Identification of a receptor required for the anti-inflammatory activity of IVIG.
The anti-inflammatory activity of intravenous Ig (IVIG) results from a minor population of the pooled IgG molecules that contains terminal alpha2,6-sialic acid linkages on their Fc-linked glycans. These anti-inflammatory properties can be recapitulated with a fully recombinant preparation of appropriately sialylated IgG Fc fragments. We now demonstrate that these sialylated Fcs require a specific C-type lectin, SIGN-R1, (specific ICAM-3 grabbing non-integrin-related 1) expressed on macrophages in the splenic marginal zone. Splenectomy, loss of SIGN-R1(+) cells in the splenic marginal zone, blockade of the carbohydrate recognition domain (CRD) of SIGN-R1, or genetic deletion of SIGN-R1 abrogated the anti-inflammatory activity of IVIG or sialylated Fc fragments. Although SIGN-R1 has not previously been shown to bind to sialylated glycans, we demonstrate that it preferentially binds to 2,6-sialylated Fc compared with similarly sialylated, biantennary glycoproteins, thus suggesting that a specific binding site is created by the sialylation of IgG Fc. A human orthologue of SIGN-R1, DC-SIGN, displays a similar binding specificity to SIGN-R1 but differs in its cellular distribution, potentially accounting for some of the species differences observed in IVIG protection. These studies thus identify an antibody receptor specific for sialylated Fc, and present the initial step that is triggered by IVIG to suppress inflammation.
Anthony
Robert M
RM
The Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA.
Wermeling
Fredrik
F
Karlsson
Mikael C I
MC
Ravetch
Jeffrey V
JV
D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000276:immunology / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D016756:Immunoglobulins, Intravenous / Q000276:immunology / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D019158:N-Acetylneuraminic Acid / Q000276:immunology; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D000894:Anti-Inflammatory Agents, Non-Steroidal; D015815:Cell Adhesion Molecules; D007141:Immunoglobulin Fc Fragments; D016756:Immunoglobulins, Intravenous; D037181:Lectins, C-Type; D019158:N-Acetylneuraminic Acid; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin