Publication Date:
2011-06-21
Description:
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 alpha2,6 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 FcgammaRIIB on effector macrophages. Systemic administration of the T(H)2 cytokines IL-33 or IL-4 upregulates FcgammaRIIB 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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694429/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694429/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Anthony, Robert M -- Kobayashi, Toshihiko -- Wermeling, Fredrik -- Ravetch, Jeffrey V -- R01 AI035875/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Jun 19;475(7354):110-3. doi: 10.1038/nature10134.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Genetics and Immunology, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21685887" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Arthritis/drug therapy/immunology/pathology
;
Autoimmune Diseases/drug therapy/immunology
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Basophils/drug effects/immunology/metabolism
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Bone Marrow
;
Cell Adhesion Molecules/genetics/immunology/metabolism
;
Crystallization
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Dendritic Cells/cytology/immunology
;
Humans
;
Immunoglobulin G/chemistry/immunology/metabolism/pharmacology
;
Immunoglobulins, Intravenous/chemistry/*immunology/metabolism/pharmacology
;
Inflammation/drug therapy/*immunology
;
Interleukin-33
;
Interleukin-4/immunology/metabolism
;
Interleukins/immunology/metabolism/pharmacology
;
Lectins, C-Type/genetics/immunology/metabolism
;
Ligands
;
Macrophages/cytology/immunology
;
Mice
;
Receptors, Cell Surface/genetics/immunology/metabolism
;
Receptors, IgG/immunology/metabolism
;
Th2 Cells/drug effects/*immunology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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