title: Comprehensive analysis of miRNA expression in T-cell subsets of rheumatoid arthritis patients reveals defined signatures of naive and memory Tregs.
abstract: Disturbed expression of microRNAs (miRNAs) in regulatory T cells (Tregs) leads to development of autoimmunity in experimental mouse models. However, the miRNA expression signature characterizing Tregs of autoimmune diseases, such as rheumatoid arthritis (RA) has not been determined yet. In this study, we have used a microarray approach to comprehensively analyze miRNA expression signatures of both naive Tregs (CD4+CD45RO-CD25++) and memory Tregs (CD4+CD45RO+CD25+++), as well as conventional naive (CD4+CD45RO-CD25-) and memory (CD4+CD45RO+CD25-) T cells (Tconvs) derived from peripheral blood of RA patients and matched healthy controls. Differential expression of selected miRNAs was validated by TaqMan-based quantitative reverse transcription-PCR. We found a positive correlation between increased expression of miR-451 in T cells of RA patients and disease activity score (DAS28), erythrocyte sedimentation rate levels and serum levels of interleukin-6. Moreover, we found characteristic, disease- and treatment-independent, global miRNA expression signatures defining naive Tregs, memory Tregs, naive Tconvs and memory Tconvs. The analysis allowed us to define miRNAs characteristic for a general naive phenotype (for example, miR-92a) and a general memory phenotype (for example, miR-21, miR-155). Importantly, the analysis allowed us to define miRNAs that are specifically expressed in both naive and memory Tregs, defining as such miRNA signature characterizing the Treg phenotype (that is, miR-146a, miR-3162, miR-1202, miR-1246 and miR-4281).
authors.affiliation: 1] Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Smigielska-Czepiel
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: van den Berg
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Jellema
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: R J
authors.initials: RJ
authors.lastname: van der Lei
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Bijzet
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Kluiver
authors.affiliation: 1] Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: A M H
authors.initials: AM
authors.lastname: Boots
authors.affiliation: 1] Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Brouwer
authors.affiliation: 1] Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [2] Groningen Research Initiative on Healthy Ageing and Immune Longevity (GRAIL), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands [3] Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: B-J
authors.initials: BJ
authors.lastname: Kroesen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000235:genetics*; D001799:Blood Sedimentation; D015704:CD4 Antigens / Q000235:genetics; D005260:Female; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D017493:Leukocyte Common Antigens / Q000235:genetics; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D015704:CD4 Antigens; C508017:IL2RA protein, human; C508600:IL6 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D035683:MicroRNAs; D017493:Leukocyte Common Antigens