title: Role of FcγRIIIA (CD16) in IVIg-mediated anti-inflammatory function.
abstract: The mechanism for anti-inflammatory action of intravenous immunoglobulin (IVIg) in the treatment of autoimmune and inflammatory diseases involves IgG Fc receptors (FcγR). Although the inhibitory FcγRIIB plays an important role in IVIg action, FcγRIIIA has recently been identified as another major anti-inflammatory actor. Interaction of FcγRIIIA with uncomplexed IgG1 or IVIg, or with bivalent anti-FcγRIII F(ab')2 dampened calcium responses, ROS production, endocytosis and phagocytosis, induced by heterologous activating receptors. This inhibitory action required the inhibitory configuration of the ITAM motif (ITAMi) present within the FcγRIII-associated FcRγ subunit. This allowed SHP-1 recruitment and formation of intracellular inhibisome clusters containing FcγRIII and the targeted activating receptor. Therefore, IVIg functionally interact with FcγRIIIA inducing ITAMi signaling which can prevent development of autoimmune and inflammatory disorders independently of FcγRIIB. This new mechanism of action for IVIg reveals a therapeutic potential for FcγRIIIA targeting in inflammatory diseases.
authors.affiliation: Inserm, U1149, Centre de Recherche sur l'Inflammation, Paris, France.
authors.forename: Sanae
authors.initials: S
authors.lastname: Ben Mkaddem
authors.forename: Meryem
authors.initials: M
authors.lastname: Aloulou
authors.forename: Marc
authors.initials: M
authors.lastname: Benhamou
authors.forename: Renato C
authors.initials: RC
authors.lastname: Monteiro
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000628:therapy*; D020013:Calcium Signaling; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000276:immunology* / Q000627:therapeutic use; D007167:Immunotherapy / Q000379:methods*; D007249:Inflammation / Q000276:immunology / Q000628:therapy*; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D010587:Phagocytosis; D011485:Protein Binding; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016756:Immunoglobulins, Intravenous; D046912:Multiprotein Complexes; D017452:Receptors, IgG; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6
references.citation: Blood. 2012 May 31;119(22):5261-4
references.pmid: 22508937
references.citation: Expert Rev Mol Med. 2009 Aug 13;11:e24
references.pmid: 19674504
references.citation: J Clin Immunol. 2010 May;30 Suppl 1:S65-9
references.pmid: 20424898
references.citation: J Immunol. 2008 Feb 15;180(4):2669-78
references.pmid: 18250479
references.citation: Nat Rev Immunol. 2002 Aug;2(8):580-92
references.pmid: 12154377
references.citation: Immunity. 2005 Jan;22(1):31-42
references.pmid: 15664157
references.citation: Nature. 2011 Jun 19;475(7354):110-3
references.pmid: 21685887
references.citation: Nat Rev Drug Discov. 2012 Mar 30;11(4):311-31
references.pmid: 22460124
references.citation: Nat Rev Immunol. 2010 May;10(5):328-43
references.pmid: 20414206
references.citation: Nat Med. 2007 Nov;13(11):1368-74
references.pmid: 17934470
references.citation: Curr Top Microbiol Immunol. 2011;350:105-25
references.pmid: 20680807
references.citation: Curr Opin Organ Transplant. 2011 Feb;16(1):7-14
references.pmid: 21150612
references.citation: Thromb Haemost. 2002 Dec;88(6):890-1
references.pmid: 12529734
references.citation: Blood. 2012 Mar 29;119(13):3084-96
references.pmid: 22337713
references.citation: Immunol Rev. 2009 Nov;232(1):59-71
references.pmid: 19909356
references.citation: Nat Rev Immunol. 2013 Mar;13(3):176-89
references.pmid: 23411799
references.citation: Immunol Today. 1997 Jun;18(6):286-91
references.pmid: 9190115
references.citation: Cell. 1998 Mar 20;92(6):705-7
references.pmid: 9529246
references.citation: Immunol Rev. 2008 Aug;224:70-84
references.pmid: 18759921
references.citation: Pediatr Blood Cancer. 2006 Oct 15;47(5 Suppl):710-3
references.pmid: 16933274
references.citation: Cell. 1994 Feb 11;76(3):519-29
references.pmid: 8313472
references.citation: J Immunol. 2013 Jan 1;190(1):106-14
references.pmid: 23209322
references.citation: Annu Rev Immunol. 2008;26:513-33
references.pmid: 18370923
references.citation: Sci Signal. 2011 Apr 19;4(169):ra24
references.pmid: 21505186
references.citation: N Engl J Med. 2001 Sep 6;345(10):747-55
references.pmid: 11547745
references.citation: Trends Immunol. 2008 Dec;29(12):608-15
references.pmid: 18926775
references.citation: J Clin Immunol. 2007 May;27(3):233-45
references.pmid: 17351760