{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T19:19:34Z","timestamp":1786821574325,"version":"build-2736575974"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T00:00:00Z","timestamp":1551744000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T00:00:00Z","timestamp":1551744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI089618-06"],"award-info":[{"award-number":["P01 AI089618-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI089618-06"],"award-info":[{"award-number":["P01 AI089618-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI089618-06"],"award-info":[{"award-number":["P01 AI089618-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01 AI089618-06"],"award-info":[{"award-number":["P01 AI089618-06"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Epitope-focused approaches for selective clonal induction of broadly neutralizing antibodies (bnAbs) inform most current vaccine strategies for influenza virus and other rapidly evolving pathogens. The two conserved epitopes on the influenza hemagglutinin (HA) - the \u201cstem\u201d and the receptor-binding site (RBS) on the \u201chead\u201d - are the focus of the current \u201cuniversal\u201d influenza vaccine development efforts. Because stem-directed serum bnAbs are much less abundant than head-directed ones, we hypothesized that the HA stem bnAbs may be autoreactive and thus eliminated through the mechanisms of self-tolerance. We compared autoreactivity profiles of a set of stem and head-directed bnAbs. Most of the stem bnAbs we examined bound autoantigens; several showed staining of HEp-2 cells. A smaller proportion of the head-directed bnAbs were polyreactive. Gene usage did not correlate with autoreactivity. We suggest that complex foreign antigens may often have surface patches resembling some host epitope; our results indicate that HA stem epitopes resemble a host epitope more frequently than does the RBS.<\/jats:p>","DOI":"10.1038\/s41598-019-40175-8","type":"journal-article","created":{"date-parts":[[2019,3,5]],"date-time":"2019-03-05T11:05:48Z","timestamp":1551783948000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Autoreactivity profiles\u00a0of influenza hemagglutinin broadly neutralizing\u00a0antibodies"],"prefix":"10.1038","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0480-4324","authenticated-orcid":false,"given":"Goran","family":"Bajic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cees E.","family":"van der Poel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masayuki","family":"Kuraoka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron G.","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael C.","family":"Carroll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garnett","family":"Kelsoe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen C.","family":"Harrison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,3,5]]},"reference":[{"key":"40175_CR1","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1146\/annurev.biochem.69.1.531","volume":"69","author":"JJ Skehel","year":"2000","unstructured":"Skehel, J. J. & Wiley, D. C. Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69, 531\u2013569 (2000).","journal-title":"Annu Rev Biochem"},{"key":"40175_CR2","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1038\/nature11414","volume":"489","author":"DC Ekiert","year":"2012","unstructured":"Ekiert, D. C. et al. Cross-neutralization of influenza A viruses mediated by a single antibody loop. Nature 489, 526\u2013532 (2012).","journal-title":"Nature"},{"key":"40175_CR3","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1073\/pnas.1218256109","volume":"110","author":"AG Schmidt","year":"2013","unstructured":"Schmidt, A. G. et al. Preconfiguration of the antigen-binding site during affinity maturation of a broadly neutralizing influenza virus antibody. Proc Natl Acad Sci USA 110, 264\u2013269 (2013).","journal-title":"Proc Natl Acad Sci USA"},{"key":"40175_CR4","doi-asserted-by":"publisher","first-page":"1026","DOI":"10.1016\/j.cell.2015.04.028","volume":"161","author":"AG Schmidt","year":"2015","unstructured":"Schmidt, A. G. et al. Viral receptor-binding site antibodies with diverse germline origins. Cell 161, 1026\u20131034 (2015).","journal-title":"Cell"},{"key":"40175_CR5","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1016\/j.immuni.2017.12.009","volume":"48","author":"KR