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Original Research Article

Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension

Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharp, Erik Samayoa, Daisuke Harada, Jan-Renier A. J. Moonen, Aiqin Cao, Pin-I Chen, Jan K. Hennigs, Mingxia Gu, Caiyun G. Li, Ryan D. Leib, Dan Li, Christopher M. Adams, Patricia A. del Rosario, Matthew A. Bill, Francois Haddad, Jose G. Montoya, William Robinson, Wendy J. Fantl, Garry P. Nolan, Roham T. Zamanian, Mark R. Nicolls, Charles Y. Chiu, Maria E. Ariza, Marlene Rabinovitch
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https://doi.org/10.1161/CIRCULATIONAHA.117.027589
Circulation. 2017;CIRCULATIONAHA.117.027589
Originally published September 21, 2017
Toshie Saito
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Kazuya Miyagawa
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Shih-Yu Chen
Department of Microbiology and Immunology & Baxer Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA
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Rasa Tamosiuniene
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Lingli Wang
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Orr Sharp
Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Erik Samayoa
Department of Laboratory Medicine and Medicine/Infectious Diseases & UCSF Viral Diagnostics and Discovery Center, University of California, San Francisco, CA
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Daisuke Harada
Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Jan-Renier A. J. Moonen
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Aiqin Cao
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Pin-I Chen
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Jan K. Hennigs
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Mingxia Gu
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Caiyun G. Li
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Ryan D. Leib
Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University School of Medicine, Stanford, CA
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Dan Li
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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Christopher M. Adams
Vincent Coates Foundation Mass Spectrometry Laboratory, Stanford University School of Medicine, Stanford, CA
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Patricia A. del Rosario
The Vera Moulton Wall Center for Pulmonary Vascular Disease & Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Matthew A. Bill
The Vera Moulton Wall Center for Pulmonary Vascular Disease & Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Francois Haddad
Cardiovascular Institute & Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Jose G. Montoya
Department of Medicine, Stanford University School of Medicine, Stanford, CA
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William Robinson
Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Wendy J. Fantl
Department of Microbiology and Immunology; Baxer Laboratory in Stem Cell Biology; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA
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Garry P. Nolan
Department of Microbiology and Immunology & Baxer Laboratory in Stem Cell Biology, Stanford University School of Medicine, Stanford, CA
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Roham T. Zamanian
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Mark R. Nicolls
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Medicine, Stanford University School of Medicine, Stanford, CA
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Charles Y. Chiu
Department of Laboratory Medicine and Medicine/Infectious Diseases & UCSF Viral Diagnostics and Discovery Center, University of California, San Francisco, CA
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Maria E. Ariza
Department of Cancer Biology and Genetics, The Ohio State University Wexner Medical Center, Columbus, OH
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Marlene Rabinovitch
The Vera Moulton Wall Center for Pulmonary Vascular Disease; Cardiovascular Institute; Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
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  • For correspondence: marlener@stanford.edu
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Abstract

Background—Immune 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 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.

Methods—Lung immune complexes were isolated and PAH target antigens were identified by liquid chromatography tandem mass spectrometry (LCMS), confirmed by ELISA, 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 (EC) and hemodynamic and lung studies in a rat.

Results—SAM domain and HD1 domain-containing protein (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 vs. 12 control lungs. Elevated SAMHD1 was localized to endothelial cells (EC), 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 vs. control lungs (n=4 each). HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) mRNAs were elevated in PAH vs. control lungs (n=10) and proteins were localized to macrophages. HERV-K dUTPase induced SAMHD1 and pro-inflammatory cytokines (e.g., IL6, IL1β and TNFα) in circulating monocytes and pulmonary arterial (PA) EC, and activated B cells. Vulnerability of PAEC to apoptosis was increased by HERV-K dUTPase in an IL6 independent manner. Furthermore, three weekly injections of HERV-K dUTPase induced hemodynamic and vascular changes of pulmonary hypertension in rats (n=8), and elevated IL6.

Conclusions—Our 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.

  • SAM domain and HD1 domain-containing protein (SAMHD1)
  • human endogenous retrovirus K (HERV-K)
  • deoxyuridine triphosphate nucleotidohydrolase (dUTPase)
  • pulmonary arterial hypertension
  • tertiary lymphoid tissue
  • pulmonary hypertension
  • inflammation
  • immune system
  • Received January 25, 2017.
  • Revision received August 9, 2017.
  • Accepted August 31, 2017.

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    Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension
    Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharp, Erik Samayoa, Daisuke Harada, Jan-Renier A. J. Moonen, Aiqin Cao, Pin-I Chen, Jan K. Hennigs, Mingxia Gu, Caiyun G. Li, Ryan D. Leib, Dan Li, Christopher M. Adams, Patricia A. del Rosario, Matthew A. Bill, Francois Haddad, Jose G. Montoya, William Robinson, Wendy J. Fantl, Garry P. Nolan, Roham T. Zamanian, Mark R. Nicolls, Charles Y. Chiu, Maria E. Ariza and Marlene Rabinovitch
    Circulation. 2017;CIRCULATIONAHA.117.027589, originally published September 21, 2017
    https://doi.org/10.1161/CIRCULATIONAHA.117.027589

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    Upregulation of HERV-K is Linked to Immunity and Inflammation in Pulmonary Arterial Hypertension
    Toshie Saito, Kazuya Miyagawa, Shih-Yu Chen, Rasa Tamosiuniene, Lingli Wang, Orr Sharp, Erik Samayoa, Daisuke Harada, Jan-Renier A. J. Moonen, Aiqin Cao, Pin-I Chen, Jan K. Hennigs, Mingxia Gu, Caiyun G. Li, Ryan D. Leib, Dan Li, Christopher M. Adams, Patricia A. del Rosario, Matthew A. Bill, Francois Haddad, Jose G. Montoya, William Robinson, Wendy J. Fantl, Garry P. Nolan, Roham T. Zamanian, Mark R. Nicolls, Charles Y. Chiu, Maria E. Ariza and Marlene Rabinovitch
    Circulation. 2017;CIRCULATIONAHA.117.027589, originally published September 21, 2017
    https://doi.org/10.1161/CIRCULATIONAHA.117.027589
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