title: Intravenous gammaglobulin suppresses inflammation through a novel T(H)2 pathway.
abstract: High-dose intravenous immunoglobulin is a widely used therapeutic preparation of highly purified immunoglobulin G (IgG) antibodies. It is administered at high doses (1-2 grams per kilogram) for the suppression of autoantibody-triggered inflammation in a variety of clinical settings. This anti-inflammatory activity of intravenous immunoglobulin is triggered by a minor population of IgG crystallizable fragments (Fcs), with glycans terminating in α2,6 sialic acids (sFc) that target myeloid regulatory cells expressing the lectin dendritic-cell-specific ICAM-3 grabbing non-integrin (DC-SIGN; also known as CD209). Here, to characterize this response in detail, we generated humanized DC-SIGN mice (hDC-SIGN), and demonstrate that the anti-inflammatory activity of intravenous immunoglobulin can be recapitulated by the transfer of bone-marrow-derived sFc-treated hDC-SIGN(+) macrophages or dendritic cells into naive recipients. Furthermore, sFc administration results in the production of IL-33, which, in turn, induces expansion of IL-4-producing basophils that promote increased expression of the inhibitory Fc receptor FcγRIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates FcγRIIB on macrophages, and suppresses serum-induced arthritis. Consistent with these results, transfer of IL-33-treated basophils suppressed induced arthritic inflammation. This novel DC-SIGN-T(H)2 pathway initiated by an endogenous ligand, sFc, provides an intrinsic mechanism for maintaining immune homeostasis that could be manipulated to provide therapeutic benefit in autoimmune diseases.
authors.affiliation: Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Anthony
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wermeling
authors.forename: Jeffrey V
authors.initials: JV
authors.lastname: Ravetch
mesh_terms: D000818:Animals; D001168:Arthritis / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000276:immunology; D001491:Basophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001853:Bone Marrow; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003460:Crystallization; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000737:chemistry / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D016756:Immunoglobulins, Intravenous / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology*; D000067596:Interleukin-33; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology*; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
chemical_list: D015815:Cell Adhesion Molecules; D007074:Immunoglobulin G; D016756:Immunoglobulins, Intravenous; D000067596:Interleukin-33; D015847:Interleukin-4; D007378:Interleukins; D037181:Lectins, C-Type; D008024:Ligands; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin; C080571:Fc gamma receptor IIB; C506535:Il33 protein, mouse