McCarthy","year":"2018","unstructured":"McCarthy, K. R. et al. Memory B Cells that Cross-React with Group 1 and Group 2 Influenza A Viruses Are Abundant in Adult Human Repertoires. Immunity 48, 174\u2013184 e179 (2018).","journal-title":"Immunity"},{"key":"40175_CR6","doi-asserted-by":"crossref","unstructured":"Henry Dunand, C. J. & Wilson, P. C. Restricted, canonical, stereotyped and convergent immunoglobulin responses. Philos Trans R Soc Lond B Biol Sci 370 (2015).","DOI":"10.1098\/rstb.2014.0238"},{"key":"40175_CR7","doi-asserted-by":"publisher","first-page":"850","DOI":"10.1126\/science.1205669","volume":"333","author":"D Corti","year":"2011","unstructured":"Corti, D. et al. A neutralizing antibody selected from plasma cells that binds to group 1 and group 2 influenza A hemagglutinins. Science 333, 850\u2013856 (2011).","journal-title":"Science"},{"key":"40175_CR8","doi-asserted-by":"publisher","first-page":"7149","DOI":"10.1128\/JVI.02975-12","volume":"87","author":"C Dreyfus","year":"2013","unstructured":"Dreyfus, C., Ekiert, D. C. & Wilson, I. A. Structure of a classical broadly neutralizing stem antibody in complex with a pandemic H2 influenza virus hemagglutinin. J Virol 87, 7149\u20137154 (2013).","journal-title":"J Virol"},{"key":"40175_CR9","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1126\/science.1171491","volume":"324","author":"DC Ekiert","year":"2009","unstructured":"Ekiert, D. C. et al. Antibody recognition of a highly conserved influenza virus epitope. Science 324, 246\u2013251 (2009).","journal-title":"Science"},{"key":"40175_CR10","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1073\/pnas.1319058110","volume":"111","author":"RH Friesen","year":"2014","unstructured":"Friesen, R. H. et al. A common solution to group 2 influenza virus neutralization. Proc Natl Acad Sci USA 111, 445\u2013450 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"40175_CR11","doi-asserted-by":"publisher","first-page":"143","DOI":"10.1038\/nm.3443","volume":"20","author":"DJ DiLillo","year":"2014","unstructured":"DiLillo, D. J., Tan, G. S., Palese, P. & Ravetch, J. V. Broadly neutralizing hemagglutinin stalk-specific antibodies require FcgammaR interactions for protection against influenza virus in vivo. Nat Med 20, 143\u2013151 (2014).","journal-title":"Nat Med"},{"key":"40175_CR12","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.immuni.2004.12.011","volume":"22","author":"RM Cardoso","year":"2005","unstructured":"Cardoso, R. M. et al. Broadly neutralizing anti-HIV antibody 4E10 recognizes a helical conformation of a highly conserved fusion-associated motif in gp41. Immunity 22, 163\u2013173 (2005).","journal-title":"Immunity"},{"key":"40175_CR13","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.cell.2014.01.052","volume":"156","author":"AP West Jr","year":"2014","unstructured":"West, A. P. Jr. et al. Structural insights on the role of antibodies in HIV-1 vaccine and therapy. Cell 156, 633\u2013648 (2014).","journal-title":"Cell"},{"key":"40175_CR14","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1126\/science.1111781","volume":"308","author":"BF Haynes","year":"2005","unstructured":"Haynes, B. F. et al. Cardiolipin polyspecific autoreactivity in two broadly neutralizing HIV-1 antibodies. Science 308, 1906\u20131908 (2005).","journal-title":"Science"},{"key":"40175_CR15","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1128\/JVI.02378-14","volume":"89","author":"M Liu","year":"2015","unstructured":"Liu, M. et al. Polyreactivity and autoreactivity among HIV-1 antibodies. J Virol 89, 784\u2013798 (2015).","journal-title":"J Virol"},{"key":"40175_CR16","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1084\/jem.20121977","volume":"210","author":"G Yang","year":"2013","unstructured":"Yang, G. et al. Identification of autoantigens recognized by the 2F5 and 4E10 broadly neutralizing HIV-1 antibodies. J Exp Med 210, 241\u2013256 (2013).","journal-title":"J Exp Med"},{"key":"40175_CR17","doi-asserted-by":"publisher","first-page":"903","DOI":"10.1002\/1521-4141(200203)32:3<903::AID-IMMU903>3.0.CO;2-D","volume":"32","author":"V De Re","year":"2002","unstructured":"De Re, V. et al. Salivary gland B cell lymphoproliferative disorders in Sjogren\u2019s syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins\u2019s