Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis

Sabre, Liis; Maddison, Paul; Sadalage, Girija; Ambrose, Philip Alexander; Punga, Anna Rostedt

doi:10.1016/j.jneuroim.2018.05.003

Cited by 31 publications

(24 citation statements)

References 16 publications

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“…This study found a steady decline in clinical MGC score at and after 1-year follow-up, which correlated with reduced levels of miR-150-5p, miR-21-5p, and miR-30e-5p (56; Figure 1), related to immunosuppression initiation after onset. Intriguingly, patients with generalized LOMG had higher levels of miR-150-5p and miR-21-5p than those with ocular LOMG (56). None of these miRNAs correlated with the AChR antibody levels, hence supporting the previous studies (48,49,51).…”

Section: Late-onset Mgsupporting

confidence: 78%

“…Interestingly, the data from another cohort study on circulating miRNA in LOMG did not overlap regarding the results from the study by Nogales-Gadea (54). The discrepancies between these two studies (54,56) could be explained by the differences in the LOMG patient cohort numbers as well as their immunosuppressive treatment status.…”

Section: Late-onset Mgmentioning

confidence: 89%

“…In order to establish a signature of extracellular miRNA in LOMG, one separate study addressed this MG group. Compared to healthy controls, five miRNAs were found strongly elevated in LOMG patients with no immunosuppressive treatment: miR-106b-3p, miR-30e-5p, miR-223-5p, miR-140-5p, and miR-19b-3p (56). To assess the prospective influence of these miRNAs in immunosuppressivenaive generalized LOMG patients with immunosuppression, these miRNAs were longitudinally analyzed in 73 LOMG patients using sera collected for 2 years after the MG onset (56).…”

Section: Late-onset Mgmentioning

confidence: 99%

“…The third miRNA in AChR+ MG, miR-30e-5p, was somewhat contradictorily downregulated in EOMG (48) and upregulated in LOMG (56). miR-30e-5p has also been associated with SLE (86).…”

Section: Link Between Elevated Circulating Mirnas In Mg and Disease Pmentioning

confidence: 99%

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Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine

Sabre

Punga

2020

Front. Immunol.

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Myasthenia gravis (MG) is an autoimmune disease caused by antibodies which attack receptors at the neuromuscular junction. One of the main difficulties in predicting the clinical course of MG is the heterogeneity of the disease, where disease progression differs greatly depending on the subgroup that the patient is classified into. MG subgroups are classified according to: age of onset [early-onset MG (EOMG; onset ≤ 50 years) versus late-onset MG (LOMG; onset > 50 years]; the presence of a thymoma (thymoma-associated MG); antibody subtype [acetylcholine receptor antibody seropositive (AChR+) and muscle-specific tyrosine kinase antibody seropositive (MuSK+)]; as well as clinical subtypes (ocular versus generalized MG). The diagnostic tests for MG, such as antibody titers, neurophysiological tests, and objective clinical fatigue score, do not necessarily reflect disease progression. Hence, there is a great need for reliable objective biomarkers in MG to follow the disease course as well as the individualized response to therapy toward personalized medicine. In this regard, circulating microRNAs (miRNAs) have emerged as promising potential biomarkers due to their accessibility in body fluids and unique profiles in different diseases, including autoimmune disorders. Several studies on circulating miRNAs in MG subtypes have revealed specific miRNA profiles in patients' sera. In generalized AChR+ EOMG, miR-150-5p and miR-21-5p are the most elevated miRNAs, with lower levels observed upon treatment with immunosuppression and thymectomy. In AChR+ generalized LOMG, the miR-150-5p, miR-21-5p, and miR-30e-5p levels are elevated and decrease in accordance with the clinical response after immunosuppression. In ocular MG, higher levels of miR-30e-5p discriminate patients who will later generalize from those remaining ocular. In contrast, in MuSK+ MG, the levels of the let-7 miRNA family members are elevated. Studies of circulating miRNA profiles in Lrp4 or agrin antibody-seropositive MG are still lacking. This review summarizes the present knowledge of circulating miRNAs in different subgroups of MG.

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Section: Late-onset Mgsupporting

confidence: 78%

Section: Late-onset Mgmentioning

confidence: 89%

Section: Late-onset Mgmentioning

confidence: 99%

“…The third miRNA in AChR+ MG, miR-30e-5p, was somewhat contradictorily downregulated in EOMG (48) and upregulated in LOMG (56). miR-30e-5p has also been associated with SLE (86).…”

Section: Link Between Elevated Circulating Mirnas In Mg and Disease Pmentioning

confidence: 99%

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Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine

Sabre

Punga

2020

Front. Immunol.

