annrheumdis-2019-215089
24.
WiseLMStohlW. Belimumab and rituximab in systemic lupus erythematosus: A tale of two B cell-targeting agents. Front Med (Lausanne)2020; 7: 303.
25.
MajaiGKissETarrT, et al.Decreased apopto-phagocytic gene expression in the macrophages of systemic lupus erythematosus patients. Lupus2014; 23: 133–145.
26.
KavaiMSzegediG. Immune complex clearance by monocytes and macrophages in systemic lupus erythematosus. Autoimmun Rev2007; 6: 497–502.
27.
WuZZhangSZhaoL, et al.Upregulation of CD16-monocyte subsets in systemic lupus erythematous patients. Clin Rheumatol2017; 36: 2281–2287.
28.
PetriMOrbaiAMAlarcónGS, et al.Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum2012; 64: 2677–2686.
29.
LiuXYeLBaiY, et al.Activation of the JAK/STAT-1 signaling pathway by IFN-gamma can down-regulate functional expression of the MHC class I-related neonatal Fc receptor for IgG. J Immunol2008; 181: 449–463.
30.
LiuXYeLChristiansonGJ, et al.NF-kappaB signaling regulates functional expression of the MHC class I-related neonatal Fc receptor for IgG via intronic binding sequences. J Immunol2007; 179: 2999–3011.
31.
MikulskaJESimisterNE. Analysis of the promoter region of the human FcRn gene. Biochim Biophys Acta2000; 1492: 180–184.
32.
MikulskaJE. Analysis of response elements involved in the regulation of the human neonatal Fc receptor gene (FCGRT). PLoS One2015; 10: e0135141.
33.
SachsUJHSocherIBraeunlichCG, et al.A variable number of tandem repeats polymorphism influences the transcriptional activity of the neonatal Fc receptor alpha-chain promoter. Immunol2006; 119: 83–89.
34.
CejasRBFergusonDCQuiñones-LombrañaA, et al.Contribution of DNA methylation to the expression of FCGRT in human liver and myocardium. Sci Rep2019; 9: 8674.
35.
FergusonDCBlancoJG. Regulation of the human Fc-neonatal receptor alpha-chain gene FCGRT by microRNA-3181. Pharm Res2018; 35: 15.
36.
Ziegler-HeitbrockHWL. Heterogeneity of human blood monocytes: The CD14+CD16+ subpopulation. Immunol Today1996; 17: 424–428.
37.
OlaruFDöbelTLonsdorfAS, et al.Intracapillary immune complexes recruit and activate slan-expressing CD16+ monocytes in human lupus nephritis. JCI Insight2018; 3: e96492. Epub ahead of print 7 June 2018. DOI: 10.1172/jci.insight.96492
38.
LoodCArveSLedbetterJ, et al.TLR7/8 activation in neutrophils impairs immune complex phagocytosis through shedding of FcgRIIA. J Exp Med2017; 214: 2103–2119.
39.
HuS-YJiaX-YLiJ-N, et al.T cell infiltration is associated with kidney injury in patients with anti-glomerular basement membrane disease. Sci China Life Sci2016; 59: 1282–1289.
40.
MunroeMELuRZhaoYD, et al.Altered type II interferon precedes autoantibody accrual and elevated type I interferon activity prior to systemic lupus erythematosus classification. Ann Rheum Dis2016; 75: 2014–2021.
41.
HubbardJJPyzikMRathT, et al.FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity. J Exp Med2020; 217: e20200359. DOI: 10.1084/jem.20200359
42.
SzücsGKávaiMKissE, et al.Correlation of IgG Fc receptors on granulocytes with serum immune complex level in systemic lupus erythematosus. Scand J Immunol1995; 42: 577–580.
43.
GanHFengSWuH, et al.Neonatal Fc receptor stimulation induces ubiquitin c-terminal hydrolase-1 overexpression in podocytes through activation of p38 mitogen-activated protein kinase. Hum Pathol2012; 43: 1482–1490.
44.
McEwanWATamJCHWatkinsonRE, et al.Intracellular antibody-bound pathogens stimulate immune signaling via the Fc receptor TRIM21. Nat Immunol2013; 14: 327–336.
NewlandACSánchez-GonzálezBRejtőL, et al.Phase 2 study of efgartigimod, a novel FcRn antagonist, in adult patients with primary immune thrombocytopenia. Am J Hematol2020; 95: 178–187.
47.
SesarmanAVidarssonGSitaruC. The neonatal Fc receptor as therapeutic target in IgG-mediated autoimmune diseases. Cell Mol Life Sci2010; 67: 2533–2550.
48.
NimmerjahnFRavetchJV. Anti-inflammatory actions of intravenous immunoglobulin. Annu Rev Immunol2008; 26: 513–533.
49.
HowardJFBrilVBurnsTM, et al.Randomized phase 2 study of FcRn antagonist efgartigimod in generalized myasthenia gravis. Neurology2019; 92: e2661–e2673. DOI: 10.1212/WNL.0000000000007600
50.
SesarmanASitaruAGOlaruF, et al.Neonatal Fc receptor deficiency protects from tissue injury in experimental epidermolysis bullosa acquisita. J Mol Med2008; 86: 951–959.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
