Short communication Type 1 immune response in progressive multiple sclerosis Giovanni Frisullo a , Domenico Plantone a , Alessandro Marti a , Raffaele Iorio a , Valentina Damato a , Viviana Nociti b , Agata Katia Patanella b , Assunta Bianco a , Anna Paola Batocchi a, ⁎ a Department of Neurology, Catholic University of Sacred Heart Rome, Rome, Italy b Don Gnocchi Foundation, Milan, Italy abstract article info Article history: Received 21 March 2012 Accepted 26 April 2012 Keywords: Multiple sclerosis T-bet Transcription factor PPMS SPMS The aim of the study was to evaluate the type-1 immune response by analyzing T-bet expression in circulat- ing T and B cells in Primary Progressive (PP) and Secondary Progressive (SP) Multiple Sclerosis (MS) patients. We found higher percentages of circulating CD4 + T-bet + and CD8 + T-bet + T cells in SPMS and PPMS than in remitting–relapsing MS patients and controls. Moreover, in SPMS, we observed a positive correlation be- tween the percentages of circulating CD4 + T-bet + or CD8 + T-bet + T cells and disease severity. The increased percentages of Th1 and Tc1 cells suggest that MS progressive forms, unlike RRMS, are characterized by a per- manent peripheral type-1 immune activation. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Multiple sclerosis (MS) is a chronic immune mediated demyelin- ating disease of the central nervous system (CNS) that usually starts with a relapsing course (relapsing–remitting MS, RRMS) which is followed by a progressive phase (secondary progressive MS, SPMS). In a minority of patients the disease follows an uninterrupted pro- gressive course from the beginning (primary progressive MS, PPMS) (Lassmann, 2009). The progressive forms of MS are thought to be char- acterized by peculiar immunological mechanisms which differ from the relapsing–remitting form (Kutzelnigg et al., 2005; Lucchinetti et al., 2005). Although the etiology of MS and of the conversion to the pro- gressive form is still unknown, it is known that both T helper 1 (Th1) cells, cytotoxic T cells (Tc1) and IFNγ-producing B effector 1 (Be1) cells are involved in the pathogenesis of MS and can play a role in the progression of disease (Noseworthy et al., 2000; Popescu and Lucchinetti, 2012). The development of type-1 polarization seems to be guaranteed by the presence of T-bet, a T-box transcription factor, that has been identified as a key factor for the development of Th1 cells (Szabo et al., 2000),Tc1 cells (Szabo et al., 2002) and Be1 cells (Harris et al., 2005). T-bet is induced during T-cell activation by the interferon-γ signal transducer and activator of transcription (STAT) ‐1 signaling pathway (Mullen et al., 2001) and by the IL12 dependent STAT4 activation (Thieu et al., 2008) and, once expressed, it orches- trates the development and the cell‐migratory program of type 1 cell by regulating the expression of chemokines and chemokine receptors (Lord et al., 2005). In a previous study (Frisullo et al., 2006) we ob- served an up-regulation of T-bet expression in CD4 + and CD8 + T cells from peripheral blood of RRMS patients during relapse. In order to study the immunological mechanisms underlying the pro- gressive forms of MS, we investigated T-bet expression in CD4 + and CD8 + T cells and in CD19 + B cells from peripheral blood of untreated SPMS and PPMS patients. 2. Materials and methods 2.1. Patients Untreated PPMS patients and RRMS patients in remission phase, previously treated SPMS patients who had stopped any immunomod- ulatory and immunosuppressive therapies for at least six months, and healthy subjects were included in the study. No corticosteroid treat- ment had been used in all patients during 3 months before the inclu- sion in the study. All patients underwent clinical examination and brain/spinal cord MRI before flow cytometric analysis, as previously described (Frisullo et al., 2007). No patient showed MRI activity (≥1 Gadolinium enhancing lesions). All patients and healthy subjects were screened for infectious conditions or other inflammatory dis- eases and then included in our study. This study was approved by the local ethics committee, and all the participants gave written in- formed consent before enrolment. Journal of Neuroimmunology 249 (2012) 112–116 ⁎ Corresponding author at: Department of Neurosciences, Catholic University of Sa- cred Heart, Largo Gemelli 8, 00168 Rome, Italy. Tel.: +39 06 30155390; fax: +39 06 35501909. E-mail address: annapaola.batocchi@rm.unicatt.it (A.P. Batocchi). 0165-5728/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.jneuroim.2012.04.019 Contents lists available at SciVerse ScienceDirect Journal of Neuroimmunology journal homepage: www.elsevier.com/locate/jneuroim