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Plasmacytoid Dendritic Cells Regulate Breach of Self-Tolerance in Autoimmune Arthritis¹

Sarah L. Jongbloed^2,*, Robert A. Benson^2,, Mohammed B. Nickdel, Paul Garside, Iain B. McInnes^* and James M. Brewer^3,

^* Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, and Centre for Biophotonics, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, United Kingdom

Achieving remission in rheumatoid arthritis (RA) remains elusive despite current biological therapeutics. Consequently, interest has increased in strategies to re-establish immune tolerance to provide long-term disease suppression. Although dendritic cells (DC) are prime candidates in initiating autoreactive T cell responses, and their presence within the synovial environment suggests a role in generation and maintenance of autoreactive, synovial T cell responses, their functional importance remains unclear. We investigated the contribution made by plasmacytoid DCs (pDCs) in the spontaneous breach of tolerance to arthritis-related self proteins, including rheumatoid factor, citrullinated peptide, and type II collagen observed in a novel arthritis model. Selective pDC depletion in vivo enhanced the severity of articular pathology and enhanced T and B cell autoimmune responses against type II collagen. pDC may offer a net anti-inflammatory function in the context of articular breach of tolerance. Such data will be vital in informing DC modulatory/therapeutic approaches.

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 funded by grants from the Chief Scientist Office of the Scottish Executive and the Arthritis Research Campaign. M.B.N. was funded through a grant from Astra Zeneca.

² S.L.J. and R.A.B. contributed equally to this work and should be considered first authors.

³ Address correspondence and reprint requests to Dr. James M. Brewer, Centre for Biophotonics, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 ONR, United Kingdom. E-mail address: james.brewer{at}strath.ac.uk

⁴ Abbreviations used in this paper: RA, rheumatoid arthritis; CCP, cyclic citrullinated peptide; CIA, collagen induced arthritis; CII, collagen type II; DC, dendritic cell; pDC, plasmacytoid DC; mDC, myeloid DC; Treg, regulatory T cell; Tg, transgenic; LN, lymph node; HAO, heat aggregated ovalbumin.