Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 50, Pages 19571-19578Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0810163105
Keywords
autoimmune disease; DC-SIGN; rheumatoid arthritis; sialylated IgG Fc; SIGN-R1
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Funding
- National Institutes of Health grants
- Virdante Pharmaceutical, Inc.
- Swedish Research Council
- Fernstrom Foundation
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The anti-inflammatory activity of intravenous Ig (IVIG) results from a minor population of the pooled IgG molecules that contains terminal alpha 2,6-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.
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