Decreased expression of miR-29 family associated with autoimmune myasthenia gravis

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Practical Management for Use of Eculizumab in the Treatment of Severe, Refractory, Non-Thymomatous, AChR + Generalized Myasthenia Gravis: A Systematic Review

“…MiR-29 subtypes play a role in modulating the IFN-I signal in the thymus of mice with EAMG by favoring increased expression of IFN-β and emergence of pro-inflammatory Th17 cells. This strategy could be considered not only for monitoring but also for possible future therapy of MG. 78 Therapy with Chemokine Antagonists (Figure 2C)…”

Myasthenia Gravis: An Acquired Interferonopathy?

“…However, it is not clear whether the decreased expression of MIR-29 subtypes in MG is either a consequence or a causative factor of the thymic inflammation. Nevertheless, the results indicate that a reduction in MIR-29 subtypes may contribute to the pathophysiological process involved in MG by favoring the emergence of pro-inflammatory Th17 cells [ 128 ].…”

Myasthenia Gravis: Novel Findings and Perspectives on Traditional to Regenerative Therapeutic Interventions

“…Reportedly, the regulation of circulating micro-RNAs (miRNAs) such as miR-29a/b1, miR-7, let-7a-5p, let-7f-5p, miR-27a-3p family miRNA [40][41][42][43][44], and vitiating methylation of tumor suppressor genes have also been associated with MG and TAMG, respectively [45]. Apart from these etiologies, the additional factors including the overdose of drugs such as prednisone, D-penicillamine, anticholinesterase drugs, anesthesia, neuromuscular blockers for thymectomy, immune checkpoint inhibitors, interferons, tyrosine kinase inhibitors, cholesterollowering drugs such as statins, alemtuzumab, macrolides, fluoroquinolones, aminoglycosides, penicillins, blockers of β-adrenergic and calcium channel, antiarrhythmics, and magnesium has been found to induce MG [46,47].…”