{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:26:01Z","timestamp":1790803561308,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T00:00:00Z","timestamp":1684281600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AR074939"],"award-info":[{"award-number":["R01 AR074939"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AR075134"],"award-info":[{"award-number":["R21 AR075134"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21 AR077266"],"award-info":[{"award-number":["R21 AR077266"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32 AR007108"],"award-info":[{"award-number":["T32 AR007108"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI145296"],"award-info":[{"award-number":["R01 AI145296"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AI127463"],"award-info":[{"award-number":["R01 AI127463"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Many patients suffering from autoimmune diseases have autoantibodies against proteins encoded by genomic retroelements, suggesting that normal epigenetic silencing is insufficient to prevent the production of the encoded proteins for which immune tolerance appears to be limited. One such protein is the transmembrane envelope (Env) protein encoded by human endogenous retrovirus K (HERV-K). We reported recently that patients with rheumatoid arthritis (RA) have IgG autoantibodies that recognize Env. Here, we use RNA sequencing of RA neutrophils to analyze HERV-K expression and find that only two loci with an intact open-reading frame for Env, HERV-K102, and K108 are expressed, but only the former is increased in RA. In contrast, other immune cells express more K108 than K102. Patient autoantibodies recognized endogenously expressed Env in breast cancer cells and in RA neutrophils but not healthy controls. A monoclonal anti-Env antibody also detected Env on the surface of RA neutrophils but very little on the surface of other immune cells. We conclude that HERV-K102 is the locus that produces Env detectable on the surface of neutrophils in RA. The low levels of HERV-K108 transcripts may contribute only marginally to cell surface Env on neutrophils or other immune cells in some patients.<\/jats:p>","DOI":"10.3390\/microorganisms11051310","type":"journal-article","created":{"date-parts":[[2023,5,18]],"date-time":"2023-05-18T06:00:29Z","timestamp":1684389629000},"page":"1310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Expression of Envelope Protein Encoded by Endogenous Retrovirus K102 in Rheumatoid Arthritis Neutrophils"],"prefix":"10.3390","volume":"11","author":[{"given":"Amanda","family":"Laine","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxing","family":"Wang","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn","family":"Ni","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E. B.","family":"Smith","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rayan","family":"Najjar","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leanne S.","family":"Whitmore","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Infectious Disease, Department of Immunology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8893-038X","authenticated-orcid":false,"given":"Michael","family":"Yacoub","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Bays","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6332-7436","authenticated-orcid":false,"suffix":"Jr.","given":"Michael","family":"Gale","sequence":"additional","affiliation":[{"name":"Center for Innate Immunity and Infectious Disease, Department of Immunology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5912-8840","authenticated-orcid":false,"given":"Tomas","family":"Mustelin","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine, University of Washington, Seattle, WA 98195, USA"},{"name":"Center for Innate Immunity and Infectious Disease, Department of Immunology, University of Washington, Seattle, WA 98195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1111\/j.0105-2896.2005.00245.x","article-title":"Rheumatoid arthritis","volume":"204","author":"Goronzy","year":"2005","journal-title":"Immunol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/1529-0131(200001)43:1<155::AID-ANR20>3.0.CO;2-3","article-title":"The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide","volume":"43","author":"Schellekens","year":"2000","journal-title":"Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1002\/art.21220","article-title":"Synovial intracellular citrullinated proteins colocalizing with peptidyl arginine deiminase as pathophysiologically relevant antigenic determinants of rheumatoid arthritis-specific humoral autoimmunity","volume":"52","author":"Nicholas","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"R250","DOI":"10.1186\/ar4093","article-title":"Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: Evidence from MyEIRA study and meta-analysis","volume":"14","author":"Too","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1038\/ng1206","article-title":"Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis","volume":"34","author":"Suzuki","year":"2003","journal-title":"Nat. Genet."},{"key":"ref_6","first-page":"255","article-title":"Association between Peptidylarginine Deiminase Type 4 rs1748033 Polymorphism and Susceptibility to Rheumatoid Arthritis in Zahedan, Southeast Iran","volume":"14","author":"Hashemi","year":"2015","journal-title":"Iran. J. Allergy Asthma Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hua, J., and Huang, W. (2018). Peptidylarginine deiminase 4 -104C\/T polymorphism and risk of rheumatoid arthritis: A pooled analysis based on different populations. