PMID- 32461333
OWN - NLM
STAT- In-Data-Review
LR  - 20200709
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 12
IP  - 545
DP  - 2020 May 27
TI  - Using genetics to prioritize diagnoses for rheumatology outpatients with
      inflammatory arthritis.
LID - eaay1548 [pii]
LID - 10.1126/scitranslmed.aay1548 [doi]
AB  - It is challenging to quickly diagnose slowly progressing diseases. To
      prioritize multiple related diagnoses, we developed G-PROB (Genetic
      Probability tool) to calculate the probability of different diseases for
      a patient using genetic risk scores. We tested G-PROB for inflammatory
      arthritis-causing diseases (rheumatoid arthritis, systemic lupus
      erythematosus, spondyloarthropathy, psoriatic arthritis, and gout). After
      validating on simulated data, we tested G-PROB in three cohorts: 1211
      patients identified by International Classification of Diseases (ICD)
      codes within the eMERGE database, 245 patients identified through ICD
      codes and medical record review within the Partners Biobank, and 243
      patients first presenting with unexplained inflammatory arthritis and
      with final diagnoses by record review within the Partners Biobank.
      Calibration of G-probabilities with disease status was high, with
      regression coefficients from 0.90 to 1.08 (1.00 is ideal).
      G-probabilities discriminated true diagnoses across the three cohorts
      with pooled areas under the curve (95% CI) of 0.69 (0.67 to 0.71), 0.81
      (0.76 to 0.84), and 0.84 (0.81 to 0.86), respectively. For all patients,
      at least one disease could be ruled out, and in 45% of patients, a likely
      diagnosis was identified with a 64% positive predictive value. In 35% of
      cases, the clinician's initial diagnosis was incorrect. Initial clinical
      diagnosis explained 39% of the variance in final disease, which improved
      to 51% (P < 0.0001) after adding G-probabilities. Converting genotype
      information before a clinical visit into an interpretable probability
      value for five different inflammatory arthritides could potentially be
      used to improve the diagnostic efficiency of rheumatic diseases in
      clinical practice.
CI  - Copyright (c) 2020 The Authors, some rights reserved; exclusive licensee
      American Association for the Advancement of Science. No claim to original
      U.S. Government Works.
FAU - Knevel, Rachel
AU  - Knevel R
AUID- ORCID: http://orcid.org/0000-0002-7494-3023
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
AD  - Department of Rheumatology, Leiden University Medical Center, 2333 ZA
      Leiden, Netherlands.
AD  - Program in Medical and Population Genetics, Broad Institute of Harvard
      and MIT, Cambridge, MA 02142, USA.
FAU - le Cessie, Saskia
AU  - le Cessie S
AUID- ORCID: http://orcid.org/0000-0003-2154-4923
AD  - Department of Clinical Epidemiology and Department of Biomedical Data
      Sciences, Leiden University Medical Center, 2333 ZA Leiden, Netherlands.
FAU - Terao, Chikashi C
AU  - Terao CC
AUID- ORCID: http://orcid.org/0000-0002-6452-4095
AD  - Laboratory for Statistical and Translational Genetics, RIKEN Center for
      Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
AD  - Clinical Research Center, Shizuoka General Hospital, Shizuoka 230-0045,
      Japan.
AD  - Department of Applied Genetics, School of Pharmaceutical Sciences,
      University of Shizuoka, Shizuoka 420-8527, Japan.
FAU - Slowikowski, Kamil
AU  - Slowikowski K
AUID- ORCID: http://orcid.org/0000-0002-2843-6370
AD  - Program in Medical and Population Genetics, Broad Institute of Harvard
      and MIT, Cambridge, MA 02142, USA.
AD  - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical
      School, Boston, MA 02115, USA.
AD  - Division of Genetics, Brigham and Women's Hospital and Harvard Medical
      School, Boston, MA 02115, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA
      02115, USA.
FAU - Cui, Jing
AU  - Cui J
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Huizinga, Tom W J
AU  - Huizinga TWJ
AUID- ORCID: http://orcid.org/0000-0001-7033-7520
AD  - Department of Rheumatology, Leiden University Medical Center, 2333 ZA
      Leiden, Netherlands.
