International Journal of Neuroscience, Early Online, 1–6, 2012 Copyright © 2012 Informa Healthcare USA, Inc. ISSN: 0020-7454 print / 1543-5245 online DOI: 10.3109/00207454.2012.678444 miR-15a and 16-1 Are Downregulated in CD4 + T Cells of Multiple Sclerosis Relapsing Patients Julio Cesar Cetrulo Lorenzi, 1,2 Doralina G. Brum, 3 Dalila L. Zanette, 1,2 Alessandra de Paula Alves Souza, 2,4 Fernanda Gonc ¸alves Barbuzano, 2 Antonio Carlos dos Santos, 5 Amilton Antunes Barreira, 3 and Wilson Araujo Silva, Jr. 1,2 1 Genetics Department, S˜ ao Paulo University Medical school of Ribeir˜ ao Preto, Ribeir˜ ao Preto, Brazil 2 National Institute of Science and Technology in Stem Cell and Cell Therapy (INCTC), Ribeir˜ ao Preto, Brazil 3 Neurosciences Department, S˜ ao Paulo University Medical School of Ribeir˜ ao Preto, Ribeir˜ ao Preto, Brazil 4 Immunology Department, S˜ ao Paulo University Medical School of Ribeir˜ ao Preto, Ribeir˜ ao Preto, Brazil 5 Internal Medicine Department, S˜ ao Paulo University Medical School of Ribeir˜ ao Preto, Ribeir˜ ao Preto, Brazil ABSTRACT The pathology of relapsing–remitting multiple sclerosis (RR-MS) is largely attributed to activated autoreactive effector T lymphocytes. The inluence of microRNAs on the immune response has been shown to occur in different pathways of lymphocyte differentiation and function. Here, the expression of the miRNAs miR-15a/16- 1 in PBMC, CD4 + , and CD8 + from RR-MS patients has been investigated. BCL2, a known miR-15a/16-1 target, has also been analyzed. The results have shown that miR-15a/16-1 is downregulated in CD4 + T cells, whereas BCL2 is highly expressed in RR-MS patients only. Our data suggest that miR-15a/16-1 can also modulate the BCL2 gene expression in CD4 + T cells from RR-MS patients, thereby affecting apoptosis processes. KEYWORDS: apoptosis, BCL-2, lymphocytes, miRNAs INTRODUCTION Multiple sclerosis (MS) is a demyelinating inlamma- tory disease of the central nervous system (CNS). The relapsing–remitting (RR) course is the most frequent clinical presentation of MS. Relapses are related to in- lammatory lesions that can be detected by magnetic resonance imaging (MRI) [1]. The pathology of MS is largely attributed to activated autoreactive T-cell effec- tors, mainly CD4 + , that migrate to the CNS through the blood–brain barrier. The inlammation caused by T lymphocytes is especially persistent in MS. This can be due to the increased proliferative capacity of autore- active cells [2]; the enhanced expression of apoptosis Received 9 November 2011. These authors contributed equally to this work. We thank Anemari Ramos Dinarte dos Santos for the technical support. This work has been supported by FAPESP (2010/00310-1, 1998/14247-6), CNPQ, CAPES, and FUNDHERP. Address correspondence to Wilson Araujo da Silva Jr., Centro Regional de Hemoterapia de Ribeir˜ ao Preto, Rua Cat˜ ao Roxo, 2501, Monte Alegre, CEP 14051-140, Ribeir˜ ao Preto, Brasil. E-mail: wilsonjr@usp.br inhibitor (IAP) family members IAP, IAP-2, and X- IAP [3]; and the higher expression of anti-apoptotic molecules, such as BCL-2 [4, 5]. The BCL-2 gene has important functions in cell survival and death, since it controls the integrity of mitochondrial membranes and the release of pro-apoptotic molecules from the mito- chondria [6, 7]. In this way, the inlammatory T cells present in MS become more resistant to apoptotic stim- uli, thereby leading to persistent tissue inlammation. The differential gene expression data regarding MS show that immune-related genes such as CXCR5, IL2RA, IL7R, IL7, IL12RB1, and IL22RA2 are related to MS [8–10]. The concepts involving gene expression regulation have evolved after the introduction of a new class of RNA, the microRNAs (miRNAs) [11], which are small RNAs that negatively regulate gene expression by degradation of mRNA targets or by interruption of translation. The inluence of miRNA on the immune re- sponse has been demonstrated in many processes, such as lymphocyte differentiation [12] and T regulatory cell function [13]. The miRNA-15a and 16-1 cluster con- trols apoptosis by targeting BCL2, as observed by the 1 Int J Neurosci Downloaded from informahealthcare.com by University of Sao Paulo on 05/18/12 For personal use only.