title: Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: University of Glasgow, Glasgow, UK.
authors: Lindsay M
authors: LM
authors: MacLellan
authors: Jennifer
authors: J
authors: Montgomery
authors: Fujimi
authors: F
authors: Sugiyama
authors: Susan M
authors: SM
authors: Kitson
authors: Katja
authors: K
authors: Thümmler
authors: Gregg J
authors: GJ
authors: Silverman
authors: Stephen A
authors: SA
authors: Beers
authors: Robert J B
authors: RJ
authors: Nibbs
authors: Iain B
authors: IB
authors: McInnes
authors: Carl S
authors: CS
authors: Goodyear
mesh_terms: D000818:Animals; D000936:Antigen-Antibody Complex / Q000494:pharmacology / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D006801:Humans; D007136:Immunoglobulins / Q000502:physiology / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy* / Q000503:physiopathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017452:Receptors, IgG / Q000235:genetics / Q000502:physiology; D013205:Staphylococcal Protein A / Q000494:pharmacology / Q000627:therapeutic use*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology*
chemical_list: D000936:Antigen-Antibody Complex; D018501:Antirheumatic Agents; D016207:Cytokines; D007136:Immunoglobulins; D017452:Receptors, IgG; D013205:Staphylococcal Protein A