FAU - Costenbader, Karen H
AU  - Costenbader KH
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Liao, Katherine P
AU  - Liao KP
AUID- ORCID: http://orcid.org/0000-0002-4797-3200
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
AD  - Massachusetts Veterans Epidemiology Research and Information Center
      (MAVERIC), VA Boston Healthcare System, Boston, MA 02130, USA.
FAU - Karlson, Elizabeth W
AU  - Karlson EW
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AUID- ORCID: http://orcid.org/0000-0002-1901-8265
AD  - Division of Rheumatology, Immunology, and Allergy, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115, USA.
      soumya@broadinstitute.org.
AD  - Program in Medical and Population Genetics, Broad Institute of Harvard
      and MIT, Cambridge, MA 02142, USA.
AD  - Center for Data Sciences, Brigham and Women's Hospital, Harvard Medical
      School, Boston, MA 02115, USA.
AD  - Division of Genetics, Brigham and Women's Hospital and Harvard Medical
      School, Boston, MA 02115, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA
      02115, USA.
AD  - Centre for Genetics and Genomics Versus Arthritis and Centre for
      Musculoskeletal Research, Manchester M13 9PL, UK.
LA  - eng
GR  - K24 AR066109/AR/NIAMS NIH HHS/United States
GR  - U01 GM092691/GM/NIGMS NIH HHS/United States
GR  - F31 AR070582/AR/NIAMS NIH HHS/United States
GR  - R01 AR049880/AR/NIAMS NIH HHS/United States
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - U01 HG009379/HG/NHGRI NIH HHS/United States
GR  - UH2 AR067677/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
SB  - IM
PMC - PMC7341896
MID - NIHMS1605236
EDAT- 2020/05/29 06:00
MHDA- 2020/05/29 06:00
CRDT- 2020/05/29 06:00
PHST- 2019/05/24 00:00 [received]
PHST- 2019/10/15 00:00 [revised]
PHST- 2020/05/03 00:00 [accepted]
PHST- 2020/05/29 06:00 [entrez]
PHST- 2020/05/29 06:00 [pubmed]
PHST- 2020/05/29 06:00 [medline]
AID - 12/545/eaay1548 [pii]
AID - 10.1126/scitranslmed.aay1548 [doi]
PST - ppublish
SO  - Sci Transl Med. 2020 May 27;12(545). pii: 12/545/eaay1548. doi:
      10.1126/scitranslmed.aay1548.

PMID- 32079724
OWN - NLM
STAT- MEDLINE
DCOM- 20200713
LR  - 20200713
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Linking)
VI  - 117
IP  - 10
DP  - 2020 Mar 10
TI  - CUX1 and IkappaBzeta (NFKBIZ) mediate the synergistic inflammatory
      response to TNF and IL-17A in stromal fibroblasts.
PG  - 5532-5541
LID - 10.1073/pnas.1912702117 [doi]
AB  - The role of stromal fibroblasts in chronic inflammation is unfolding. In
      rheumatoid arthritis, leukocyte-derived cytokines TNF and IL-17A work
      together, activating fibroblasts to become a dominant source of the
      hallmark cytokine IL-6. However, IL-17A alone has minimal effect on
      fibroblasts. To identify key mediators of the synergistic response to TNF
      and IL-17A in human synovial fibroblasts, we performed time series, dose-
      response, and gene-silencing transcriptomics experiments. Here we show
      that in combination with TNF, IL-17A selectively induces a specific set
      of genes mediated by factors including cut-like homeobox 1 (CUX1) and
      IkappaBzeta (NFKBIZ). In the promoters of CXCL1, CXCL2, and CXCL3, we
      found a putative CUX1-NF-kappaB binding motif not found elsewhere in the
      genome. CUX1 and NF-kappaB p65 mediate transcription of these genes
      independent of LIFR, STAT3, STAT4, and ELF3. Transcription of NFKBIZ,
      encoding the atypical IkappaB factor IkappaBzeta, is IL-17A dose-
      dependent, and IkappaBzeta only mediates the transcriptional response to
      TNF and IL-17A, but not to TNF alone. In fibroblasts, IL-17A response
      depends on CUX1 and IkappaBzeta to engage the NF-kappaB complex to
      produce chemoattractants for neutrophil and monocyte recruitment.