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“…In AChR+ MG, the miRNAs miR-150-5p, and miR-21-5p were upregulated compared to healthy controls and these levels were also lower in patients treated with immunosuppression as compared to immunosuppression naïve patients (5,6). In addition to miR-150-5p and miR-21-5p, levels of miR-30e-5p were found to be upregulated in late onset AChR+ MG patients and expression of these miRNAs correlated with disease course (7). Interestingly, miR-30e-5p levels were found to be higher in patients with ocular AChR+ MG who later develop generalized MG as compared to those that remain ocular.…”

Section: Introductionmentioning

confidence: 92%

Estrogen Receptor, Inflammatory, and FOXO Transcription Factors Regulate Expression of Myasthenia Gravis-Associated Circulating microRNAs

et al. 2020

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MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate important intracellular biological processes. In myasthenia gravis (MG), a disease-specific pattern of elevated circulating miRNAs has been found, and proposed as potential biomarkers. These elevated miRNAs include miR-150-5p, miR-21-5p, and miR-30e-5p in acetylcholine receptor antibody seropositive (AChR+) MG and miR-151a-3p, miR-423-5p, let-7a-5p, and let-7f-5p in muscle-specific tyrosine kinase antibody seropositive (MuSK+) MG. In this study, we examined the regulation of each of these miRNAs using chromatin immunoprecipitation sequencing (ChIP-seq) data from the Encyclopedia of DNA Elements (ENCODE) to gain insight into the transcription factor pathways that drive their expression in MG. Our aim was to look at the transcription factors that regulate miRNAs and then validate some of those in vivo with cell lines that have sufficient expression of these transcription factors This analysis revealed several transcription factor families that regulate MG-specific miRNAs including the Forkhead box or the FOXO proteins (FoxA1, FoxA2, FoxM1, FoxP2), AP-1, interferon regulatory factors (IRF1, IRF3, IRF4), and signal transducer and activator of transcription proteins (Stat1, Stat3, Stat5a). We also found binding sites for nuclear factor of activated T-cells (NFATC1), nuclear factor kappa-light-chainenhancer of activated B cells (NF-κB), early growth response factor (EGR1), and the estrogen receptor 1 (ESR1). AChR+ MG miRNAs showed a stronger overall regulation by the FOXO transcription factors, and of this group, miR-21-5p, let-7a, and let 7f were found to possess ESR1 binding sites. Using a murine macrophage cell line, we found activation of NF-κB -mediated inflammation by LPS induced expression of miR-21-5p, miR-30e-5p, miR-423-5p, let-7a, and let-7f. Pre-treatment of cells with the anti-inflammatory drugs prednisone or deflazacort attenuated induction of inflammation-induced miRNAs. Interestingly, the activation of inflammation induced packaging of the AChR+-specific miRNAs miR-21-5p and miR-30e-5p into exosomes, suggesting a possible mechanism for the elevation of these miRNAs in MG Fiorillo et al.Transcription Factors for MG-Associated miRNAs patient serum. In conclusion, our study summarizes the regulatory transcription factors that drive expression of AChR+ and MuSK+ MG-associated miRNAs. Our findings of elevated miR-21-5p and miR-30e-5p expression in immune cells upon inflammatory stimulation and the suppressive effect of corticosteroids strengthens the putative role of these miRNAs in the MG autoimmune response.

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miR‐30e‐5p as predictor of generalization in ocular myasthenia gravis

Sabre

Maddison

Wong

et al. 2019

Ann Clin Transl Neurol

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Objective To determine a predictive factor for the risk of conversion from ocular myasthenia gravis ( OMG ) to generalized MG ( GMG ) in a prospective study. Methods RNA was isolated from serum samples and detection of micro RNA (mi RNA ) expression analyzed with qPCR . In the discovery set, 179 human mi RNA s were assayed for profiling of five OMG patients and four age‐ and gender‐matched healthy controls. Based on the specific accumulation pattern of 19 mi RNA s from the discovery set, in addition to mi RNA s previously found elevated in generalized MG ( GMG ; miR‐150‐5p and miR‐30e‐5p), 21 mi RNA s were subsequently analyzed in a validation cohort of 83 OMG patients (82 immunosuppression treatment naive; 49 male) within 3 months of diagnosis and at a follow‐up visit (median duration 28 months from first visit). Results Thirteen patients generalized 14.8 ± 12.0 months after the diagnosis and the majority (85%) belonged to the late onset MG group. Two mi RNA s were significantly higher in secondary GMG ( SGMG ) patients compared to OMG patients with late onset MG : miR‐30e‐5p (9.1 ± 0.5 vs. 6.3 ± 0.9; P < 0.0001) and miR‐150‐5p (7.4 ± 1.1 vs. 6.4 ± 1.1; P = 0.01). The sensitivity for miR‐30e‐5p in differentiating OMG and SGMG was 96% in all OMG patients and 100% in late onset OMG patients. Interpretation This is the first study to describe a potential predictive factor associated with the risk of generalization for patients with OMG . Raised levels (>8) of miR‐30e‐5p at initial presentation in patients with ocular MG symptoms, give a predictive cut‐off for subsequent generalization of 96–100%.

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Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis

Cited by 31 publications

References 16 publications

Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine

Circulating miRNAs as Potential Biomarkers in Myasthenia Gravis: Tools for Personalized Medicine

Estrogen Receptor, Inflammatory, and FOXO Transcription Factors Regulate Expression of Myasthenia Gravis-Associated Circulating microRNAs

miR‐30e‐5p as predictor of generalization in ocular myasthenia gravis

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