lncrna and multiple sclerosis - mondino.it · lncrna and multiple sclerosis matteo lucchini phd...
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lncRNA and Multiple Sclerosis
Matteo Lucchini
PhD student and neurologist at Fondazione Policlinico
Universitario Agostino Gemelli IRCCS, Università Cattolica
del Sacro Cuore - Roma
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• Most common cause of neurological disability among young people
• Women>men (3:1 ratio)
• Typical onset between 20 to 40 years
• Approximately 2 million people are diagnosed with MS globally
• Estimated median incidence is 2.5 per 100,000
• The incidence of MS varies geographically (latitudinal gradient)
• Wide clinical variability
• 85% relapsing-remitting course at onset (nearly an half eventually developing progressive course within 20 years)
• 15% primary progressive course
Multiple Sclerosis
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Multiple Sclerosis
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Several treatment options with different immunological targets
Several known risk factors: genetic, ambiental and behaviour susceptibility such as low vitamin D levels, EBV infections, female sex, smoke, obesity and risk genes
Multiple Sclerosis
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Evolving diagnostic criteria (McDonald 2017 revision) allowing early diagnosis based on clinical and radiological findings
In the last revision new relevance to CSF-restricted Oligoclonal bands (OCBs)
Multiple Sclerosis
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Complex physiopathology primarlyinvolving adaptative immune system
Interplay between autoreactive T cells (Th17 and Th1), B cells with macrophagic and microglialactivation
Inbalance between pro-inflammatoryand anti-inflammatory pathways
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Currently available treatment options exert different and specific effects on immune system
- Immunomodulating agents
- Sequestrant agents
- Depletive agents
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Multiple Sclerosis and sncRNAs
• 650 dysregulated miRNA (at least one study) 179 at least two studies 58 at least three studies 8 at least four studies
• Heterogeneity between samples, cohorts and methodologies
• TGF-b signaling is the most significant pathway affected (involved in proliferation of Th1 and Th17 cells and Treg differentiation, upregulated miR-142, miR-145 and miR-210)
• Upregulated miR-155 in T cells and PBMCs: promoted development and differentiation of Th1 and Th17 cells; reduced after specific treatments
• Upregulated miR-326 in EAE: promotion of Th17 differentiation
• Targeting miR-155 and miR-326 in EAE model produce a milder phenotype
• Circulating miR-150 and miR-181c as possible disease biomarkers
• miR-320, miR-320b and miR-629 for PML risk profile
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Multiple Sclerosis and lncRNA
• 28 papers from 2016 explored the relationship between specific lncRNA subsets and MS
• Different sources explored: serum, PBMCs, microglial and biopsy/autopsy samples from MS patients; EAE mouse model
• Array analysis
• Expression of putative lncRNAs involved in specific immunological processes
• Association between MS and specific lncRNA polymorphisms (only one cohort)
• Cohorts including non treated and treated (exclusively IFNb-1a) MS patients
• Mainly RRMS patients; only few papers includes some progressive MS
• 11 papers from the same cohort
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- TUG1 may be a component of p53-regulatory network participating to the apoptotic pathways active in early stages of neurodegenerative and inflammatory diseases
- NEAT1 is induced by activation of TLR3-p38 pathway; high levels of NEAT1 promote the transcriptional activation of IL-8, that is significantly high in MS patients
- RN7SK RNA was part of the 7SK snRNP complex that can repress the cellular kinase complex P-TEFb, involved in CD4+ T lymphocytes activation
- RN7SK RNA was up-regulated also in idiopathic inflammatory myopathy patients- TUG1 and NEAT1 upregulated in whole blood samples from an Iranian cohort
(Dastmalchi 2018, Multiple Sclerosis and related disorders)
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Multiple Sclerosis and lncRNA
- PCR array with 90 common lncRNA in PBMCs from MS patients- 2 lncRNAs downregulated validated in independent cohort: NRON and
TUG1
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Multiple Sclerosis and GAS5
• Growth arrest specific 5 (GAS5) accumulates in cells during growth arrest modulating apoptosis and interferes with glucorticoid receptor (GR) and glucorticoid response element (GRE) regulation
• GAS5 upregulated in blood samples of RRMS and correlated with NR3C1 expression (its nuclear target gene)
• GAS5 rs2067079 SNP, located in the promoter region, is more frequent in MS patients
