{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:57:21Z","timestamp":1768510641571,"version":"3.49.0"},"reference-count":52,"publisher":"American Society for Microbiology","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clin. Vaccine Immunol."],"published-print":{"date-parts":[[2011,4]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The clinical picture of herpes simplex virus type 2 (HSV-2) infection includes genital blisters and less frequently meningitis, and some individuals suffer from recurrent episodes of these manifestations. We hypothesized that adaptive and\/or innate immune functional deficiencies may be a major contributing factor in susceptibility to recurrent HSV-2 meningitis. Ten patients with recurrent HSV-2 meningitis were studied during clinical remission. For comparison, 10 patients with recurrent genital HSV infections as well as 21 HSV-seropositive and 19 HSV-seronegative healthy blood donors were included. HSV-specific T cell blasting and cytokine secretion were evaluated in whole blood cultures. HSV-2-induced NK cell gamma interferon production, dendritic cell Toll-like receptor (TLR) expression, and TLR agonist-induced alpha interferon secretion were analyzed. Patients with recurrent HSV-2 meningitis had elevated T cell blasting and Th1 and Th2 cytokine production in response to HSV antigens compared to those of patients with recurrent genital infections. A somewhat increased NK cell response, increased dendritic cell expression of TLR3 and -9, and increased TLR-induced alpha interferon responses were also noted. Contrary to our expectation, recurrent HSV-2 meningitis patients have increased HSV-specific adaptive and innate immune responses, raising the possibility of immune-mediated pathology in the development of recurrent HSV2 meningitis.<\/jats:p>","DOI":"10.1128\/cvi.00333-10","type":"journal-article","created":{"date-parts":[[2011,2,17]],"date-time":"2011-02-17T03:35:31Z","timestamp":1297913731000},"page":"655-660","source":"Crossref","is-referenced-by-count":15,"title":["Increased Cell-Mediated Immune Responses in Patients with Recurrent Herpes Simplex Virus Type 2 Meningitis"],"prefix":"10.1128","volume":"18","author":[{"given":"Elisabeth","family":"Franzen-R\u00f6hl","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danika","family":"Schepis","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Lagrelius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kristina","family":"Franck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petra","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan-\u00c5ke","family":"Liljeqvist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomas","family":"Bergstr\u00f6m","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elisabeth","family":"Aurelius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klas","family":"K\u00e4rre","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Louise","family":"Berg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hans","family":"Gaines","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"235","published-online":{"date-parts":[[2011,2,16]]},"reference":[{"key":"key20180919073509_B1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.diagmicrobio.2006.09.002","article-title":"Appropriate use of polymerase chain reaction for detection of herpes simplex virus 2 in cerebrospinal fluid of patients at an inner-city hospital","volume":"57","author":"Afonso","year":"2007","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"key20180919073509_B2","first-page":"317","article-title":"Neurological disease in herpes simplex virus type 2 infection","author":"Aurelius","year":"2006","journal-title":"Herpes simplex viruses"},{"key":"key20180919073509_B3","first-page":"278","article-title":"Neurologic morbidity after herpes simplex virus type 2 meningitis: a retrospective study of 40 patients. Scand","volume":"34","author":"Aurelius","year":"2002","journal-title":"J. Infect. Dis."},{"key":"key20180919073509_B4","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/jmv.1890390302","article-title":"Encephalitis in immunocompetent patients due to herpes simplex virus type 1 or 2 as determined by type-specific polymerase chain reaction and antibody assays of cerebrospinal fluid","volume":"39","author":"Aurelius","year":"1993","journal-title":"J. Med. Virol."},{"key":"key20180919073509_B5","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/0140-6736(91)92155-U","article-title":"Rapid diagnosis of herpes simplex encephalitis by nested polymerase chain reaction assay of cerebrospinal fluid","volume":"337","author":"Aurelius","year":"1991","journal-title":"Lancet"},{"key":"key20180919073509_B6","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1093\/infdis\/162.2.322","article-title":"Primary and recurrent herpes simplex virus type 2-induced meningitis","volume":"162","author":"Bergstrom","year":"1990","journal-title":"J. Infect. Dis."},{"key":"key20180919073509_B7","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1126\/science.1128346","article-title":"Herpes simplex virus encephalitis in human UNC-93B deficiency","volume":"314","author":"Casrouge","year":"2006","journal-title":"Science"},{"key":"key20180919073509_B8","doi-asserted-by":"crossref","first-page":"958","DOI":"10.7326\/0003-4819-98-6-958","article-title":"Genital herpes simplex virus infections: clinical manifestations, course, and complications","volume":"98","author":"Corey","year":"1983","journal-title":"Ann. Intern. Med."},{"key":"key20180919073509_B9","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1038\/ng1097","article-title":"Impaired response to interferon-alpha\/beta and lethal viral disease in human STAT1 deficiency","volume":"33","author":"Dupuis","year":"2003","journal-title":"Nat. Genet."},{"key":"key20180919073509_B10","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1080\/00365540802235741","article-title":"High diagnostic yield by CSF-PCR for entero- and herpes simplex viruses and TBEV serology in adults with acute aseptic meningitis in Stockholm","volume":"40","author":"Franzen-Rohl","year":"2008","journal-title":"Scand. J. Infect. Dis."},{"key":"key20180919073509_B11","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1128\/JCM.00141-07","article-title":"Increased detection rate in diagnosis of herpes simplex virus type 2 meningitis by real-time PCR using cerebrospinal fluid samples","volume":"45","author":"Franzen-Rohl","year":"2007","journal-title":"J. Clin. Microbiol."