{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T21:45:53Z","timestamp":1759009553338},"reference-count":38,"publisher":"American Society for Microbiology","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin. Vaccine Immunol."],"published-print":{"date-parts":[[2012,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The mycobacterial heparin-binding hemagglutinin (HBHA) protein induces a potent gamma interferon (IFN-\u03b3) response in latent tuberculosis (TB) infection and is a candidate vaccine and diagnostic antigen. We have assessed HBHA-specific intracellular IFN-\u03b3, interleukin-2 (IL-2), and IL-17 production by CD4<jats:sup>+<\/jats:sup>T cells in TB cases and household contacts (HHCs) as well as the level of secreted IFN-\u03b3 in whole-blood culture supernatant. HHCs were further classified as tuberculin skin test (TST) positive or negative, and the group was also divided as HIV positive or negative. Our study revealed that HBHA induces multifunctional IFN-\u03b3-, IL-2-, and IL-17-coexpressing CD4<jats:sup>+<\/jats:sup>T cells in HHCs but not in active TB cases; however, IFN-\u03b3 levels in culture supernatant did not differ between participant groups. Further studies are needed to completely understand how HBHA induces immune responses in different disease groups.<\/jats:p>","DOI":"10.1128\/cvi.00047-12","type":"journal-article","created":{"date-parts":[[2012,3,30]],"date-time":"2012-03-30T05:45:05Z","timestamp":1333086305000},"page":"746-751","source":"Crossref","is-referenced-by-count":22,"title":["Heparin-Binding Hemagglutinin Induces IFN-\u03b3<sup>+<\/sup>IL-2<sup>+<\/sup>IL-17<sup>+<\/sup>Multifunctional CD4<sup>+<\/sup>T Cells during Latent but Not Active Tuberculosis Disease"],"prefix":"10.1128","volume":"19","author":[{"given":"Andr\u00e9 G.","family":"Loxton","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gillian F.","family":"Black","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kim","family":"Stanley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Walzl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","published-online":{"date-parts":[[2012,3,29]]},"reference":[{"key":"key20180919073605_B1","doi-asserted-by":"crossref","first-page":"1849","DOI":"10.1084\/jem.20070663","article-title":"Phenotypic and functional features of human Th17 cells","volume":"204","author":"Annunziato","year":"2007","journal-title":"J. Exp. Med."},{"key":"key20180919073605_B2","doi-asserted-by":"crossref","first-page":"4781","DOI":"10.1182\/blood-2005-12-4818","article-title":"HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells","volume":"107","author":"Betts","year":"2006","journal-title":"Blood"},{"key":"key20180919073605_B3","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1086\/322042","article-title":"Patterns and implications of naturally acquired immune responses to environmental and tuberculous mycobacterial antigens in northern Malawi","volume":"184","author":"Black","year":"2001","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B4","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/nm1592","article-title":"Multifunctional TH1 cells define a correlate of vaccine-mediated protection against Leishmania major","volume":"13","author":"Darrah","year":"2007","journal-title":"Nat. Med."},{"key":"key20180919073605_B5","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1016\/j.femsle.2004.08.015","article-title":"Expression and purification of recombinant methylated HBHA in Mycobacterium smegmatis","volume":"239","author":"Delogu","year":"2004","journal-title":"FEMS Microbiol. Lett."},{"key":"key20180919073605_B6","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.3201\/eid1308.051327","article-title":"High prevalence of tuberculosis in previously treated patients, Cape Town, South Africa","volume":"13","author":"den Boon","year":"2007","journal-title":"Emerg. Infect. Dis."},{"key":"key20180919073605_B7","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1183\/09031936.00005309","article-title":"Utility of quantitative T cell responses versus unstimulated IFN-\u03b3 for the diagnosis of pleural tuberculosis","volume":"34","author":"Dheda","year":"2009","journal-title":"Eur. Respir. J."},{"key":"key20180919073605_B8","doi-asserted-by":"crossref","first-page":"1165","DOI":"10.1128\/CVI.00084-08","article-title":"Differential expression of interleukin-4 (IL-4) and IL-4\u03942 mRNA, but not transforming growth factor beta (TGF-\u03b2), TGF-\u03b2RII, Foxp3, gamma interferon, T-bet, or GATA-3 mRNA, in patients with fast and slow responses to antituberculosis treatment","volume":"15","author":"Djoba Siawaya","year":"2008","journal-title":"Clin. Vaccine Immunol."