Evidence map›Paper›PMID 28935667›Full record

ArticleCirculation2017

Upregulation of Human Endogenous Retrovirus-K Is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension.

Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharpe, Erik Samayoa, Daisuke Harada, Jan-Renier A J Moonen, Aiqin Cao and 19 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
50citing papers in PubMed, 1 pooled it
2.5field-weighted citation impact, top 9% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

50 citing papers in PubMed, 1 synthesis or guideline pooled it, 70 citations in OpenAlex.

  1. Pooled it
  2. Article
  3. Review
  4. Review
  5. Article
  6. Article
  7. Review
  8. Article
  9. Article
  10. Article
  11. Article
  12. Review
  13. Review
  14. Review
  15. Article
  16. Review
  17. Article
  18. Review
  19. Review
  20. Endogenous Retroviruses as Modulators of Innate Immunity.Pathogens (Basel, Switzerland) · 2023
    Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

29 authors at 1 institution in 1 country.

Toshie SaitoVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Kazuya MiyagawaVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Shih-Yu ChenDepartment of Microbiology and Immunology (S.-Y.C., W.J.F., G.P.N.).
Rasa TamosiunieneVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Lingli WangVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Orr SharpeDepartment of Medicine (R.T., O.S., D.H., P.A.d.R., M.B., F.H., J.G.M., W.H.R., R.T.Z., M.R.N.).
Erik SamayoaStanford University School of Medicine, CA. Department of Laboratory Medicine and Medicine/Infectious Diseases (E.S., C.Y.C.), and Viral Diagnostics and Discovery Center University of California, San Francisco (E.S., C.Y.C.).
Daisuke HaradaDepartment of Medicine (R.T., O.S., D.H., P.A.d.R., M.B., F.H., J.G.M., W.H.R., R.T.Z., M.R.N.).
Jan-Renier A J MoonenVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Aiqin CaoVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Pin-I ChenVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Jan K HennigsVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Mingxia GuVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Caiyun G LiVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Ryan D Leib
Dan LiVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Christopher M Adams
Patricia A Del RosarioVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Matthew BillVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Francois HaddadCardiovascular Institute (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., F.H., R.T.Z., M.R.N., M.R.).
Jose G MontoyaDepartment of Medicine (R.T., O.S., D.H., P.A.d.R., M.B., F.H., J.G.M., W.H.R., R.T.Z., M.R.N.).
William H RobinsonDepartment of Medicine (R.T., O.S., D.H., P.A.d.R., M.B., F.H., J.G.M., W.H.R., R.T.Z., M.R.N.).
Wendy J FantlDepartment of Microbiology and Immunology (S.-Y.C., W.J.F., G.P.N.).
Garry P NolanDepartment of Microbiology and Immunology (S.-Y.C., W.J.F., G.P.N.).
Roham T ZamanianVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Mark R NicollsVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.).
Charles Y ChiuStanford University School of Medicine, CA. Department of Laboratory Medicine and Medicine/Infectious Diseases (E.S., C.Y.C.), and Viral Diagnostics and Discovery Center University of California, San Francisco (E.S., C.Y.C.).
Maria E ArizaDepartment of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH (M.E.A.).
Marlene RabinovitchVera Moulton Wall Center for Pulmonary Vascular Disease (T.S., K.M., R.T., L.W., J.-R.A.J.M., A.C., P.-I.C., J.K.H., M.G., C.G.L., D.L., P.A.d.R., M.B., R.T.Z., M.R.N., M.R.), marlener@stanford.edu.
United States Nuclear Regulatory Commission · US

