Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome

Chiara Farroni, Emiliano Marasco, Valentina Marcellini, Ezio Giorda, Diletta Valentini, Stefania Petrini, Valentina D'Oria, Marco Pezzullo, Simona Cascioli, Marco Scarsella, Alberto G Ugazio, Giovanni C De Vincentiis, Ola Grimsholm, Rita Carsetti

Research output: Contribution to journalArticle

Abstract

Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS.

Original languageEnglish
Pages (from-to)2683
Number of pages12
JournalFrontiers in Immunology
Volume9
DOIs
Publication statusPublished - Nov 20 2018

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Down Syndrome
B-Lymphocytes
Germinal Center
MicroRNAs
Chromosomes, Human, Pair 21
Palatine Tonsil
Helper-Inducer T-Lymphocytes
Plasma Cells
Dementia
Leukemia
Vaccination
Tissue Donors
Pharmacology
T-Lymphocytes
In Vitro Techniques
Proteins

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Dysregulated miR-155 and miR-125b Are Related to Impaired B-cell Responses in Down Syndrome. / Farroni, Chiara; Marasco, Emiliano; Marcellini, Valentina; Giorda, Ezio; Valentini, Diletta; Petrini, Stefania; D'Oria, Valentina; Pezzullo, Marco; Cascioli, Simona; Scarsella, Marco; Ugazio, Alberto G; De Vincentiis, Giovanni C; Grimsholm, Ola; Carsetti, Rita.

In: Frontiers in Immunology, Vol. 9, 20.11.2018, p. 2683.

Research output: Contribution to journalArticle

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AU - Farroni, Chiara

AU - Marasco, Emiliano

AU - Marcellini, Valentina

AU - Giorda, Ezio

AU - Valentini, Diletta

AU - Petrini, Stefania

AU - D'Oria, Valentina

AU - Pezzullo, Marco

AU - Cascioli, Simona

AU - Scarsella, Marco

AU - Ugazio, Alberto G

AU - De Vincentiis, Giovanni C

AU - Grimsholm, Ola

AU - Carsetti, Rita

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AB - Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS.

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