Belinda J Kaskow, Thomas S Buttrick, Hans-Ulrich Klein, Charles White, Justin R Bourgeois, Russell J Ferland, Nikolaos Patsopoulos, Elizabeth M Bradshaw, Philip L De Jager, Wassim Elyaman
Author Information
Belinda J Kaskow: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Thomas S Buttrick: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Hans-Ulrich Klein: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Charles White: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Justin R Bourgeois: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Russell J Ferland: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Nikolaos Patsopoulos: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Elizabeth M Bradshaw: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Philip L De Jager: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
Wassim Elyaman: Ann Romney Center for Neurologic Diseases (B.J.K., T.S.B., N.P.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Center for Translational and Computational Neuroimmunology (H.-U.K., E.M.B., P.L.D.J., W.E.), Department of Neurology, Columbia University Medical Center, New York, NY; Program in Medical and Population Genetics (H.-U.K., C.W., E.M.B., P.L.D.J., W.E.), Broad Institute, Cambridge, MA; and Departments of Neuroscience and Experimental Therapeutics, and Neurology (J.R.B., R.J.F.), Albany Medical College, Albany, NY.
OBJECTIVE: To study the influence of the Abelson helper integration site 1 () locus associated with MS susceptibility on CD4 T cell function. METHODS: We characterized the chromatin state of T cells in the MS-associated linkage disequilibrium (LD) block. The expression and the role of the variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of was explored using T cells from knockout mice. RESULTS: Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, = 1.65 × 10), overlaps with strong enhancer regions that are present in human naive and memory CD4 T cells. Relative to the rs4896153 protective allele, the rs4896153 susceptibility allele is associated with decreased mRNA expression, specifically in naive CD4 T cells ( = 1.73 × 10, n = 213), and we replicate this effect in an independent set of subjects ( = 2.5 × 10, n = 32). Functional studies then showed that the rs4896153 risk variant and the subsequent decreased expression were associated with reduced CD4 T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153 allele. This T cell phenotype was also observed in murine CD4 T cells with genetic deletion of . CONCLUSIONS: Our findings suggest that the effect of the genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ T cells that have previously been implicated in MS and its mouse models.
References
Mult Scler. 2010 Feb;16(2):208-17
[PMID: 20007431]
