title: Protection in antibody- and T cell-mediated autoimmune diseases by antiinflammatory IgG Fcs requires type II FcRs.
abstract: The antiinflammatory activity of intravenous immunoglobulin (IVIG) is dependent on the presence of sialic acid in the core IgG fragment crystallizable domain (Fc) glycan, resulting in increased conformational flexibility of the CH2 domain with corresponding modulation of Fc receptor (FcR) binding specificity from type I to type II receptors. Sialylated IgG Fc (sFc) increases the activation threshold of innate effector cells to immune complexes by stimulating the up-regulation of the inhibitory receptor FcγRIIB. We have found that the structural alterations induced by sialylation can be mimicked by specific amino acid modifications to the CH2 domain. An IgG Fc variant with a point mutation at position 241 (F→A) exhibits antiinflammatory activity even in the absence of sialylation. F241A and sFc protect mice from arthritis in the K/BxN-induced model and, in the T cell-mediated experimental autoimmune encephalomyelitis (EAE) mouse model, suppress disease by specifically activating regulatory T cells (Treg cells). Protection by these antiinflammatory Fcs in both antibody- and T cell-mediated autoimmune diseases required type II FcRs and the induction of IL-33. These results further clarify the mechanism of action of IVIG in both antibody- and T cell-mediated inflammatory diseases and demonstrate that Fc variants that mimic the structural alterations induced by sialylation, such as F241A, can be promising therapeutic candidates for the treatment of various autoimmune disorders.
authors: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
authors: Benjamin M
authors: BM
authors: Fiebiger
authors: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
authors: Jad
authors: J
authors: Maamary
authors: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065.
authors: Andrew
authors: A
authors: Pincetic
authors: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065 ravetch@rockefeller.edu.
authors: Jeffrey V
authors: JV
authors: Ravetch
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001854:Bone Marrow Cells / Q000166:cytology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000378:metabolism; D011961:Receptors, Fc / Q000276:immunology*; D017455:Receptors, IgE / Q000378:metabolism; D012794:Sialic Acids / Q000737:chemistry; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D000906:Antibodies; D015815:Cell Adhesion Molecules; D007074:Immunoglobulin G; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D011961:Receptors, Fc; D017455:Receptors, IgE; D012794:Sialic Acids; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
keywords: IgG Fc sialylation; Treg cells; antiinflammatory; conformational change