Funding

Michigan Institute for Clinical and Health Research (MICHR)UL1TR002240 · NCATS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI LUMENG, JULIE C, MASHOUR, GEORGE ALEXANDER · 2017 to 2022
$54.9M
MICHIGAN INSTITUTE FOR CLINICAL AND HEALTH RESEARCH (MICHR) (UL1): (BPCA)UL1RR024986 · NCRR · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI SHANLEY, THOMAS P. · 2007 to 2011
$51.2M
The Cellular Response to Elafin in PAHP01HL108797 · NHLBI · STANFORD UNIVERSITY · PI ZAMANIAN, ROHAM · 2011 to 2021
$19.7M
Pulmonary Hypertension Breakthrough InitiativeR24HL123767 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI ALDRED, MICHEALA A, ERZURUM, SERPIL C. · 2014 to 2017
$10.1M
Stress Effects on Virus Protein induced Inflammation and Sickness BehaviorR01AI084898 · NIAID · OHIO STATE UNIVERSITY · PI ARIZA, MARIA-EUGENIA, WILLIAMS, MARSHALL VANCE · 2010 to 2024
$8.8M
iPSC Derived EC as Surrogates Using Pulmonary Hypertension as a Prototype DiseaseU01HL107393 · NHLBI · STANFORD UNIVERSITY · PI RABINOVITCH, MARLENE, SNYDER, MICHAEL P. · 2011 to 2015
$8.7M
Pan-Genomic Approaches for Comprehensive Blood Screening of Novel or Emerging Infectious AgentsR01HL105704 · NHLBI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CHIU, CHARLES YEN · 2011 to 2020
$5.9M
Endothelial Injury, BMPR2 Dysfunction and Macrophage Activation Cause EndMT and PAHR01HL138473 · NHLBI · STANFORD UNIVERSITY · PI Mark Robert Nicolls, Marlene Rabinovitch · 2017 to 2026
$4.9M
Integrative Omics as a Discovery Tool for Pulmonary HypertensionR01HL122887 · NHLBI · STANFORD UNIVERSITY · PI NICOLLS, MARK ROBERT, RABINOVITCH, MARLENE · 2015 to 2018
$4.1M
An Autoimmune Basis for Pulmonary Hypertension.R01HL082662 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI NICOLLS, MARK ROBERT · 2006 to 2009
$1.8M
LTQ Orbitrap XL ETD Mass SpectrometerS10RR027425 · NCRR · STANFORD UNIVERSITY · PI WANDLESS, THOMAS JAMES · 2010 to 2010
$500k
Uncovering compensatory mechanisms in family members with disease causing mutations of pulmonary hypertensionK99HL135258 · NHLBI · STANFORD UNIVERSITY · PI GU, MINGXIA · 2017 to 2018
$336k
NCATS NIH HHS UL1 TR002240NCRR NIH HHS S10 RR027425NCRR NIH HHS UL1 RR024986NHLBI NIH HHS K99 HL135258NHLBI NIH HHS N01 HV028183NHLBI NIH HHS P01 HL108797NHLBI NIH HHS R01 HL082662NHLBI NIH HHS R01 HL105704NHLBI NIH HHS R01 HL122887NHLBI NIH HHS R01 HL138473NHLBI NIH HHS R24 HL123767NHLBI NIH HHS U01 HL107393NIAID NIH HHS R01 AI084898
6 · The paper itself

Abstract

backgroundImmune dysregulation has been linked to occlusive vascular remodeling in pulmonary arterial hypertension (PAH) that is hereditary, idiopathic, or associated with other conditions. Circulating autoantibodies, lung perivascular lymphoid tissue, and elevated cytokines have been related to PAH pathogenesis but without a clear understanding of how these abnormalities are initiated, perpetuated, and connected in the progression of disease. We therefore set out to identify specific target antigens in PAH lung immune complexes as a starting point toward resolving these issues to better inform future application of immunomodulatory therapies.

methodsLung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry, confirmed by enzyme-linked immunosorbent assay, and localized by confocal microscopy. One PAH antigen linked to immunity and inflammation was pursued and a link to PAH pathophysiology was investigated by next-generation sequencing, functional studies in cultured monocytes and endothelial cells, and hemodynamic and lung studies in a rat.

resultsSAM domain and HD domain-containing protein 1 (SAMHD1), an innate immune factor that suppresses HIV replication, was identified and confirmed as highly expressed in immune complexes from 16 hereditary and idiopathic PAH versus 12 control lungs. Elevated SAMHD1 was localized to endothelial cells, perivascular dendritic cells, and macrophages, and SAMHD1 antibodies were prevalent in tertiary lymphoid tissue. An unbiased screen using metagenomic sequencing related SAMHD1 to increased expression of human endogenous retrovirus K (HERV-K) in PAH versus control lungs (n=4). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase mRNAs were elevated in PAH versus control lungs (n=10), and proteins were localized to macrophages. HERV-K deoxyuridine triphosphate nucleotidohydrolase induced SAMHD1 and proinflammatory cytokines (eg, interleukin 6, interleukin 1β, and tumor necrosis factor α) in circulating monocytes, pulmonary arterial endothelial cells, and also activated B cells. Vulnerability of pulmonary arterial endothelial cells (PAEC) to apoptosis was increased by HERV-K deoxyuridine triphosphate nucleotidohydrolase in an interleukin 6-independent manner. Furthermore, 3 weekly injections of HERV-K deoxyuridine triphosphate nucleotidohydrolase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8) and elevated interleukin 6.

conclusionsOur study reveals that upregulation of the endogenous retrovirus HERV-K could both initiate and sustain activation of the immune system and cause vascular changes associated with PAH.

Indexed as

AdolescentAdultAnimalsAntigen-Antibody ComplexCells, CulturedChildCoculture TechniquesFemaleHumansHypertension, PulmonaryInfantInflammationInflammation MediatorsLeukocytes, MononuclearMaleMiddle AgedAntigen-Antibody ComplexHERV-K cORF protein, Human endogenous retrovirus KInflammation MediatorsSAM Domain and HD Domain-Containing Protein 1Viral Proteinsdeoxyuridine triphosphate nucleotidohydrolase (dUTPase)human endogenous retrovirus K (HERV-K)pulmonary arterial hypertension (PAH)SAM domain and HD domain-containing protein 1 (SAMHD1)tertiary lymphoid tissue

Identifiers

PMID28935667
PMCPMC5685911
OpenAlexW2756682806

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.