{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T07:19:15Z","timestamp":1773127155580,"version":"3.50.1"},"reference-count":42,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2012,9,25]],"date-time":"2012-09-25T00:00:00Z","timestamp":1348531200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>A Japanese randomized controlled study showed that Interferon \u00e2 (IFN-\u00e21b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-\u00e2 (IFN-\u00e21a\/IFN-\u00e21b) treatment was not effective in neuromyelitis optica (NMO) patients and that the diminished benefit of IFN-\u00e2\uf020 treatment in NMO may be due to different immune responses to IFN-\u00e2. We determined longitudinally the expression of CCR5, CXCR3 and CCR4 on CD4+ T and CD8+ T cells in the blood from patients with NMO and MS treated with IFN-\u00e21b. During a 12-month period of IFN-\u00e21b therapy, the annualized relapse rate decreased in MS patients but not in NMO patients. There was no significant difference in the expression of the chemokine receptors between NMO and MS at baseline. The percentages of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of the Th1 response, were decreased in both NMO and MS after treatment. The percentage of CD4+CCR4+ T cells, representative of the Th2 response, was decreased in MS, but those for NMO was significantly increased compared with the pretreatment levels. Our results indicate that IFN-\u00e21b-induced up-modulation of the Th2 response in NMO patients may be the source of differences in the therapeutic response to IFN-\u00e21b therapy. In the present study, Th2 predominance is involved in the pathogenesis of NMO.<\/jats:p>","DOI":"10.3390\/ijms131012213","type":"journal-article","created":{"date-parts":[[2012,9,25]],"date-time":"2012-09-25T20:54:33Z","timestamp":1348606473000},"page":"12213-12223","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Interferon-\u03b21b Increases Th2 Response in Neuromyelitis Optica"],"prefix":"10.3390","volume":"13","author":[{"given":"Hideto","family":"Nakajima","sequence":"first","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takafumi","family":"Hosokawa","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshimitu","family":"Doi","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiyuki","family":"Ikemoto","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shimon","family":"Ishida","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fumiharu","family":"Kimura","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiaki","family":"Hanafusa","sequence":"additional","affiliation":[{"name":"Division of Neurology, Department of Internal Medicine I, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2012,9,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1191\/1352458502ms781oa","article-title":"Selective suppression of chemokine receptor CXCR3 expression by interferon-beta1a in multiple sclerosis","volume":"8","author":"Sellebjerg","year":"2002","journal-title":"Mult. Scler"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.clineuro.2004.02.010","article-title":"IFN-beta1a and IFN-beta1b have different patterns of influence on cytokines","volume":"106","author":"Sega","year":"2004","journal-title":"Clin. Neurol. Neurosurg"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1111\/j.1468-1331.2004.00986.x","article-title":"The effects of interferon-beta on interleukin-10 in multiple sclerosis patients","volume":"12","author":"Ersoy","year":"2005","journal-title":"Eur. J. Neurol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1365-3083.2006.01788.x","article-title":"Dynamic T-lymphocyte chemokine receptor expression induced by interferon-beta therapy in multiple sclerosis","volume":"64","author":"Krakauer","year":"2006","journal-title":"Scand. J. Immunol"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1159\/000329576","article-title":"Association of Th1\/Th2-related chemokine receptors in peripheral T cells with disease activity in patients with multiple sclerosis and neuromyelitis optica","volume":"66","author":"Shimizu","year":"2011","journal-title":"Eur. Neurol"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/S1474-4422(07)70216-8","article-title":"The spectrum of neuromyelitis optica","volume":"6","author":"Wingerchuk","year":"2007","journal-title":"Lancet Neurol"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1093\/brain\/awf151","article-title":"A role for humoral mechanisms in the pathogenesis of Devic\u2019s neuromyelitis optica","volume":"125","author":"Lucchinetti","year":"2002","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.jneuroim.2011.04.009","article-title":"Increased serum matrix metalloproteinase-9 in neuromyelitis optica: Implication of disruption of blood-brain