FAU - Slowikowski, Kamil
AU  - Slowikowski K
AUID- ORCID: 0000-0002-2843-6370
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
AD  - Division of Genetics, Brigham and Women's Hospital, Harvard Medical
      School, Boston, MA 02115.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA
      02115.
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115.
FAU - Nguyen, Hung N
AU  - Nguyen HN
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Noss, Erika H
AU  - Noss EH
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Simmons, Daimon P
AU  - Simmons DP
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
AD  - Department of Pathology, Brigham and Women's Hospital, Harvard Medical
      School, Boston, MA 02115.
FAU - Mizoguchi, Fumitaka
AU  - Mizoguchi F
AUID- ORCID: 0000-0002-3956-7122
AD  - Department of Rheumatology, Graduate School of Medical and Dental
      Sciences, Tokyo Medical and Dental University, 113-8519 Tokyo, Japan.
FAU - Watts, Gerald F M
AU  - Watts GFM
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Gurish, Michael F
AU  - Gurish MF
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115.
FAU - Brenner, Michael B
AU  - Brenner MB
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115;
      mbrenner@research.bwh.harvard.edu soumya@broadinstitute.org.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AD  - Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's
      Hospital, Harvard Medical School, Boston, MA 02115;
      mbrenner@research.bwh.harvard.edu soumya@broadinstitute.org.
AD  - Division of Genetics, Brigham and Women's Hospital, Harvard Medical
      School, Boston, MA 02115.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA 02142.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA
      02115.
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA 02115.
AD  - Centre for Genetics and Genomics Versus Arthritis, Manchester Academic
      Health Science Centre, University of Manchester, M13 9PL Manchester,
      United Kingdom.
LA  - eng
GR  - T32 HL007627/HL/NHLBI NIH HHS/United States
GR  - U19 AI111224/AI/NIAID NIH HHS/United States
GR  - T32 HG002295/HG/NHGRI NIH HHS/United States
GR  - U01 GM092691/GM/NIGMS NIH HHS/United States
GR  - F31 AR070582/AR/NIAMS NIH HHS/United States
GR  - R01 AR063709/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067677/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200220
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of
      America
JID - 7505876
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (CUX1 protein, human)
RN  - 0 (CXCL1 protein, human)
RN  - 0 (CXCL2 protein, human)
RN  - 0 (CXCL3 protein, human)
RN  - 0 (Chemokine CXCL1)
RN  - 0 (Chemokine CXCL2)
RN  - 0 (Chemokines, CXC)
RN  - 0 (Chemotactic Factors)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (IL6 protein, human)
RN  - 0 (Interleukin-17)
RN  - 0 (Interleukin-6)
RN  - 0 (NFKBIZ protein, human)
RN  - 0 (RELA protein, human)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Repressor Proteins)
RN  - 0 (Transcription Factor RelA)
RN  - 0 (Transcription Factors)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.24.17 (Matrix Metalloproteinase 3)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Arthritis, Rheumatoid/genetics/*metabolism
MH  - Cells, Cultured
MH  - Chemokine CXCL1/genetics
MH  - Chemokine CXCL2/genetics
MH  - Chemokines, CXC/genetics
MH  - Chemotactic Factors/genetics
MH  - Fibroblasts/drug effects/*metabolism
MH  - Homeodomain Proteins/genetics/*metabolism
MH  - Humans
MH  - Inflammation/genetics/*metabolism
MH  - Interleukin-17/pharmacology/*physiology
MH  - Interleukin-6/genetics
MH  - Matrix Metalloproteinase 3/metabolism
MH  - Monocytes/drug effects/physiology
MH  - RNA, Small Interfering/genetics
MH  - Repressor Proteins/genetics/*metabolism
MH  - Stromal Cells/drug effects/metabolism
MH  - Synovial Fluid
MH  - Transcription Factor RelA/metabolism
MH  - Transcription Factors/genetics/*metabolism
MH  - Transcriptome/*physiology/radiation effects
MH  - Tumor Necrosis Factor-alpha/pharmacology/*physiology
PMC - PMC7071902
OTO - NOTNLM
OT  - *RNA-seq
OT  - *inflammation
OT  - *regulation
OT  - *time series
OT  - *transcription
COIS- The authors declare no competing interest.
