Decreased expression of miR-29 family associated with autoimmune myasthenia gravis
Open Access
- 8 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Neuroinflammation
- Vol. 17 (1), 1-13
- https://doi.org/10.1186/s12974-020-01958-3
Abstract
Myasthenia gravis (MG) is a rare autoimmune disease mainly mediated by autoantibodies against the acetylcholine receptor (AChR) at the neuromuscular junction. The thymus is the effector organ, and its removal alleviates the symptoms of the disease. In the early-onset form of MG, the thymus displays functional and morphological abnormalities such as B cell infiltration leading to follicular hyperplasia, and the production of AChR antibodies. Type-I interferon (IFN-I), especially IFN-β, is the orchestrator of thymic changes observed in MG. As Dicer and miR-29 subtypes play a role in modulating the IFN-I signalization in mouse thymus, we investigated their expression in MG thymus. The expression of DICER and miR-29 subtypes were thoroughly investigated by RT-PCR in human control and MG thymuses, and in thymic epithelial cells (TECs). Using miR-29a/b-1-deficient mice, with lower miR-29a/b-1 expression, we investigated their susceptibility to experimental autoimmune MG (EAMG) as compared to wild-type mice. DICER mRNA and all miR-29 subtypes were down-regulated in the thymus of MG patients and DICER expression was correlated with the lower expression of miR-29a-3p. A decreased expression of miR-29 subtypes was similarly observed in MG TECs; a decrease also induced in TECs upon IFN-β treatment. We demonstrated that miR-29a/b-1-deficient mice were more susceptible to EAMG without higher levels of anti-AChR IgG subtypes. In the thymus, if no B cell infiltration was observed, an increased expression of Ifn-β associated with Baff expression and the differentiation of Th17 cells associated with increased expression of Il-6, Il-17a and Il-21 and decreased Tgf-β1 mRNA were demonstrated in miR-29a/b-1-deficient EAMG mice. It is not clear if the decreased expression of miR-29 subtypes in human MG is a consequence or a causative factor of thymic inflammation. However, our results from the EAMG mouse model indicated that a reduction in miR-29a/b1 may contribute to the pathophysiological process involved in MG by favoring the increased expression of IFN-β and the emergence of pro-inflammatory Th17 cells.Funding Information
- FP7 Ideas: European Research Council (FIGHT-MG/HEALTH-2009-242-210)
- AFM-Téléthon
This publication has 34 references indexed in Scilit:
- MicroRNA Expression Changes during Interferon-Beta Treatment in the Peripheral Blood of Multiple Sclerosis PatientsInternational Journal of Molecular Sciences, 2013
- An evolutionarily conserved mutual interdependence between Aire and microRNAs in promiscuous gene expressionEuropean Journal of Immunology, 2013
- The thymic epithelial microRNA network elevates the threshold for infection-associated thymic involution via miR-29a mediated suppression of the IFN-α receptorNature Immunology, 2011
- Important parameters for evaluation of antibody avidity by immunosorbent assayAnalytical Biochemistry, 2011
- BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune EncephalomyelitisPLOS ONE, 2011
- The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γNature Immunology, 2011
- DICER1 deficit induces Alu RNA toxicity in age-related macular degenerationNature, 2011
- CCL21 overexpressed on lymphatic vessels drives thymic hyperplasia in myastheniaAnnals of Neurology, 2009
- TGF-β-induced Foxp3 inhibits TH17 cell differentiation by antagonizing RORγt functionNature, 2008
- The chemokine CXCL13 is a key molecule in autoimmune myasthenia gravisBlood, 2006