lymphomas. Eur J Immunol 32, 903\u2013910 (2002).","journal-title":"Eur J Immunol"},{"key":"40175_CR18","doi-asserted-by":"publisher","first-page":"2499","DOI":"10.1182\/blood-2004-03-0818","volume":"104","author":"GF Widhopf 2nd","year":"2004","unstructured":"Widhopf, G. F. 2nd et al. Chronic lymphocytic leukemia B cells of more than 1% of patients express virtually identical immunoglobulins. Blood 104, 2499\u20132504 (2004).","journal-title":"Blood"},{"key":"40175_CR19","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1038\/nsmb.1566","volume":"16","author":"J Sui","year":"2009","unstructured":"Sui, J. et al. Structural and functional bases for broad-spectrum neutralization of avian and human influenza A viruses. Nat Struct Mol Biol 16, 265\u2013273 (2009).","journal-title":"Nat Struct Mol Biol"},{"key":"40175_CR20","doi-asserted-by":"publisher","first-page":"e1004103","DOI":"10.1371\/journal.ppat.1004103","volume":"10","author":"Y Avnir","year":"2014","unstructured":"Avnir, Y. et al. Molecular signatures of hemagglutinin stem-directed heterosubtypic human neutralizing antibodies against influenza A viruses. PLoS Pathog 10, e1004103 (2014).","journal-title":"PLoS Pathog"},{"key":"40175_CR21","doi-asserted-by":"publisher","first-page":"316ra192","DOI":"10.1126\/scitranslmed.aad0522","volume":"7","author":"SF Andrews","year":"2015","unstructured":"Andrews, S. F. et al. Immune history profoundly affects broadly protective B cell responses to influenza. Sci Transl Med 7, 316ra192 (2015).","journal-title":"Sci Transl Med"},{"key":"40175_CR22","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/j.cell.2017.07.026","volume":"170","author":"SE Degn","year":"2017","unstructured":"Degn, S. E. et al. Clonal Evolution of Autoreactive Germinal Centers. Cell 170, 913\u2013926 e919 (2017).","journal-title":"Cell"},{"key":"40175_CR23","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1007\/s004410050718","volume":"286","author":"D Vazquez-Abad","year":"1996","unstructured":"Vazquez-Abad, D., Carson, J. H. & Rothfield, N. Localization of histidyl-tRNA synthetase (Jo-1) in human laryngeal epithelial carcinoma cell line (HEp-2 cells). Cell Tissue Res 286, 487\u2013491 (1996).","journal-title":"Cell Tissue Res"},{"key":"40175_CR24","doi-asserted-by":"publisher","first-page":"2686","DOI":"10.1002\/art.10542","volume":"46","author":"J Delgado Alves","year":"2002","unstructured":"Delgado Alves, J. et al. Antibodies to high-density lipoprotein and beta2-glycoprotein I are inversely correlated with paraoxonase activity in systemic lupus erythematosus and primary antiphospholipid syndrome. Arthritis Rheum 46, 2686\u20132694 (2002).","journal-title":"Arthritis Rheum"},{"key":"40175_CR25","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1093\/rheumatology\/39.4.427","volume":"39","author":"EL Radway-Bright","year":"2000","unstructured":"Radway-Bright, E. L., Ravirajan, C. T. & Isenberg, D. A. The prevalence of antibodies to anionic phospholipids in patients with the primary antiphospholipid syndrome, systemic lupus erythematosus and their relatives and spouses. Rheumatology (Oxford) 39, 427\u2013431 (2000).","journal-title":"Rheumatology (Oxford)"},{"key":"40175_CR26","doi-asserted-by":"publisher","first-page":"102","DOI":"10.1111\/j.1365-2141.1999.01292.x","volume":"105","author":"M Zhu","year":"1999","unstructured":"Zhu, M. et al. Characterization of IgG monoclonal anti-cardiolipin\/anti-beta2GP1 antibodies from two patients with antiphospholipid syndrome reveals three species of antibodies. Br J Haematol 105, 102\u2013109 (1999).","journal-title":"Br J Haematol"},{"key":"40175_CR27","doi-asserted-by":"publisher","first-page":"596","DOI":"10.1016\/j.cell.2016.05.073","volume":"166","author":"NL Kallewaard","year":"2016","unstructured":"Kallewaard, N. L. et al. Structure and Function Analysis of an Antibody Recognizing All Influenza A Subtypes. Cell 166, 596\u2013608 (2016).","journal-title":"Cell"},{"key":"40175_CR28","doi-asserted-by":"crossref","unstructured":"Doud, M. B. & Bloom, J. D. Accurate Measurement of the Effects of All Amino-Acid Mutations on Influenza Hemagglutinin. Viruses 8 (2016).","DOI":"10.1101\/047571"},{"key":"40175_CR29","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/j.1365-2567.2006.02421.x","volume":"119","author":"M