EDAT- 2020/02/23 06:00
MHDA- 2020/07/14 06:00
CRDT- 2020/02/22 06:00
PMCR- 2020/08/20 00:00
PHST- 2020/08/20 00:00 [pmc-release]
PHST- 2020/02/23 06:00 [pubmed]
PHST- 2020/07/14 06:00 [medline]
PHST- 2020/02/22 06:00 [entrez]
AID - 1912702117 [pii]
AID - 10.1073/pnas.1912702117 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2020 Mar 10;117(10):5532-5541. doi:
      10.1073/pnas.1912702117. Epub 2020 Feb 20.

PMID- 31740819
OWN - NLM
STAT- MEDLINE
DCOM- 20200213
LR  - 20200807
IS  - 1548-7105 (Electronic)
IS  - 1548-7091 (Linking)
VI  - 16
IP  - 12
DP  - 2019 Dec
TI  - Fast, sensitive and accurate integration of single-cell data with
      Harmony.
PG  - 1289-1296
LID - 10.1038/s41592-019-0619-0 [doi]
AB  - The emerging diversity of single-cell RNA-seq datasets allows for the
      full transcriptional characterization of cell types across a wide variety
      of biological and clinical conditions. However, it is challenging to
      analyze them together, particularly when datasets are assayed with
      different technologies, because biological and technical differences are
      interspersed. We present Harmony
      (https://github.com/immunogenomics/harmony), an algorithm that projects
      cells into a shared embedding in which cells group by cell type rather
      than dataset-specific conditions. Harmony simultaneously accounts for
      multiple experimental and biological factors. In six analyses, we
      demonstrate the superior performance of Harmony to previously published
      algorithms while requiring fewer computational resources. Harmony enables
      the integration of ~10(6) cells on a personal computer. We apply Harmony
      to peripheral blood mononuclear cells from datasets with large
      experimental differences, five studies of pancreatic islet cells, mouse
      embryogenesis datasets and the integration of scRNA-seq with spatial
      transcriptomics data.
FAU - Korsunsky, Ilya
AU  - Korsunsky I
AUID- ORCID: http://orcid.org/0000-0003-4848-3948
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Millard, Nghia
AU  - Millard N
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Fan, Jean
AU  - Fan J
AUID- ORCID: http://orcid.org/0000-0002-0212-5451
AD  - Department of Chemistry and Chemical Biology, Harvard University,
      Cambridge, MA, USA.
FAU - Slowikowski, Kamil
AU  - Slowikowski K
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Zhang, Fan
AU  - Zhang F
AUID- ORCID: http://orcid.org/0000-0002-6102-2970
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Wei, Kevin
AU  - Wei K
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Baglaenko, Yuriy
AU  - Baglaenko Y
AUID- ORCID: http://orcid.org/0000-0002-9020-6824
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Brenner, Michael
AU  - Brenner M
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Loh, Po-Ru
AU  - Loh PR
AUID- ORCID: http://orcid.org/0000-0001-5542-9064
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AUID- ORCID: http://orcid.org/0000-0002-1901-8265
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
      soumya@broadinstitute.org.
AD  - Divisions of Genetics and Rheumatology, Department of Medicine, Brigham
      and Women's Hospital and Harvard Medical School, Boston, MA, USA.
      soumya@broadinstitute.org.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA. soumya@broadinstitute.org.
AD  - Program in Medical and Population Genetics, Broad Institute of MIT and
      Harvard, Cambridge, MA, USA. soumya@broadinstitute.org.