},{"key":"key20180919073605_B9","first-page":"172","article-title":"Gamma interferon\u2014key, but not sufficient for protection against TB?","volume":"November 2007","author":"Dockrell","year":"2007","journal-title":"Microbiol. Today"},{"key":"key20180919073605_B10","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1016\/S0140-6736(95)92348-9","article-title":"Variation in protection by BCG: implications of and for heterologous immunity","volume":"346","author":"Fine","year":"1995","journal-title":"Lancet"},{"key":"key20180919073605_B11","doi-asserted-by":"crossref","first-page":"1923","DOI":"10.1016\/S0264-410X(98)00124-8","article-title":"The effect of heterologous immunity upon the apparent efficacy of (e.g., BCG) vaccines","volume":"16","author":"Fine","year":"1998","journal-title":"Vaccine"},{"key":"key20180919073605_B12","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1146\/annurev.immunol.19.1.93","article-title":"Immunology of tuberculosis","volume":"19","author":"Flynn","year":"2001","journal-title":"Annu. Rev. Immunol."},{"key":"key20180919073605_B13","doi-asserted-by":"crossref","first-page":"1491","DOI":"10.1086\/592450","article-title":"A new recombinant bacille Calmette-Guerin vaccine safely induces significantly enhanced tuberculosis-specific immunity in human volunteers","volume":"198","author":"Hoft","year":"2008","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B14","doi-asserted-by":"crossref","first-page":"13853","DOI":"10.1073\/pnas.250480397","article-title":"Recombinant bacillus Calmette-Guerin (BCG) vaccines expressing the Mycobacterium tuberculosis 30-kDa major secretory protein induce greater protective immunity against tuberculosis than conventional BCG vaccines in a highly susceptible animal model","volume":"97","author":"Horwitz","year":"2000","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"key20180919073605_B15","doi-asserted-by":"crossref","first-page":"e926","DOI":"10.1371\/journal.pone.0000926","article-title":"Heparin-binding-hemagglutinin-induced IFN-gamma release as a diagnostic tool for latent tuberculosis","volume":"2","author":"Hougardy","year":"2007","journal-title":"PLoS One"},{"key":"key20180919073605_B16","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1086\/509895","article-title":"Immune gene networks of mycobacterial vaccine-elicited cellular responses and immunity","volume":"195","author":"Huang","year":"2007","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B17","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1007\/s00109-007-0157-6","article-title":"Candidate biomarkers for discrimination between infection and disease caused by Mycobacterium tuberculosis","volume":"85","author":"Jacobsen","year":"2007","journal-title":"J. Mol. Med."},{"key":"key20180919073605_B18","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/j.1365-3156.2008.02213.x","article-title":"No decrease in annual risk of tuberculosis infection in endemic area in Cape Town, South Africa","volume":"14","author":"Kritzinger","year":"2009","journal-title":"Trop. Med. Int. Health"},{"key":"key20180919073605_B19","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/j.tube.2006.01.016","article-title":"Heparin-binding hemagglutinin, from an extrapulmonary dissemination factor to a powerful diagnostic and protective antigen against tuberculosis","volume":"86","author":"Locht","year":"2006","journal-title":"Tuberculosis (Edinb.)"},{"key":"key20180919073605_B20","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1086\/338833","article-title":"Differential T and B cell responses against Mycobacterium tuberculosis heparin-binding hemagglutinin adhesin in infected healthy individuals and patients with tuberculosis","volume":"185","author":"Masungi","year":"2002","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B21","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1086\/510397","article-title":"Gene-expression patterns in whole blood identify subjects at risk for recurrent tuberculosis","volume":"195","author":"Mistry","year":"2007","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B22","doi-asserted-by":"crossref","first-page":"12434","DOI":"10.1073\/pnas.0703510104","article-title":"Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis","volume":"104","author":"Mittrucker","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"key20180919073605_B23","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.mcp.2006.10.001","article-title":"Host susceptibility to tuberculosis: CARD15 polymorphisms in a South African population","volume":"21","author":"Moller","year":"2007","journal-title":"Mol. Cell Probes."},{"key":"key20180919073605_B24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.tube.2008.10.001","article-title":"Investigation of chromosome 17 candidate genes in susceptibility to TB in a South African population","volume":"89","author":"Moller","year":"2009","journal-title":"Tuberculosis (Edinb.)"},{"key":"key20180919073605_B25","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.cyto.2008.05.002","article-title":"Mycobacterium tuberculosis-specific CD4+, IFN\u03b3+, and TNF\u03b1+ multifunctional memory T cells coexpress GM-CSF","volume":"43","author":"Mueller","year":"2008","journal-title":"Cytokine"},{"key":"key20180919073605_B26","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1016\/S1473-3099(07)70086-5","article-title":"T-cell assays for the diagnosis of latent tuberculosis infection: moving the research agenda forward","volume":"7","author":"Pai","year":"2007","journal-title":"Lancet Infect. Dis."