},{"key":"key20180919073509_B12","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1016\/j.gastro.2005.05.002","article-title":"Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution","volume":"129","author":"Heller","year":"2005","journal-title":"Gastroenterology"},{"key":"key20180919073509_B13","doi-asserted-by":"crossref","first-page":"11416","DOI":"10.1073\/pnas.0403555101","article-title":"Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways","volume":"101","author":"Hochrein","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. 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Virol."},{"key":"key20180919073509_B30","first-page":"57","article-title":"La meningite endothelio-leucocytaire multirecurrente benigne. Syndrome nouveau ou maladie nouvelle. Documents clinique","volume":"76","author":"Mollaret","year":"1944","journal-title":"Rev. Neurol. Paris"},{"key":"key20180919073509_B31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.clim.2005.10.011","article-title":"Natural killer cells in human health and disease","volume":"118","author":"Orange","year":"2006","journal-title":"Clin. Immunol."},{"key":"key20180919073509_B32","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1136\/sti.2003.005850","article-title":"The seroepidemiology of herpes simplex virus type 1 and 2 in Europe","volume":"80","author":"Pebody","year":"2004","journal-title":"Sex. Transm. 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Ther."},{"key":"key20180919073509_B36","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1093\/clinids\/20.4.842","article-title":"Herpes simplex virus type 2 meningitis in the absence of genital lesions: improved recognition with use of the polymerase chain reaction","volume":"20","author":"Schlesinger","year":"1995","journal-title":"Clin. Infect. Dis."},{"key":"key20180919073509_B37","doi-asserted-by":"crossref","first-page":"227","DOI":"10.3109\/inf.1975.7.issue-4.01","article-title":"Herpes simplex virus type 2 and acute aseptic meningitis. Clinical features of cases with isolation of herpes simplex virus from cerebrospinal fluids","volume":"7","author":"Skoldenberg","year":"1975","journal-title":"Scand. J. Infect. Dis."},{"key":"key20180919073509_B38","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature07665","article-title":"Adaptive immune features of natural killer cells","volume":"457","author":"Sun","year":"2009","journal-title":"Nature"},{"key":"key20180919073509_B39","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1128\/JCM.20.1.94-98.1984","article-title":"Virus-specific immunoglobulin G subclasses in herpes simplex and varicella-zoster virus infections","volume":"20","author":"Sundqvist","year":"1984","journal-title":"J. Clin. Microbiol."},{"key":"key20180919073509_B40","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0022-1759(03)00111-X","article-title":"Development and evaluation of a flow-cytometric assay of specific cell-mediated immune response in activated whole blood for the detection of cell-mediated immunity against varicella-zoster virus","volume":"277","author":"Svahn","year":"2003","journal-title":"J. Immunol. Methods"},{"key":"key20180919073509_B41","doi-asserted-by":"crossref","first-page":"3516","DOI":"10.1073\/pnas.0400525101","article-title":"Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection","volume":"101","author":"Tabeta","year":"2004","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"key20180919073509_B42","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1038\/ni1297","article-title":"The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9","volume":"7","author":"Tabeta","year":"2006","journal-title":"Nat. Immunol."},{"key":"key20180919073509_B43","doi-asserted-by":"crossref","first-page":"334","DOI":"10.7326\/0003-4819-121-5-199409010-00004","article-title":"Herpes simplex virus infection as a cause of benign recurrent lymphocytic meningitis","volume":"121","author":"Tedder","year":"1994","journal-title":"Ann. Intern. Med."},{"key":"key20180919073509_B44","doi-asserted-by":"crossref","first-page":"2179","DOI":"10.1016\/S0002-9440(10)63575-4","article-title":"Latent herpesvirus infection in human trigeminal ganglia causes chronic immune response","volume":"163","author":"Theil","year":"2003","journal-title":"Am. J. Pathol."},{"key":"key20180919073509_B45","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1128\/JVI.01545-07","article-title":"Human immunodeficiency virus viremia induces plasmacytoid dendritic cell activation in vivo and diminished alpha interferon production in vitro","volume":"82","author":"Tilton","year":"2008","journal-title":"J. Virol."},{"key":"key20180919073509_B46","doi-asserted-by":"crossref","first-page":"3496","DOI":"10.1073\/pnas.0610847104","article-title":"Selective retention of herpes simplex virus-specific T cells in latently infected human trigeminal ganglia","volume":"104","author":"Verjans","year":"2007","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"key20180919073509_B47","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1056\/NEJM199509213331205","article-title":"Virologic characteristics of subclinical and symptomatic genital herpes infections","volume":"333","author":"Wald","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"key20180919073509_B48","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1086\/340041","article-title":"Seroprevalence and coinfection with herpes simplex virus type 1 and type 2 in the United States, 1988-1994","volume":"185","author":"Xu","year":"2002","journal-title":"J. Infect. Dis."},{"key":"key20180919073509_B49","doi-asserted-by":"crossref","first-page":"964","DOI":"10.1001\/jama.296.8.964","article-title":"Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States","volume":"296","author":"Xu","year":"2006","journal-title":"JAMA"},{"key":"key20180919073509_B50","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1111\/j.1600-065X.2007.00564.x","article-title":"Human Toll-like receptor-dependent induction of interferons in protective immunity to viruses","volume":"220","author":"Zhang","year":"2007","journal-title":"Immunol. Rev."},{"key":"key20180919073509_B51","doi-asserted-by":"crossref","first-page":"1522","DOI":"10.1126\/science.1139522","article-title":"TLR3 deficiency in patients with herpes simplex encephalitis","volume":"317","author":"Zhang","year":"2007","journal-title":"Science"},{"key":"key20180919073509_B52","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1084\/jem.20061792","article-title":"Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation","volume":"204","author":"Zhu","year":"2007","journal-title":"J. Exp. 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