AD  - Versus Arthritis Centre for Genetics and Genomics, Centre for
      Musculoskeletal Research, Manchester Academic Health Science Centre, The
      University of Manchester, Manchester, UK. soumya@broadinstitute.org.
LA  - eng
GR  - U19 AI111224/AI/NIAID NIH HHS/United States
GR  - T32 HG002295/HG/NHGRI NIH HHS/United States
GR  - T32 AR007530/AR/NIAMS NIH HHS/United States
GR  - K00 CA222750/CA/NCI NIH HHS/United States
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - U01 HG009379/HG/NHGRI NIH HHS/United States
GR  - UH2 AR067677/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20191118
PL  - United States
TA  - Nat Methods
JT  - Nature methods
JID - 101215604
SB  - IM
MH  - Algorithms
MH  - Animals
MH  - Base Sequence
MH  - Datasets as Topic
MH  - HEK293 Cells
MH  - Humans
MH  - Jurkat Cells
MH  - Mice
MH  - Single-Cell Analysis/*methods
PMC - PMC6884693
MID - NIHMS1539299
EDAT- 2019/11/20 06:00
MHDA- 2020/02/14 06:00
CRDT- 2019/11/20 06:00
PHST- 2018/11/05 00:00 [received]
PHST- 2019/09/06 00:00 [accepted]
PHST- 2019/11/20 06:00 [pubmed]
PHST- 2020/02/14 06:00 [medline]
PHST- 2019/11/20 06:00 [entrez]
AID - 10.1038/s41592-019-0619-0 [doi]
AID - 10.1038/s41592-019-0619-0 [pii]
PST - ppublish
SO  - Nat Methods. 2019 Dec;16(12):1289-1296. doi: 10.1038/s41592-019-0619-0.
      Epub 2019 Nov 18.

PMID- 31061532
OWN - NLM
STAT- MEDLINE
DCOM- 20190709
LR  - 20200617
IS  - 1529-2916 (Electronic)
IS  - 1529-2908 (Linking)
VI  - 20
IP  - 7
DP  - 2019 Jul
TI  - Defining inflammatory cell states in rheumatoid arthritis joint synovial
      tissues by integrating single-cell transcriptomics and mass cytometry.
PG  - 928-942
LID - 10.1038/s41590-019-0378-1 [doi]
AB  - To define the cell populations that drive joint inflammation in
      rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-
      seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to
      T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial
      tissue from patients with RA or osteoarthritis (OA). Utilizing an
      integrated strategy based on canonical correlation analysis of 5,265
      scRNA-seq profiles, we identified 18 unique cell populations. Combining
      mass cytometry and transcriptomics revealed cell states expanded in RA
      synovia: THY1(CD90)(+)HLA-DRA(hi) sublining fibroblasts, IL1B(+) pro-
      inflammatory monocytes, ITGAX(+)TBX21(+) autoimmune-associated B cells
      and PDCD1(+) peripheral helper T (TPH) cells and follicular helper T
      (TFH) cells. We defined distinct subsets of CD8(+) T cells characterized
      by GZMK(+), GZMB(+), and GNLY(+) phenotypes. We mapped inflammatory
      mediators to their source cell populations; for example, we attributed
      IL6 expression to THY1(+)HLA-DRA(hi) fibroblasts and IL1B production to
      pro-inflammatory monocytes. These populations are potentially key
      mediators of RA pathogenesis.
FAU - Zhang, Fan
AU  - Zhang F
AUID- ORCID: http://orcid.org/0000-0002-6102-2970
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Division of Genetics, Department of Medicine, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Wei, Kevin
AU  - Wei K
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Slowikowski, Kamil
AU  - Slowikowski K
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Division of Genetics, Department of Medicine, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Fonseka, Chamith Y
AU  - Fonseka CY
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
AD  - Division of Genetics, Department of Medicine, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Rao, Deepak A
AU  - Rao DA
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Kelly, Stephen
AU  - Kelly S
AD  - Department of Rheumatology, Barts Health NHS Trust, London, UK.
