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* Division of Molecular Immunology, Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115;
Program in Medical and Population Genetics, Broad Institute, Massachusetts Institute of Technology and Harvard University, Cambridge, MA 02139;
Biostatistics Center, Massachusetts General Hospital, Boston, MA 02115;
Department of Chemical Engineering and
¶ Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139; and
|| Partners Center for Personalized Medicine, Boston, MA 02115
Multiple sclerosis (MS) is an organ-specific autoimmune disorder that is in part genetically determined. The gene encoding the 
-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis. Here, we show that the IL2RA genotypes differentially affects soluble IL-2RA (sIL-2RA) levels in MS cases vs healthy controls; the two variants associated with MS (rs12722489 and rs2104286) account for 15 and 18% of the total variance in log10-transformed sIL-2RA concentration in control subjects but less so in subjects with MS (2 and 5%), suggesting that perturbations associated with disease or treatment may influence sIL-2RA levels in subjects with MS. Whereas analyses demonstrate that sIL-2RA serum concentrations are a remarkably stable phenotype in both healthy controls and untreated MS subjects, a difference is observed between benign and malignant MS. These data indicate that, in addition to specific allelic variants at IL2RA, immunological perturbations associated with aggressive forms of the disease can influence sIL-2RA levels in serum of MS subjects. We also demonstrate, functionally, that sIL-2RA can inhibit IL-2 signaling, yet enhance T cell proliferation and expansion. In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS.
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 the National Multiple Sclerosis Society, the National Institutes of Health-National Institute of Allergy and Infectious Diseases (P01 AI39671) and the National Institutes of Health (R01 NS049477). Further support was provided by a JDRF Postdoctoral Fellowship (to L.M.M.), a grant by the American Cancer Society (to D.E.A.), a Harry Weaver Neuroscience Scholar award by the National Multiple Sclerosis Society (to P.L.D.), and Jacob Javits Merit Award NS2427 (to D.A.H.) from the National Institute of Neurological Disorders and Stroke.
2 Address correspondence and reprint requests to Dr. Lisa M. Maier, Center for Neurologic Diseases, New Research Building, 77 Louis Pasteur Ave., Boston, MA 02115. E-mail address: lmaier{at}rics.bwh.harvard.edu
3 Abbreviations used in this paper: MS, multiple sclerosis; SNP, single nucleotide polymorphism; T1D, type 1 diabetes; sIL-2RA, soluble IL-2RA; EDSS, Expanded Disability Status Scale; AICD, activation-induced cell death.
4 The online version of this article contains supplemental material.
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