Altered miRNA expression in T regulatory cells in course of multiple sclerosis.
OBJECTIVE
Multiple sclerosis (MS) is a chronic inflammatory response against constituents of the central nervous system. It is known that regulatory T cells (Tregs) play a key role in the autoimmune balance and their improper function may facilitate the expansion of autoaggressive T cell clones. Recently, microRNAs (miRNAs) have been involved in autoimmune disorders and their loss-of-function in immune cells was shown to facilitate systemic autoimmune disorders. Here, we analyzed the miRNA expression profile in Tregs from MS-RR.


METHODS
We assessed miRNA genome-wide expression profile by microarray analysis on CD4(+)CD25(+high) T cells from 12 MS relapsing-remitting patients in stable condition and 14 healthy controls. Since CD4(+)CD25(+high) T cells comprise both T regulatory cells (CD4(+)CD25(+high)CD127(dim/-)) and T effector cells (CD4(+)CD25(+high)CD127(+)), we performed a quantitative RT-PCR on CD4(+)CD25(+high)CD127(dim/-) and CD4(+)CD25(+high)CD127(+) cells isolated from the same blood sample.


RESULTS
We found 23 human miRNAs differentially expressed between CD4(+)CD25(high)bona fide Treg cells from MS patients vs. healthy donors, but, conversely, among the deregulated miRNAs, members of the miR-106b-25 were found down-regulated in MS patients when compared to healthy donors in CD4(+)CD25(high)CD127(dim/-) T regulatory cells. More interesting, the ratio between Treg/Teff showed an enrichment of these microRNA in T regulatory cells derived from patients if compared to healthy controls.


CONCLUSIONS
miR-106b and miR-25 were previously shown to modulate the TGF-β signaling pathway through their action on CDKN1A/p21 and BCL2L11/Bim. TGF-β is involved in T regulatory cells differentiation and maturation. Therefore, the deregulation of this miRNA cluster may alter Treg cells activity in course of MS, by altering TGF-β biological functions.
De Santis
Giuseppe
G
Section of Neurology, Department of Medical and Surgical Sciences of the Communication and Behaviour, University of Ferrara, Ferrara, Italy.
Ferracin
Manuela
M
Biondani
Andrea
A
Caniatti
Luisa
L
Rosaria Tola
Maria
M
Castellazzi
Massimiliano
M
Zagatti
Barbara
B
Battistini
Luca
L
Borsellino
Giovanna
G
Fainardi
Enrico
E
Gavioli
Riccardo
R
Negrini
Massimo
M
Furlan
Roberto
R
Granieri
Enrico
E
D000328:Adult; D000704:Analysis of Variance; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D018920:Coculture Techniques / Q000379:methods; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000276:immunology / Q000502:physiology*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015703:Antigens, CD; D035683:MicroRNAs; D016212:Transforming Growth Factor beta