FAU - Goodman, Susan M
AU  - Goodman SM
AD  - Division of Rheumatology, Hospital for Special Surgery, New York, NY,
      USA.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
FAU - Tabechian, Darren
AU  - Tabechian D
AD  - Division of Allergy, Immunology and Rheumatology, Department of Medicine,
      University of Rochester Medical Center, Rochester, NY, USA.
FAU - Hughes, Laura B
AU  - Hughes LB
AD  - Division of Clinical Immunology and Rheumatology, Department of Medicine,
      University of Alabama at Birmingham, Birmingham, AL, USA.
FAU - Salomon-Escoto, Karen
AU  - Salomon-Escoto K
AD  - Division of Rheumatology, Department of Medicine, University of
      Massachusetts Medical School, Worcester, MA, USA.
FAU - Watts, Gerald F M
AU  - Watts GFM
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Jonsson, A Helena
AU  - Jonsson AH
AUID- ORCID: http://orcid.org/0000-0002-9558-2474
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Rangel-Moreno, Javier
AU  - Rangel-Moreno J
AD  - Division of Allergy, Immunology and Rheumatology, Department of Medicine,
      University of Rochester Medical Center, Rochester, NY, USA.
FAU - Meednu, Nida
AU  - Meednu N
AD  - Division of Allergy, Immunology and Rheumatology, Department of Medicine,
      University of Rochester Medical Center, Rochester, NY, USA.
FAU - Rozo, Cristina
AU  - Rozo C
AD  - Arthritis and Tissue Degeneration, Hospital for Special Surgery, New
      York, NY, USA.
FAU - Apruzzese, William
AU  - Apruzzese W
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Eisenhaure, Thomas M
AU  - Eisenhaure TM
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Lieb, David J
AU  - Lieb DJ
AUID- ORCID: http://orcid.org/0000-0001-7459-4719
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Boyle, David L
AU  - Boyle DL
AD  - Department of Medicine, Division of Rheumatology, Allergy and Immunology,
      University of California, San Diego, La Jolla, CA, USA.
FAU - Mandelin, Arthur M 2nd
AU  - Mandelin AM 2nd
AD  - Division of Rheumatology, Department of Medicine, Northwestern University
      Feinberg School of Medicine, Chicago, IL, USA.
CN  - Accelerating Medicines Partnership Rheumatoid Arthritis and Systemic
      Lupus Erythematosus (AMP RA/SLE) Consortium
FAU - Boyce, Brendan F
AU  - Boyce BF
AD  - Department of Pathology and Laboratory Medicine, University of Rochester
      Medical Center, Rochester, NY, USA.
FAU - DiCarlo, Edward
AU  - DiCarlo E
AD  - Department of Pathology and Laboratory Medicine, Hospital for Special
      Surgery, New York, NY, USA.
FAU - Gravallese, Ellen M
AU  - Gravallese EM
AD  - Division of Rheumatology, Department of Medicine, University of
      Massachusetts Medical School, Worcester, MA, USA.
FAU - Gregersen, Peter K
AU  - Gregersen PK
AD  - Feinstein Institute for Medical Research, Northwell Health, Manhasset,
      New York, NY, USA.
FAU - Moreland, Larry
AU  - Moreland L
AD  - Division of Rheumatology and Clinical Immunology, University of
      Pittsburgh School of Medicine, Pittsburgh, PA, USA.
FAU - Firestein, Gary S
AU  - Firestein GS
AD  - Department of Medicine, Division of Rheumatology, Allergy and Immunology,
      University of California, San Diego, La Jolla, CA, USA.
FAU - Hacohen, Nir
AU  - Hacohen N
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Nusbaum, Chad
AU  - Nusbaum C
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
FAU - Lederer, James A
AU  - Lederer JA
AD  - Department of Surgery, Brigham and Women's Hospital and Harvard Medical
      School, Boston, MA, USA.
FAU - Perlman, Harris
AU  - Perlman H
AD  - Division of Rheumatology, Department of Medicine, Northwestern University
      Feinberg School of Medicine, Chicago, IL, USA.