},{"key":"key20180919073605_B27","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1055\/s-0028-1085707","article-title":"New diagnostics for latent and active tuberculosis: state of the art and future prospects","volume":"29","author":"Pai","year":"2008","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"key20180919073605_B28","doi-asserted-by":"crossref","first-page":"177","DOI":"10.7326\/0003-4819-149-3-200808050-00241","article-title":"Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection: an update","volume":"149","author":"Pai","year":"2008","journal-title":"Ann. Intern. Med."},{"key":"key20180919073605_B29","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/35084083","article-title":"The heparin-binding haemagglutinin of M. tuberculosis is required for extrapulmonary dissemination","volume":"412","author":"Pethe","year":"2001","journal-title":"Nature"},{"key":"key20180919073605_B30","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1086\/592448","article-title":"Severe tuberculosis induces unbalanced up-regulation of gene networks and overexpression of IL-22, MIP-1\u03b1, CCL27, IP-10, CCR4, CCR5, CXCR3, PD1, PDL2, IL-3, IFN-\u03b2, TIM1, and TLR2 but low antigen-specific cellular responses","volume":"198","author":"Qiu","year":"2008","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B31","doi-asserted-by":"crossref","first-page":"870","DOI":"10.1086\/511277","article-title":"Immunosuppression during active tuberculosis is characterized by decreased interferon-gamma production and CD25 expression with elevated forkhead box P3, transforming growth factor-beta, and interleukin-4 mRNA levels","volume":"195","author":"Roberts","year":"2007","journal-title":"J. Infect. Dis."},{"key":"key20180919073605_B32","doi-asserted-by":"crossref","first-page":"e3272","DOI":"10.1371\/journal.pone.0003272","article-title":"Pilot study of diagnostic potential of the Mycobacterium tuberculosis recombinant HBHA protein in a vaccinated population in Finland","volume":"3","author":"Savolainen","year":"2008","journal-title":"PLoS One"},{"key":"key20180919073605_B33","doi-asserted-by":"crossref","first-page":"1962","DOI":"10.4049\/jimmunol.180.3.1962","article-title":"Distinct, specific IL-17- and IL-22-producing CD4+ T cell subsets contribute to the human anti-mycobacterial immune response","volume":"180","author":"Scriba","year":"2008","journal-title":"J. Immunol."},{"key":"key20180919073605_B34","doi-asserted-by":"crossref","first-page":"3569","DOI":"10.4049\/jimmunol.180.5.3569","article-title":"Bacillus Calmette-Guerin vaccination of human newborns induces T cells with complex cytokine and phenotypic profiles","volume":"180","author":"Soares","year":"2008","journal-title":"J. Immunol."},{"key":"key20180919073605_B35","unstructured":"Stop TB Partnership. 2008. TB vaccines pipeline. http:\/\/www.stoptb.org\/assets\/documents\/global\/retooling\/StopTB%202008%20Vaccines%20Pipeline%20March%2008.pdf."},{"key":"key20180919073605_B36","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/eji.200838693","article-title":"Pattern and diversity of cytokine production differentiates between Mycobacterium tuberculosis infection and disease","volume":"39","author":"Sutherland","year":"2009","journal-title":"Eur. J. Immunol."},{"key":"key20180919073605_B37","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1128\/IAI.00685-08","article-title":"Immunogenicity and protective efficacy of prime-boost regimens with recombinant \u0394ureC hly+ Mycobacterium bovis BCG and modified vaccinia virus Ankara expressing M. tuberculosis antigen 85A against murine tuberculosis","volume":"77","author":"Tchilian","year":"2009","journal-title":"Infect. Immun."},{"key":"key20180919073605_B38","doi-asserted-by":"crossref","first-page":"e1850","DOI":"10.1371\/journal.pone.0001850","article-title":"T-cell assays for tuberculosis infection: deriving cut-offs for conversions using reproducibility data","volume":"3","author":"Veerapathran","year":"2008","journal-title":"PLoS One"}],"container-title":["Clinical and Vaccine Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1128\/CVI.00047-12","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,7,29]],"date-time":"2021-07-29T20:47:36Z","timestamp":1627591656000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/CVI.00047-12"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,29]]},"references-count":38,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2012,4,26]]},"published-print":{"date-parts":[[2012,5]]}},"alternative-id":["10.1128\/CVI.00047-12"],"URL":"https:\/\/doi.org\/10.1128\/cvi.00047-12","relation":{},"ISSN":["1556-6811","1556-679X"],"issn-type":[{"value":"1556-6811","type":"print"},{"value":"1556-679X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3,29]]}}}