Knossow","year":"2006","unstructured":"Knossow, M. & Skehel, J. J. Variation and infectivity neutralization in influenza. Immunology 119, 1\u20137 (2006).","journal-title":"Immunology"},{"key":"40175_CR30","doi-asserted-by":"publisher","first-page":"13133","DOI":"10.1073\/pnas.1414070111","volume":"111","author":"AH Ellebedy","year":"2014","unstructured":"Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc Natl Acad Sci USA 111, 13133\u201313138 (2014).","journal-title":"Proc Natl Acad Sci USA"},{"key":"40175_CR31","doi-asserted-by":"publisher","first-page":"2842","DOI":"10.1016\/j.celrep.2015.11.063","volume":"13","author":"AG Schmidt","year":"2015","unstructured":"Schmidt, A. G. et al. Immunogenic Stimulus for Germline Precursors of Antibodies that Engage the Influenza Hemagglutinin Receptor-Binding Site. Cell Rep 13, 2842\u20132850 (2015).","journal-title":"Cell Rep"},{"key":"40175_CR32","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1038\/nbt.2197","volume":"30","author":"BF Haynes","year":"2012","unstructured":"Haynes, B. F., Kelsoe, G., Harrison, S. C. & Kepler, T. B. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol 30, 423\u2013433 (2012).","journal-title":"Nat Biotechnol"},{"key":"40175_CR33","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1080\/14760584.2017.1299576","volume":"16","author":"F Krammer","year":"2017","unstructured":"Krammer, F. Strategies to induce broadly protective antibody responses to viral glycoproteins. Expert Rev Vaccines 16, 503\u2013513 (2017).","journal-title":"Expert Rev Vaccines"},{"key":"40175_CR34","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.coi.2016.05.012","volume":"42","author":"KE Neu","year":"2016","unstructured":"Neu, K. E., Henry Dunand, C. J. & Wilson, P. C. Heads, stalks and everything else: how can antibodies eradicate influenza as a human disease? Curr Opin Immunol 42, 48\u201355 (2016).","journal-title":"Curr Opin Immunol"},{"key":"40175_CR35","doi-asserted-by":"publisher","first-page":"521","DOI":"10.1016\/j.coviro.2013.07.007","volume":"3","author":"F Krammer","year":"2013","unstructured":"Krammer, F. & Palese, P. Influenza virus hemagglutinin stalk-based antibodies and vaccines. Curr Opin Virol 3, 521\u2013530 (2013).","journal-title":"Curr Opin Virol"},{"key":"40175_CR36","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.chom.2015.10.003","volume":"18","author":"F Krammer","year":"2015","unstructured":"Krammer, F. The Quest for a Universal Flu Vaccine: Headless HA 2.0. Cell Host Microbe 18, 395\u2013397 (2015).","journal-title":"Cell Host Microbe"},{"key":"40175_CR37","doi-asserted-by":"publisher","first-page":"542","DOI":"10.1016\/j.immuni.2016.02.010","volume":"44","author":"M Kuraoka","year":"2016","unstructured":"Kuraoka, M. et al. Complex Antigens Drive Permissive Clonal Selection in Germinal Centers. Immunity 44, 542\u2013552 (2016).","journal-title":"Immunity"},{"key":"40175_CR38","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2006-7-10-r100","volume":"7","author":"AE Carpenter","year":"2006","unstructured":"Carpenter, A. E. et al. CellProfiler: image analysis software for identifying and quantifying cell phenotypes. Genome Biol 7, R100 (2006).","journal-title":"Genome Biol"},{"key":"40175_CR39","doi-asserted-by":"publisher","first-page":"11502","DOI":"10.1128\/JVI.05363-11","volume":"85","author":"GD Tomaras","year":"2011","unstructured":"Tomaras, G. D. et al. Polyclonal B cell responses to conserved neutralization epitopes in a subset of HIV-1-infected individuals. J Virol 85, 11502\u201311519 (2011).","journal-title":"J Virol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40175-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40175-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40175-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T07:07:41Z","timestamp":1671260861000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-40175-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,5]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["40175"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-40175-8","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,5]]},"assertion":[{"value":"9 August 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 February 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 March 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3492"}}