FAU - Pitzalis, Costantino
AU  - Pitzalis C
AUID- ORCID: http://orcid.org/0000-0003-1326-5051
AD  - Centre for Experimental Medicine & Rheumatology, William Harvey Research
      Institute, Queen Mary University of London, London, UK.
FAU - Filer, Andrew
AU  - Filer A
AUID- ORCID: http://orcid.org/0000-0001-8164-6249
AD  - NIHR Birmingham Biomedical Research Centre, University Hospitals
      Birmingham NHS Foundation Trust and University of Birmingham, Birmingham,
      UK.
AD  - University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
FAU - Holers, V Michael
AU  - Holers VM
AD  - Division of Rheumatology, University of Colorado School of Medicine,
      Aurora, CO, USA.
FAU - Bykerk, Vivian P
AU  - Bykerk VP
AD  - Division of Rheumatology, Hospital for Special Surgery, New York, NY,
      USA.
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
FAU - Donlin, Laura T
AU  - Donlin LT
AUID- ORCID: http://orcid.org/0000-0002-1428-090X
AD  - Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
AD  - Arthritis and Tissue Degeneration, Hospital for Special Surgery, New
      York, NY, USA.
FAU - Anolik, Jennifer H
AU  - Anolik JH
AD  - Division of Allergy, Immunology and Rheumatology, Department of Medicine,
      University of Rochester Medical Center, Rochester, NY, USA.
AD  - Center for Musculoskeletal Research, University of Rochester Medical
      Center, Rochester, NY, USA.
FAU - Brenner, Michael B
AU  - Brenner MB
AUID- ORCID: http://orcid.org/0000-0001-6202-8445
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
FAU - Raychaudhuri, Soumya
AU  - Raychaudhuri S
AUID- ORCID: http://orcid.org/0000-0002-1901-8265
AD  - Center for Data Sciences, Brigham and Women's Hospital, Boston, MA, USA.
      soumya@broadinstitute.org.
AD  - Division of Genetics, Department of Medicine, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
      soumya@broadinstitute.org.
AD  - Department of Biomedical Informatics, Harvard Medical School, Boston, MA,
      USA. soumya@broadinstitute.org.
AD  - Broad Institute of MIT and Harvard, Cambridge, MA, USA.
      soumya@broadinstitute.org.
AD  - Division of Rheumatology, Immunology, Allergy, Brigham and Women's
      Hospital and Harvard Medical School, Boston, MA, USA.
      soumya@broadinstitute.org.
AD  - Arthritis Research UK Centre for Genetics and Genomics, Centre for
      Musculoskeletal Research, The University of Manchester, Manchester, UK.
      soumya@broadinstitute.org.
LA  - eng
GR  - R01 AR046713/AR/NIAMS NIH HHS/United States
GR  - KL2 TR002542/TR/NCATS NIH HHS/United States
GR  - UM2 AR067678/AR/NIAMS NIH HHS/United States
GR  - R21 AR071670/AR/NIAMS NIH HHS/United States
GR  - R01 AI046712/AI/NIAID NIH HHS/United States
GR  - T32 HG002295/HG/NHGRI NIH HHS/United States
GR  - UH2 AR067689/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067694/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067679/AR/NIAMS NIH HHS/United States
GR  - MR/S025308/1/MRC_/Medical Research Council/United Kingdom
GR  - UH2 AR067685/AR/NIAMS NIH HHS/United States
GR  - K01 AR066063/AR/NIAMS NIH HHS/United States
GR  - U19 AI111224/AI/NIAID NIH HHS/United States
