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Destructive Arthritis in the Absence of Both FcRI and FcRIII¹

Peter Boross^*, Peter L. van Lent, Javier Martin-Ramirez^*, Jos van der Kaa^*, Melissa H. C. M. Mulder^*, Jill W. C. Claassens^*, Wim B. van den Berg, Victoria L. Arandhara^* and J. Sjef Verbeek^2,*

^* Department of Human Genetics, Leiden University Medical Center, Leiden; and Department of Rheumatology, University Medical Center St. Radboud, Nijmegen, The Netherlands

Fc receptors for IgG (FcR) have been implicated in the development of arthritis. However, the precise contribution of the individual FcR to joint pathology is unclear. In this study, the role of the different FcR was assessed both in an active and in a passive mouse model of arthritis by analyzing disease development in double and triple knockout (KO) offspring from crosses of FcRI KO, FcRIII KO, FcRI/III double KO, or FcR -chain KO with the FcRII KO on C57BL6 background, which is susceptible for collagen-induced arthritis (CIA). In the active CIA model, onset was significantly delayed in the absence of FcRIII, whereas incidence and maximum severity were significantly decreased in FcRI/II/III triple KO but not in FcRII/III double KO and FcRI/II double KO mice as compared with FcRII KO animals. Remarkably, fully destructive CIA developed in FcRI/II/III triple KO mice. In contrast, FcR /FcRII double KO mice were resistant to CIA. These findings were confirmed with the passive KRN serum-induced arthritis model. These results indicate that all activating FcR play a role in the development of arthritis, mainly in the downstream effector phase. FcRIII is critically required for early arthritis onset, and FcRI can substantially contribute to arthritis pathology. Importantly, FcRI and FcRIII were together dispensable for the development of destructive arthritis but the FcR -chain was not, suggesting a role for another FcR -chain associated receptor, most likely FcRIV. In addition, FcRII plays a negative regulatory role in both the central and effector phase of arthritis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Dutch Arthritis Association (Nationaal Reumafonds, to P.L.v.L. and W.B.v.d.B.). V.A. and J.M.R. were supported by the European Union Grant IMDEMI MRTN-CT-2004-005632.

² Address correspondence and reprint requests to Dr. J. Sjef Verbeek, Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, Postzone S4-P, 2333 ZA Leiden, The Netherlands. E-mail address: j.s.verbeek{at}lumc.nl

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; bCII, bovine type II collagen; KO, knockout; GPI, glucose-6-phosphate isomerase; IC, immune complex; AIA, Ag-induced arthritis; PG, proteoglycan; K/BxN, KRN.