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Multiple Sclerosis and GAS5
• GAS5 upregulation in microglia suppresses microglial M2 polarization through TRF4 inhibition (independently from GR and GRE)
• Explored in EAE model and microglial cells from MS patients
• GAS5 interference promotes remyelination following lysolecithin-induceddemyelination
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Multiple Sclerosis and MALAT1
• Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) regulates leukocyte differentiation and function and is highly expressed in CNS tissues
• MALAT1 downregulated in MS brain and spinal cord EAE samples (Masoumi 2019, Journal of Neuroimmunology)
• MALAT1 also downregulated in macrophages and T cells, influencing the balance between Th1/Th17 and Tregs (Masoumi 2019, Journal of Neuroimmunology)
• Silencing MALAT1 promotes Th1/Th17 differentiation and reduces Tregs (Masoumi2019, Journal of Neuroimmunology)
• MALAT1 SNPs and MS risk: G allele rs619586 SNP less frequent in MS; A allele rs619586 and T allele rs3200401 associated with MS (Eftekharian 2019, Immunological investigations)
• MALAT1 also modulates endogenous expression of slicing factors and alternative splicing of MS-associated genes (such as IL7R and SP140) (Cardamone 2019, Human Molecular Genetics)
• MALAT1 is found upregulated in serum of MS patients and strongly correlates with lnc-DC (Shaker 2019, Bioscience reports)
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Multiple Sclerosis and HOTAIR
• HOX transcript antisense intergenic RNA (HOTAIR) higher expression in whole blood sample of MS patients, reduced after vitamin D supplementation
• HOTAIR decreased in spinal cord and cortex and increased in cerebellum of EAE mice
(Kakhki 2017, Immunology)
HOTAIR modulation in EAE mouse model under different condition: sulfasalazine as promyelinating agent and cuprizone as demyelination inducer
• HOTAIR modulates a M1 pro-inflammatory polarization of microglia through interaction with miR-136-5p and NF-kB pathway activation
(Duan 2018, Biochemical pharmacology)
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Multiple Sclerosis and linc-MAF4
• linc-MAF4 upregulated in PBMCs from MS compared to controls and strongly correlates with MAF downregulation
• Th1-like stimulation promotes linc-MAF4 expression
• Th2-like stimulation promotes MAF expression
• linc-MAF4 overexpression leads to Th1 differentiation and its downregulation guides to a Th2 phenotype
• linc-MAF4 correlates with annual relapse rate and MRI lesion load
(Zhang 2017, FASEB Journal)
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Multiple Sclerosis and IFNg/TNFa
• GSTT1-AS1 and IFNG-AS1 inhibit IFNg and TNFa gene expression
• Those lncRNAs were found downregulated in whole blood sample of RRMS patients (IFNg and TNFa were upregulated in the same cohort)
• Expression GSTT1-AS1 / IFNG-AS1 and IFNg / TNFa genes were correlated
(Ganji 2019, Neurol Sci)
Aim: explores Th1 related lncRNAs expression in MS
• IFNG-AS1-001 and AC007278.2 upregulated in PMBCs from relapsing MS patients
• IFNG-AS1-002 upregulated in PMBCs from remitting MS patients
(Hosseini 2019, J Cell Physiol)
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lncRNAs as potential biomarkers for MS?
- HULC downregulated (whole blood sample)- Role in immune system not clarify- Significative differences regarding age and gender
- HUR1 and OIP5-AS1 upregulated in whole blood- Suppose to be involved in Th17 celldifferentiation
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Progressive Multiple Sclerosis and lncRNA
- TUG1 was up-regulated in SP-MS- down-regulation of non-protein coding RNA 188 (LRRC75A-AS1) and a significant up-
regulation of long intergenic non-protein coding RNA 293 (LINC00293) and RP11-29G8.3 in PP-MS
unpublished data
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Conclusion
• Multiple Sclerosis has a complex physiopathology involving both adaptative and innate immune systems with a complex interplay within reparative and degenerative mechanism in CNS
• Only few studies regarding lncRNAs exploring different samples (serum, whole blood, PBMCs, EAE model, biopsy/autopsy)
• Differences regarding patients’ cohort: treated vs untreated; stable vs relapsing; only few reports regarding progressive patients
• lncRNAs dysregulated are involved in lymphocyte or microglial activation and differentiation (GAS5, MALAT1, HOTAIR, linc-MAF4)
Future perspective:
• Explore and confirm potential role of specific lncRNAs in MS pathology
• Evaluate the modulation of such lncRNAs under treatment and explore their potential as markers of response
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GRAZIE PER L’ATTENZIONE!
Centro SM PoliclinicoGemelli:
Prof. M. Mirabella
Dr.ssa V. Nociti
Dr.ssa C. De Fino
Dr. F.A. Losavio
Dr.ssa M. Loiodice
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Dr. M. Santoro