barrier","volume":"236","author":"Hosokawa","year":"2011","journal-title":"J. Neuroimmunol"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/1471-2377-10-45","article-title":"Visual field defects of optic neuritis in neuromyelitis optica compared with multiple sclerosis","volume":"10","author":"Nakajima","year":"2010","journal-title":"BMC Neurol"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2106","DOI":"10.1016\/S0140-6736(04)17551-X","article-title":"A serum autoantibody marker of neuromyelitis optica: Distinction from multiple sclerosis","volume":"364","author":"Lennon","year":"2004","journal-title":"Lancet"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3072","DOI":"10.1093\/brain\/awn240","article-title":"Antibody to aquaporin-4 in the long-term course of neuromyelitis optica","volume":"131","author":"Jarius","year":"2008","journal-title":"Brain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1212\/01.WNL.0000151856.10387.E2","article-title":"Interferon Beta-1b Multiple Sclerosis Study Group of Japan. Interferon beta-1b is effective in Japanese RRMS patients: A randomized multicenter study","volume":"64","author":"Saida","year":"2005","journal-title":"Neurology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1159\/000227277","article-title":"Interferon-beta(1b) treatment in neuromyelitis optica","volume":"62","author":"Tanaka","year":"2009","journal-title":"Eur. Neurol"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1111\/j.1468-1331.2009.02897.x","article-title":"Different responses to interferon beta-1b treatment in patients with neuromyelitis optica and multiple sclerosis","volume":"17","author":"Uzawa","year":"2010","journal-title":"Eur. J. Neurol"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/S0165-5728(97)00208-7","article-title":"Expression of monocyte chemoattractant protein-1 and other beta-chemokines by resident glia and inflammatory cells in multiple sclerosis lesions","volume":"84","author":"Simpson","year":"1998","journal-title":"J. Neuroimmunol"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1172\/JCI5150","article-title":"Expression of specific chemokines and chemokine receptors in the central nervous system of multiple sclerosis patients","volume":"103","author":"Sorensen","year":"1999","journal-title":"J. Clin. Invest"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6873","DOI":"10.1073\/pnas.96.12.6873","article-title":"CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions","volume":"96","author":"Balashov","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1159\/000081856","article-title":"Expression of TH1\/TH2-related chemokine receptors on peripheral T cells and correlation with clinical disease activity in patients with multiple sclerosis","volume":"52","author":"Nakajima","year":"2004","journal-title":"Eur. Neurol"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1186\/1471-2377-10-113","article-title":"Expression of chemokine receptors on peripheral blood lymphocytes in multiple sclerosis and neuromyelitis optica","volume":"10","author":"Uzawa","year":"2010","journal-title":"BMC Neurol"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.jns.2006.10.008","article-title":"Interferon beta-1b exacerbates multiple sclerosis with severe optic nerve and spinal cord demyelination","volume":"252","author":"Warabi","year":"2007","journal-title":"J. Neurol. Sci"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s00415-007-0730-5","article-title":"Development of extensive brain lesions following interferon beta therapy in relapsing neuromyelitis optica and longitudinally extensive myelitis","volume":"255","author":"Shimizu","year":"2008","journal-title":"J. Neurol"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1212\/WNL.0b013e3181f8832e","article-title":"IFN\u03b2-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum","volume":"75","author":"Shimizu","year":"2010","journal-title":"Neurology"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1093\/brain\/awm062","article-title":"Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: A study on antibody titre","volume":"130","author":"Takahashi","year":"2007","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1224","DOI":"10.1093\/brain\/awm047","article-title":"Loss of aquaporin 4 in lesions of neuromyelitis optica: Distinction from multiple sclerosis","volume":"130","author":"Misu","year":"2007","journal-title":"Brain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/j.yexcr.2011.03.002","article-title":"Beta-interferon for multiple sclerosis","volume":"317","author":"Rudick","year":"2011","journal-title":"Exp Cell Res"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"491","DOI":"10.2165\/11591110-000000000-00000","article-title":"The mechanism of action of interferon-\u00e2 in relapsing multiple