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CD4⁺ T Cells Recognizing a Single Self-Peptide Expressed by APCs Induce Spontaneous Autoimmune Arthritis¹

Andrew L. Rankin^*, Amy J. Reed^*,, Soyoung Oh^*, Cristina Cozzo Picca^*, Heath M. Guay^*, Joseph Larkin, III^*, Laura Panarey^*, Malinda K. Aitken^*, Brigitte Koeberlein, Peter E. Lipsky, John E. Tomaszewski, Ali Naji and Andrew J. Caton^2,*

^* The Wistar Institute, Department of Surgery, and Department of Pathology and Laboratory Medicine, University of Pennsylvania Medical Center, Philadelphia, PA 19104; and National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892

We have examined processes leading to the spontaneous development of autoimmune inflammatory arthritis in transgenic mice containing CD4⁺ T cells targeted to a nominal Ag (hemagglutinin (HA)) and coexpressing HA driven by a MHC class II promoter. Despite being subjected to multiple tolerance mechanisms, autoreactive CD4⁺ T cells accumulate in the periphery of these mice and promote systemic proinflammatory cytokine production. The majority of mice spontaneously develop inflammatory arthritis, which is accompanied by an enhanced regional immune response in lymph nodes draining major joints. Arthritis development is accompanied by systemic B cell activation; however, neither B cells nor Ab is required for arthritis development, since disease develops in a B cell-deficient background. Moreover, arthritis also develops in a recombinase activating gene-deficient background, indicating that the disease process is driven by CD4⁺ T cells recognizing the neo-self HA Ag. These findings show that autoreactive CD4⁺ T cells recognizing a single self-Ag, expressed by systemically distributed APCs, can induce arthritis via a mechanism that is independent of their ability to provide help for autoantibody production.

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 National Institutes of Health, Sibley Memorial Hospital, Lupus Foundation of Southeastern Pennsylvania, and by the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health.

² Address correspondence and reprint requests to Dr. Andrew J. Caton, The Wistar Institute, Room 262, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address: caton{at}wistar.org

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CCP, cyclic citrullinated peptide; CIA, collagen-induced arthritis; GPI, glucose 6-phosphate isomerase; HA, hemagglutinin; LN, lymph node; DC, dendritic cell; AP, alkaline phosphatase; CD4SP, CD4 single positive.

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The JI 2008 180: 681-682. [Full Text]  

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