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0193674"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1136\/ard.2004.029389","article-title":"Antibodies to citrullinated human fibrinogen (ACF) have diagnostic and prognostic value in early arthritis","volume":"64","author":"Nielen","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1093\/rheumatology\/keaa623","article-title":"Is seronegative rheumatoid arthritis true rheumatoid arthritis? A nationwide cohort study","volume":"60","author":"Paalanen","year":"2021","journal-title":"Rheumatology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1046\/j.1365-2249.2002.01735.x","article-title":"Autoantibodies to human endogenous retrovirus-K are frequently detected in health and disease and react with multiple epitopes","volume":"128","author":"Herve","year":"2002","journal-title":"Clin. Exp. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1111\/cei.12964","article-title":"Identification of a HERV-K env surface peptide highly recognized in Rheumatoid Arthritis (RA) patients: A cross-sectional case-control study","volume":"189","author":"Mameli","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1952","DOI":"10.3899\/jrheum.130502","article-title":"Rheumatoid arthritis is associated with IgG antibodies to human endogenous retrovirus gag matrix: A potential pathogenic mechanism of disease?","volume":"41","author":"Nelson","year":"2014","journal-title":"J. Rheumatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"26","DOI":"10.3899\/jrheum.201492","article-title":"Autoantibodies Against Unmodified and Citrullinated Human Endogenous Retrovirus K Envelope Protein in Patients With Rheumatoid Arthritis","volume":"49","author":"Wang","year":"2022","journal-title":"J. Rheumatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1089\/aid.1996.12.491","article-title":"Epitope specificity of anti-HIV antibodies in human and murine autoimmune diseases","volume":"12","author":"Fraziano","year":"1996","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1136\/ard.2004.031146","article-title":"The potential role of human endogenous retrovirus K10 in the pathogenesis of rheumatoid arthritis: A preliminary study","volume":"65","author":"Ejtehadi","year":"2006","journal-title":"Ann. Rheum. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1111\/j.1365-3083.2009.02271.x","article-title":"Increase in human endogenous retrovirus HERV-K (HML-2) viral load in active rheumatoid arthritis","volume":"70","author":"Reynier","year":"2009","journal-title":"Scand. J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1111\/j.1365-2249.2010.04110.x","article-title":"A role for human endogenous retrovirus-K (HML-2) in rheumatoid arthritis: Investigating mechanisms of pathogenesis","volume":"160","author":"Freimanis","year":"2010","journal-title":"Clin. Exp. Immunol."},{"key":"ref_18","first-page":"16","article-title":"Human endogenous retrovirus HERV-K(HML-2) Rec expression and transcriptional activities in normal and rheumatoid arthritis synovia","volume":"33","author":"Ehlhardt","year":"2006","journal-title":"J. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1186\/1742-4690-8-90","article-title":"Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses","volume":"8","author":"Subramanian","year":"2011","journal-title":"Retrovirology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1099\/vir.0.83534-0","article-title":"Human endogenous retrovirus HERV-K113 is capable of producing intact viral particles","volume":"89","author":"Boller","year":"2008","journal-title":"J. Gen. Virol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1101\/gr.5565706","article-title":"Identification of an infectious progenitor for the multiple-copy HERV-K human endogenous retroelements","volume":"16","author":"Dewannieux","year":"2006","journal-title":"Genome Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1080\/1040841X.2018.1501345","article-title":"Human endogenous retrovirus-K (HML-2): A comprehensive review","volume":"44","author":"Henderson","year":"2018","journal-title":"Crit. Rev. Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Geis, F.K., and Goff, S.P. (2020). Silencing and Transcriptional Regulation of Endogenous Retroviruses: An Overview. Viruses, 12.","DOI":"10.3390\/v12080884"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nature14308","article-title":"Intrinsic retroviral reactivation in human preimplantation embryos and pluripotent cells","volume":"522","author":"Grow","year":"2015","journal-title":"Nature"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1093\/carcin\/bgr181","article-title":"Selective changes of retroelement expression in human prostate cancer","volume":"32","author":"Goering","year":"2011","journal-title":"Carcinogenesis"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4172","DOI":"10.1158\/0008-5472.CAN-04-2983","article-title":"Expression of human endogenous retrovirus K in melanomas and melanoma cell lines","volume":"65","author":"Buscher","year":"2005","journal-title":"Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"11108","DOI":"10.1128\/JVI.01623-14","article-title":"HIV-1 infection leads to increased transcription of human endogenous retrovirus HERV-K (HML-2) proviruses in vivo but not to increased virion production","volume":"88","author":"Bhardwaj","year":"2014","journal-title":"J. Virol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1212\/WNL.0000000000003258","article-title":"HIV-associated motor neuron disease: HERV-K activation and response to antiretroviral therapy","volume":"87","author":"Bowen","year":"2016","journal-title":"Neurology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1089\/aid.2007.0054","article-title":"Comparative longitudinal studies of HERV-K and HIV-1 RNA titers in HIV-1-infected patients receiving successful versus unsuccessful highly active antiretroviral therapy","volume":"23","author":"Lorenzo","year":"2007","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.jviromet.2006.03.029","article-title":"A new Real-Time-RT-PCR for quantitation of human endogenous retroviruses type K (HERV-K) RNA load in plasma samples: Increased HERV-K RNA titers in HIV-1 patients with HAART non-suppressive regimens","volume":"136","author":"Gonzalez","year":"2006","journal-title":"J. Virol. Methods"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1089\/aid.2006.22.979","article-title":"Detection of HERV-K(HML-2) viral RNA in plasma of HIV type 1-infected individuals","volume":"22","author":"Kaplan","year":"2006","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1089\/aid.2006.0117","article-title":"HIV-1 infection increases the expression of human endogenous retroviruses type K (HERV-K) in vitro","volume":"23","author":"Lopez","year":"2007","journal-title":"AIDS Res. Hum. Retrovir."