Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice
Article first published online: 29 NOV 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 12, pages 3897–3907, December 2011
How to Cite
MacLellan, L. M., Montgomery, J., Sugiyama, F., Kitson, S. M., Thümmler, K., Silverman, G. J., Beers, S. A., Nibbs, R. J. B., McInnes, I. B. and Goodyear, C. S. (2011), Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice. Arthritis & Rheumatism, 63: 3897–3907. doi: 10.1002/art.30629
- Issue published online: 29 NOV 2011
- Article first published online: 29 NOV 2011
- Accepted manuscript online: 30 AUG 2011 10:06AM EST
- Manuscript Accepted: 16 AUG 2011
- Manuscript Received: 3 OCT 2010
- University of Glasgow
- Arthritis Research UK
- Medical Research Scotland (Vipiana Award)
- Capacity Building Award in Integrative Mammalian Biology
- Biotechnology and Biological Sciences Research Council
- British Pharmacological Society Integrative Pharmacology Fund (donors AstraZeneca, GlaxoSmithKline, and Pfizer)
- Knowledge Transfer Network
- Medical Research Council
- Scottish Further and Higher Education Funding Council
- DFG. Grant Number: postdoctoral fellowship TH1599/1-1
- Arthritis Research UK. Grant Number: 17653
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.
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).
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.
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.