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Controls Immunoglobulin Production and Th1/Th2 Cytokine Balance in the Adaptive Immune Response to Allergen1
* Department of Medicine, Division of Pulmonary and Critical Care Medicine, and
Department of Genetics University of North Carolina, Chapel Hill, NC 27599; and
Laboratory of Respiratory Biology, Cell Biology Section, and
Laboratory of Experimental Pathology, Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709
The retinoid-related orphan receptors (ROR) comprise a distinct subfamily of nuclear receptors with the capacity to act as both repressors and activators of transcription. ROR
, the most recently identified member of the ROR family, has been shown to be important for the development of normal lymphocyte compartments as well as organogenesis of some lymphoid organs. In this report, we examine the capacity of ROR-deficient mice to develop an adaptive immune response to Ag using OVA-induced inflammation in mice as a model for allergic airway disease. In sham-treated mice lacking ROR, low-grade pulmonary inflammation was observed and characterized by the perivascular accumulation of B and T lymphocytes, increased numbers of inflammatory cells in the lung lavage fluid, and polyclonal Ig activation. Following sensitization and challenge, the capacity of these animals to develop the allergic phenotype was severely impaired as evidenced by attenuated eosinophilic pulmonary inflammation, reduced numbers of CD4+ lymphocytes, and lower Th2 cytokines/chemokine protein and mRNA expression in the lungs. IFN- and IL-10 production was markedly greater in splenocytes from ROR-deficient mice following in vitro restimulation with OVA compared with wild-type splenocytes, and a shift toward a Th1 immune response was observed in sensitized/challenged ROR-deficient animals in vivo. These data reveal a critical role for ROR in the regulation of Ig production and Th1/Th2 balance in adaptive immunity.
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 is supported by Intramural Research Program of the National Institute on Environmental Health Sciences, National Institutes of Health, and the extramural National Institutes of Health Grant HL071802.
2 Address correspondence and reprint requests to Stephen L. Tilley, 8033 Burnett-Womack, CB# 7219, University of North Carolina, Chapel Hill, NC 27599-7219. E-mail address: stephen_tilley{at}med.unc.edu
3 Abbreviations used in this paper: GR, glucocorticoid receptor; EOS, eosinophil; PAS, periodic acid-Schiff; PMN, polymorphonuclear neutrophil; Raw, airway resistance; RL, dynamic resistance; ROR, retinoid-related orphan receptor; Th17, IL-17-producing Th.
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