title: Rheumatoid arthritis-associated RBPJ polymorphism alters memory CD4+ T cells.
abstract: Notch signaling has recently emerged as an important regulator of immune responses in autoimmune diseases. The recombination signal-binding protein for immunoglobulin kappa J region (RBPJ) is a transcriptional repressor, but converts into a transcriptional activator upon activation of the canonical Notch pathway. Genome-wide association studies of rheumatoid arthritis (RA) identified a susceptibility locus, rs874040(CC), which implicated the RBPJ gene. Here, chromatin state mapping generated using the chromHMM algorithm reveals strong enhancer regions containing DNase I hypersensitive sites overlapping the rs874040 linkage disequilibrium block in human memory, but not in naïve CD4(+) T cells. The rs874040 overlapping this chromatin state was associated with increased RBPJ expression in stimulated memory CD4(+) T cells from healthy subjects homozygous for the risk allele (CC) compared with memory CD4(+) T cells bearing the protective allele (GG). Transcriptomic analysis of rs874040(CC) memory T cells showed a repression of canonical Notch target genes IL (interleukin)-9, IL-17 and interferon (IFN)γ in the basal state. Interestingly, activation of the Notch pathway using soluble Notch ligand, Jagged2-Fc, induced IL-9 and IL-17A while delta-like 4Fc, another Notch ligand, induced higher IFNγ expression in the rs874040(CC) memory CD4(+) T cells compared with their rs874040(GG) counterparts. In RA, RBPJ expression is elevated in memory T cells from RA patients compared with control subjects, and this was associated with induced inflammatory cytokines IL-9, IL-17A and IFNγ in response to Notch ligation in vitro. These findings demonstrate that the rs874040(CC) allele skews memory T cells toward a pro-inflammatory phenotype involving Notch signaling, thus increasing the susceptibility to develop RA.
authors.affiliation: Ann Romney Center for Neurologic Diseases.
authors.forename: William
authors.initials: W
authors.lastname: Orent
authors.affiliation: Ann Romney Center for Neurologic Diseases.
authors.forename: Allison R
authors.initials: AR
authors.lastname: Mchenry
authors.affiliation: Division of Rheumatology, Immunology and Allergy and.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Rao
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Charles
authors.initials: C
authors.lastname: White
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Klein
authors.affiliation: Ann Romney Center for Neurologic Diseases.
authors.forename: Ribal
authors.initials: R
authors.lastname: Bassil
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Gyan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Replogle
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Towfique
authors.initials: T
authors.lastname: Raj
authors.affiliation: Ann Romney Center for Neurologic Diseases.
authors.forename: Michael
authors.initials: M
authors.lastname: Frangieh
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Maria
authors.initials: M
authors.lastname: Cimpean
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Nicole
authors.initials: N
authors.lastname: Cuerdon
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Lori
authors.initials: L
authors.lastname: Chibnik
authors.affiliation: Ann Romney Center for Neurologic Diseases, Abu Haidar Neuroscience Institute, American University of Beirut Medical Center, Beirut, Lebanon.
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.affiliation: Division of Rheumatology, Immunology and Allergy and.
authors.forename: Elizabeth W
authors.initials: EW
authors.lastname: Karlson
authors.affiliation: Division of Rheumatology, Immunology and Allergy and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Brenner
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and.
authors.forename: Philip
authors.initials: P
authors.lastname: De Jager
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and welyaman@rics.bwh.harvard.edu ebradshaw@rics.bwh.harvard.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Bradshaw
authors.affiliation: Ann Romney Center for Neurologic Diseases, Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Broad Institute at Harvard University and MIT, NRB-641, 77 Avenue Louis Pasteur, Boston, MA 02115, USA and welyaman@rics.bwh.harvard.edu ebradshaw@rics.bwh.harvard.edu.
authors.forename: Wassim
authors.initials: W
authors.lastname: Elyaman
mesh_terms: D000328:Adult; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000235:genetics* / Q000276:immunology; D007156:Immunologic Memory; D008297:Male; D020641:Polymorphism, Single Nucleotide; D051880:Receptors, Notch; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D016207:Cytokines; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C497570:RBPJ protein, human; D051880:Receptors, Notch