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and Nitric Oxide1
* Laboratory of Experimental Rheumatology, Robert S. Boas Center for Genomics and Human Genetics, The Feinstein Institute for Medical Research, Manhasset, NY;
North Shore-LIJ Graduate School of Molecular Medicine, Manhasset, NY 11030;
Center for Immunology and Inflammation, The Feinstein Institute for Medical Research, Manhasset, NY 11030;
Center for Patient-Oriented Research, The Feinstein Institute for Medical Research, Manhasset, NY 11030;
¶ Division of Rheumatology, Department of Medicine, North Shore University Hospital, Manhasset, NY;
|| Department of Medicine, New York University School of Medicine, New York, NY 11030
Neutrophils are required for the development of arthritis, and their migration into the synovial tissue coincides with the onset of clinical disease. Synovial neutrophil numbers also correlate with rheumatoid arthritis disease activity and severity. We hypothesized that certain arthritis severity genes regulate disease via the regulation of neutrophil migration into the joint. This hypothesis was tested in the synovial-like air pouch model injected with carrageenan using arthritis-susceptible DA and arthritis-resistant F344 rats. DA had nearly 3-fold higher numbers of exudate neutrophils compared with F344 (p < 0.001). Five DA.F344(QTL) strains congenic for severity loci and protected from autoimmune arthritis were studied. Only DA.F344(Cia4) (chromosome 7) and DA.F344(Cia6) (chromosome 8) congenics had significantly lower exudate neutrophil counts compared with DA. TNF-
levels were 2.5-fold higher in DA exudates as compared with F344 exudates, and that difference was accounted for by the Cia4 locus. Exudate levels of NO, a known inhibitor of neutrophil chemotaxis, were higher in F344, compared with DA, and that difference was accounted for by Cia6. This is the first time that non-MHC autoimmune arthritis loci are found to regulate three central components of the innate immune response implicated in disease pathogenesis, namely neutrophil migration into an inflammatory site, as well as exudate levels of TNF- and NO. These observations underscore the importance of identifying the Cia4 and Cia6 genes, and suggest that they should generate useful novel targets for development of new therapies.
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 Funded by National Institutes of Health Grants R01-AR46213, R01-AR052439 (National Institute of Arthritis and Musculoskeletal and Skin Diseases) and R01-AI54348 (National Institute of Allergy and Infectious Diseases) to P.S.G.
2 Address correspondence and reprint requests to Dr. Pércio S. Gulko, Laboratory of Experimental Rheumatology, The Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institute for Medical Research at North Shore-LIJ, 350 Community Drive, Room 139, Manhasset, NY 11030. E-mail address: pgulko{at}nshs.edu
3 Abbreviations used in this paper: RA, rheumatoid arthritis; QTL, quantitative trait loci; SOD, superoxide dismutase; LXA4, lipoxin A4; LTB4, leukotriene B4.
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