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1186\/s12977-017-0365-2","article-title":"Anti-HERV-K (HML-2) capsid antibody responses in HIV elite controllers","volume":"14","author":"SenGupta","year":"2017","journal-title":"Retrovirology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"7790","DOI":"10.1128\/JVI.07215-11","article-title":"Expression of human endogenous retrovirus type K (HML-2) is activated by the Tat protein of HIV-1","volume":"86","author":"Swanson","year":"2012","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e20191766","DOI":"10.1084\/jem.20191766","article-title":"Antibodies against human endogenous retrovirus K102 envelope activate neutrophils in systemic lupus erythematosus","volume":"218","author":"Tokuyama","year":"2021","journal-title":"J. Exp. Med."},{"key":"ref_36","first-page":"1306","article-title":"Autoantibodies against the envelope proteins of endogenous retroviruses K102 and K108 in patients with systemic lupus erythematosus correlate with active disease","volume":"40","author":"Khadjinova","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1093\/bioinformatics\/bts635","article-title":"STAR: Ultrafast universal RNA-seq aligner","volume":"29","author":"Dobin","year":"2013","journal-title":"Bioinformatics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2184","DOI":"10.1093\/bioinformatics\/bts356","article-title":"RSeQC: Quality control of RNA-seq experiments","volume":"28","author":"Wang","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1093\/bioinformatics\/btv422","article-title":"TEtranscripts: A package for including transposable elements in differential expression analysis of RNA-seq datasets","volume":"31","author":"Jin","year":"2015","journal-title":"Bioinformatics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2213","DOI":"10.1101\/gr.124321.111","article-title":"Differential expression in RNA-seq: A matter of depth","volume":"21","author":"Tarazona","year":"2011","journal-title":"Genome Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1128\/jvi.61.6.2059-2062.1987","article-title":"Stimulation of expression of the human endogenous retrovirus genome by female steroid hormones in human breast cancer cell line T47D","volume":"61","author":"Ono","year":"1987","journal-title":"J. Virol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/6766","article-title":"An almost-intact human endogenous retrovirus K on human chromosome 7","volume":"21","author":"Mayer","year":"1999","journal-title":"Nat. Genet."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1006\/geno.2000.6488","article-title":"Genomic organization of the human endogenous retrovirus HERV-K(HML-2.HOM) (ERVK6) on chromosome 7","volume":"72","author":"Reus","year":"2001","journal-title":"Genomics"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s13075-017-1220-5","article-title":"Discovery of new candidate genes for rheumatoid arthritis through integration of genetic association data with expression pathway analysis","volume":"19","author":"Shchetynsky","year":"2017","journal-title":"Arthritis Res. Ther."},{"key":"ref_46","first-page":"1553","article-title":"Expression of human endogenous retrovirus k envelope transcripts in human breast cancer","volume":"7","author":"Frost","year":"2001","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1186\/s12977-018-0441-2","article-title":"Promoter expression of HERV-K (HML-2) provirus-derived sequences is related to LTR sequence variation and polymorphic transcription factor binding sites","volume":"15","author":"Montesion","year":"2018","journal-title":"Retrovirology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.virol.2007.09.036","article-title":"Molecular cloning and functional characterization of the human endogenous retrovirus K113","volume":"371","author":"Beimforde","year":"2008","journal-title":"Virology"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Robinson-McCarthy, L.R., McCarthy, K.R., Raaben, M., Piccinotti, S., Nieuwenhuis, J., Stubbs, S.H., Bakkers, M.J.G., and Whelan, S.P.J. (2018). Reconstruction of the cell entry pathway of an extinct virus. PLoS Pathog., 14.","DOI":"10.1101\/331363"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5869","DOI":"10.1158\/0008-5472.CAN-07-6838","article-title":"Human endogenous retrovirus K triggers an antigen-specific immune response in breast cancer patients","volume":"68","author":"Radvanyi","year":"2008","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1002\/ijc.28389","article-title":"Human endogenous retrovirus type K antibodies and mRNA as serum biomarkers of early-stage breast cancer","volume":"134","author":"Li","year":"2014","journal-title":"Int. J. Cancer"}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/5\/1310\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:36:40Z","timestamp":1760125000000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/11\/5\/1310"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,17]]},"references-count":51,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["microorganisms11051310"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms11051310","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,17]]}}}