GR  - MR/N026977/1/MRC_/Medical Research Council/United Kingdom
GR  - UH2 AR067681/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067688/AR/NIAMS NIH HHS/United States
GR  - F31 AR070582/AR/NIAMS NIH HHS/United States
GR  - K08 AR072791/AR/NIAMS NIH HHS/United States
GR  - R01 AR063759/AR/NIAMS NIH HHS/United States
GR  - UH2 AR067690/AR/NIAMS NIH HHS/United States
GR  - U01 HG009379/HG/NHGRI NIH HHS/United States
GR  - UH2 AR067677/AR/NIAMS NIH HHS/United States
GR  - WT_/Wellcome Trust/United Kingdom
GR  - R01 HL134375/HL/NHLBI NIH HHS/United States
GR  - UH2 AR067676/AR/NIAMS NIH HHS/United States
GR  - G0800648/MRC_/Medical Research Council/United Kingdom
GR  - UH2 AR067691/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190506
PL  - United States
TA  - Nat Immunol
JT  - Nature immunology
JID - 100941354
RN  - 0 (Biomarkers)
RN  - 0 (Cytokines)
RN  - 0 (Histocompatibility Antigens Class II)
SB  - IM
MH  - Arthritis, Rheumatoid/*genetics/*metabolism/pathology
MH  - Autoimmunity/genetics
MH  - Biomarkers
MH  - Computational Biology/methods
MH  - Cross-Sectional Studies
MH  - Cytokines/metabolism
MH  - Fibroblasts/metabolism
MH  - Flow Cytometry
MH  - Gene Expression
MH  - *Gene Expression Profiling/methods
MH  - High-Throughput Nucleotide Sequencing
MH  - Histocompatibility Antigens Class II/genetics/immunology
MH  - Humans
MH  - Leukocytes/immunology/metabolism
MH  - Monocytes/immunology/metabolism
MH  - Signal Transduction
MH  - Single-Cell Analysis/methods
MH  - Synovial Membrane/*metabolism/pathology
MH  - T-Lymphocyte Subsets/immunology/metabolism
MH  - *Transcriptome
MH  - Workflow
PMC - PMC6602051
MID - NIHMS1524330
IR  - Albrecht J
FIR - Albrecht, Jennifer
IR  - Bridges SL Jr
FIR - Bridges, S Louis Jr
IR  - Buckley CD
FIR - Buckley, Christopher D
IR  - Buckner JH
FIR - Buckner, Jane H
IR  - Dolan J
FIR - Dolan, James
IR  - Guthridge JM
FIR - Guthridge, Joel M
IR  - Gutierrez-Arcelus M
FIR - Gutierrez-Arcelus, Maria
IR  - Ivashkiv LB
FIR - Ivashkiv, Lionel B
IR  - James EA
FIR - James, Eddie A
IR  - James JA
FIR - James, Judith A
IR  - Keegan J
FIR - Keegan, Josh
IR  - Lee YC
FIR - Lee, Yvonne C
IR  - McGeachy MJ
FIR - McGeachy, Mandy J
IR  - McNamara MA
FIR - McNamara, Michael A
IR  - Mears JR
FIR - Mears, Joseph R
IR  - Mizoguchi F
FIR - Mizoguchi, Fumitaka
IR  - Nguyen JP
FIR - Nguyen, Jennifer P
IR  - Noma A
FIR - Noma, Akiko
IR  - Orange DE
FIR - Orange, Dana E
IR  - Rohani-Pichavant M
FIR - Rohani-Pichavant, Mina
IR  - Ritchlin C
FIR - Ritchlin, Christopher
IR  - Robinson WH
FIR - Robinson, William H
IR  - Seshadri A
FIR - Seshadri, Anupamaa
IR  - Sutherby D
FIR - Sutherby, Danielle
IR  - Seifert J
FIR - Seifert, Jennifer
IR  - Turner JD
FIR - Turner, Jason D
IR  - Utz PJ
FIR - Utz, Paul J
EDAT- 2019/05/08 06:00
MHDA- 2019/07/10 06:00
CRDT- 2019/05/08 06:00
PHST- 2018/06/19 00:00 [received]
PHST- 2019/03/18 00:00 [accepted]
PHST- 2019/05/08 06:00 [pubmed]
PHST- 2019/07/10 06:00 [medline]
PHST- 2019/05/08 06:00 [entrez]
AID - 10.1038/s41590-019-0378-1 [doi]
AID - 10.1038/s41590-019-0378-1 [pii]
PST - ppublish
SO  - Nat Immunol. 2019 Jul;20(7):928-942. doi: 10.1038/s41590-019-0378-1. Epub
      2019 May 6.