sclerosis","volume":"25","author":"Kieseier","year":"2011","journal-title":"CNS Drugs"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1002\/ana.1096","article-title":"Complex immunomodulatory effects of interferon-beta in multiple sclerosis include the upregulation of T helper 1-associated marker genes","volume":"50","author":"Wandinger","year":"2001","journal-title":"Ann. Neurol"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1093\/brain\/awn077","article-title":"Interferon-beta increases BAFF levels in multiple sclerosis: implications for B cell autoimmunity","volume":"131","author":"Krumbholz","year":"2008","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s10875-005-4091-5","article-title":"Association between circulating levels of the novel TNF family members APRIL and BAFF and lymphoid organization in primary Sj\u00f6gren\u2019s syndrome","volume":"25","author":"Jonsson","year":"2005","journal-title":"J. Clin. Immunol"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3475","DOI":"10.1002\/art.11354","article-title":"B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: Longitudinal observations","volume":"48","author":"Stohl","year":"2003","journal-title":"Arthritis. Rheum"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1016\/j.jaut.2005.08.004","article-title":"BAFF is elevated in serum of patients with Wegener\u2019s granulomatosis","volume":"25","author":"Krumbholz","year":"2005","journal-title":"J. Autoimmun"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1001\/archneurol.2010.188","article-title":"Interferon Beta treatment in neuromyelitis optica: Increase in relapses and aquaporin 4 antibody titers","volume":"67","author":"Palace","year":"2010","journal-title":"Arch. Neurol"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.jneuroim.2003.10.036","article-title":"Cyclophosphamide modulates CD4+ T cells into a T helper type 2 phenotype and reverses increased IFN-gamma production of CD8+ T cells in secondary progressive multiple sclerosis","volume":"146","author":"Karni","year":"2004","journal-title":"J. Neuroimmunol"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1038\/ni1467","article-title":"Surface phenotype and antigenic specificity of human interleukin 17-producing T helper memory cells","volume":"8","author":"Rivino","year":"2007","journal-title":"Nat. Immunol"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"122","DOI":"10.4049\/jimmunol.180.1.122","article-title":"Human Th17 cells share major trafficking receptors with both polarized effector T cells and FOXP3+ regulatory T cells","volume":"180","author":"Lim","year":"2008","journal-title":"J. Immunol"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.it.2011.03.008","article-title":"Interferon-\u03b2 exacerbates Th17-mediated inflammatory disease","volume":"32","author":"Axtell","year":"2011","journal-title":"Trends. Immunol"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1093\/brain\/awh453","article-title":"Intrathecal activation of the IL-17\/IL-8 axis in opticospinal multiple sclerosis","volume":"128","author":"Ishizu","year":"2005","journal-title":"Brain"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1212\/01.wnl.0000216139.44259.74","article-title":"Revised diagnostic criteria for neuromyelitis optica","volume":"66","author":"Wingerchuk","year":"2006","journal-title":"Neurology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1002\/ana.1032","article-title":"Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis","volume":"50","author":"McDonald","year":"2001","journal-title":"Ann. Neurol"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1212\/WNL.33.11.1444","article-title":"Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS)","volume":"33","author":"Kurtzke","year":"1983","journal-title":"Neurology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1177\/117727190700200028","article-title":"Increased Intrathecal Chemokine Receptor CCR2 Expression in Multiple Sclerosis","volume":"2","author":"Nakajima","year":"2007","journal-title":"Biomark. Insights"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.neulet.2004.04.006","article-title":"Decreased CD14+CCR2+ monocytes in active multiple sclerosis","volume":"363","author":"Nakajima","year":"2004","journal-title":"Neurosci. Lett"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/10\/12213\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T21:52:32Z","timestamp":1760219552000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/13\/10\/12213"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,9,25]]},"references-count":42,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2012,10]]}},"alternative-id":["ijms131012213"],"URL":"https:\/\/doi.org\/10.3390\/ijms131012213","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,9,25]]}}}