Document Detail

Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice.
MedLine Citation:
PMID:  22127707     Owner:  NLM     Status:  MEDLINE    
OBJECTIVE: Cells of the monocytic lineage play fundamental roles in the regulation of health, ranging from the initiation and resolution of inflammation to bone homeostasis. In rheumatoid arthritis (RA), the inflamed synovium exhibits characteristic infiltration of macrophages along with local osteoclast maturation, which, together, drive chronic inflammation and downstream articular destruction. The aim of this study was to explore an entirely novel route of immunoglobulin-mediated regulation, involving simultaneous suppression of the inflammatory and erosive processes in the synovium.
METHODS: Using in vivo and in vitro studies of human cells and a murine model of RA, the ability of staphylococcal protein A (SPA) to interact with and modulate cells of the monocytic lineage was tested. In addition, the efficacy of SPA as a therapeutic agent was evaluated in murine collagen-induced arthritis (CIA).
RESULTS: SPA showed a capacity to appropriate circulating IgG, by generating small immunoglobulin complexes that interacted with monocytes, macrophages, and preosteoclasts. Formation of these complexes resulted in Fcγ receptor type I-dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-γ. The antiinflammatory complexes also had the capacity to directly inhibit differentiation of preosteoclasts into osteoclasts in humans. Moreover, administration of SPA in the early stages of disease substantially alleviated the clinical and histologic erosive features of CIA in mice.
CONCLUSION: These findings demonstrate the overarching utility of immunoglobulin complexes for the prevention and treatment of inflammatory diseases. The results shed light on the interface between immunoglobulin complex-mediated pathways, osteoclastogenesis, and associated pathologic processes. Thus, therapeutic agents designed to harness all of these properties may be an effective treatment for arthritis, by targeting both the innate inflammatory response and prodestructive pathways.
Lindsay M MacLellan; Jennifer Montgomery; Fujimi Sugiyama; Susan M Kitson; Katja Thümmler; Gregg J Silverman; Stephen A Beers; Robert J B Nibbs; Iain B McInnes; Carl S Goodyear
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Arthritis and rheumatism     Volume:  63     ISSN:  1529-0131     ISO Abbreviation:  Arthritis Rheum.     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-11-30     Completed Date:  2012-01-27     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  0370605     Medline TA:  Arthritis Rheum     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3897-907     Citation Subset:  AIM; IM    
Copyright Information:
Copyright © 2011 by the American College of Rheumatology.
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MeSH Terms
Antigen-Antibody Complex / pharmacology,  therapeutic use*
Antirheumatic Agents / pharmacology,  therapeutic use
Arthritis, Experimental / drug therapy*,  immunology,  physiopathology
Cell Differentiation / physiology*
Cell Proliferation
Cells, Cultured
Cytokines / physiology
Disease Models, Animal
Immunoglobulins / physiology,  therapeutic use*
Inflammation / drug therapy*,  physiopathology
Leukocytes, Mononuclear / cytology,  drug effects,  physiology
Macrophages / cytology,  drug effects,  physiology
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Knockout
Osteoclasts / cytology,  drug effects,  physiology*
Receptors, IgG / genetics,  physiology
Staphylococcal Protein A / pharmacology,  therapeutic use*
Stem Cells / cytology,  drug effects,  physiology*
Grant Support
17653//Arthritis Research UK; 17653//Arthritis Research UK; 19701//Arthritis Research UK; R01 AI040305/AI/NIAID NIH HHS; R01 AI068063/AI/NIAID NIH HHS; R01 AI090118/AI/NIAID NIH HHS; R03 AI046637/AI/NIAID NIH HHS; R21 CA104815/CA/NCI NIH HHS; //Biotechnology and Biological Sciences Research Council
Reg. No./Substance:
0/Antigen-Antibody Complex; 0/Antirheumatic Agents; 0/Cytokines; 0/Immunoglobulins; 0/Receptors, IgG; 0/Staphylococcal Protein A

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