Co-opting endogenous immunoglobulin for the regulation of inflammation and osteoclastogenesis in humans and mice

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 and Rheumatism, 63(12), pp. 3897-3907. (doi:10.1002/art.30629) (PMID:22127707) (PMCID:PMC3598489)

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Publisher's URL: http://dx.doi.org/10.1002/art.30629

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 Fc gamma receptor type I-dependent polarization of macrophages to a regulatory phenotype, rendering them unresponsive to activators such as interferon-gamma. 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McInnes, Professor Iain and Kitson, Miss Susan and Montgomery, Dr Jennifer and Nibbs, Professor Robert and Sugiyama, Ms Fujimi and Maclellan, Dr Lindsay and Goodyear, Professor Carl
Authors: 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.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Arthritis and Rheumatism
ISSN:0004-3591
ISSN (Online):1529-0131

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