Circulating small non-coding RNAs reflect IFN status and B cell hyperactivity in patients with primary Sjögren’s syndrome

Lopes, Ana P; Hillen, Maarten R; Chouri, Eleni; Blokland, Sofie L M; Bekker, Cornelis P. J.; Kruize, Aike A.; Rossato, Marzia; Roon, Joël A G van

doi:10.1371/journal.pone.0193157

Cited by 11 publications

(9 citation statements)

References 29 publications

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“…They suggest that cellular miR-150 could be regulated by its release into the extracellular space (43). In addition, similarly to what we observed in MG, different studies demonstrated that miR-150 is decreased in PBMCs from Sjögren Syndrome patients while it is increased in the serum of patients and in inflammatory salivary glands (26, 40, 44).…”

Section: Discussionsupporting

confidence: 88%

“…As miR-150 is highly expressed in hyperplastic thymuses, the question is whether the serum increase of miR-150 in MG could be linked to a release from the thymus that would explain the serum decrease after thymectomy (10). Indeed, increased expression of miR-150 is often observed both in the serum and inflammatory organs characterized by ectopic lymphoid infiltrations, such as in Sjögren Syndrome (26, 40) and in lupus nephritis (27, 41). To support this hypothesis, we should observe a higher serum level of miR-150 in MG patients with highly hyperplastic thymus.…”

Section: Discussionmentioning

confidence: 99%

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Causes and Consequences of miR-150-5p Dysregulation in Myasthenia Gravis

et al. 2019

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Autoimmune Myasthenia gravis (MG) is a chronic neuromuscular disease mainly due to antibodies against the acetylcholine receptor (AChR) at the neuromuscular junction that induce invalidating muscle weaknesses. In early-onset MG, the thymus is the effector organ and is often characterized by B-cell infiltrations leading to ectopic germinal center (GC) development. The microRNA miR-150-5p has been previously characterized as a biomarker in MG due to its increase in the serum of patients and its decrease after thymectomy, correlated with an improvement of symptoms. Here, we investigated the causes and consequences of the miR-150 increase in the serum of early-onset MG patients. We observed that miR-150 expression was upregulated in MG thymuses in correlation with the presence of thymic B cells and showed by in situ hybridization experiments, that miR-150 was mainly expressed by cells of the mantle zone of GCs. However, we did not observe any correlation between the degree of thymic hyperplasia and the serum levels in MG patients. In parallel, we also investigated the expression of miR-150 in peripheral blood mononuclear cells (PBMCs) from MG patients. We observed that miR-150 was down-regulated, especially in CD4 + T cells compared to controls. These results suggest that the increased serum levels of miR-150 could result from a release from activated peripheral CD4 + T cells. Next, we demonstrated that the in vitro treatment of PBMCs with miR-150 or antimiR-150 oligonucleotides, respectively, decreased or increased the expression of one of its major target gene: the proto-oncogene MYB , a well-known actor of hematopoiesis. These results revealed that increased serum levels of miR-150 in MG patients could have a functional effect on PBMCs. We also showed that antimiR-150 caused increased cellular death of CD4 + and CD8 + T cells, along with the overexpression of pro-apoptotic genes targeted by miR-150 suggesting that miR-150 controlled the survival of these cells. Altogether, these results showed that miR-150 could play a role in MG both at the thymic level and in periphery by modulating the expression of target genes and peripheral cell survival.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Causes and Consequences of miR-150-5p Dysregulation in Myasthenia Gravis

et al. 2019

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“…One hypothesis is that miR-150 could be regulated by its release into the extracellular space (80). Similar to the observations in MG, other studies demonstrate reduced miR-150-5p in PBMCs from patients with Sjogren's syndrome, while levels are still increased in the serum and salivary glands (81,82), in analogy with miR-150-5p in PBMCs versus the thymus in MG.…”

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

confidence: 56%

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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“…Identification of differentially expressed miRNAs was carried out in two independent phases. First, expression of 758 miRNAs was screened in MACS-isolated CD1c-expressing cDC2s from the donors included in the discovery cohort using the OpenArray platform as previously described (24, 25) (discovery phase; Supplementary Figure 1). miRNAs with a poor amplification score (<1.24) were excluded from the analysis and low expressed miRNAs (CT>27) were set at 27.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

et al. 2019

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Objectives: Considering the critical role of microRNAs (miRNAs) in regulation of cell activation, we investigated their role in circulating type-2 conventional dendritic cells (cDC2s) of patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC). Methods: CD1c-expressing cDC2s were isolated from peripheral blood. A discovery cohort (15 pSS, 6 HC) was used to screen the expression of 758 miRNAs and a replication cohort (15 pSS, 11 HC) was used to confirm differential expression of 18 identified targets. Novel targets for two replicated miRNAs were identified by SILAC in HEK-293T cells and validated in primary cDC2s. Differences in cytokine production between pSS and HC cDC2s were evaluated by intracellular flow-cytometry. cDC2s were cultured in the presence of MSK1-inhibitors to investigate their effect on cytokine production. Results: Expression of miR-130a and miR-708 was significantly decreased in cDC2s from pSS patients compared to HC in both cohorts, and both miRNAs were downregulated upon stimulation via endosomal TLRs. Upstream mediator of cytokine production MSK1 was identified as a novel target of miR-130a and overexpression of miR-130a reduced MSK1 expression in cDC2s. pSS cDC2s showed higher MSK1 expression and an increased fraction of IL-12 and TNF-α-producing cells. MSK1-inhibition reduced cDC2 activation and production of IL-12, TNF-α, and IL-6. Conclusions: The decreased expression of miR-130a and miR-708 in pSS cDC2s seems to reflect cell activation. miR-130a targets MSK1, which regulates pro-inflammatory cytokine production, and we provide proof-of-concept for MSK1-inhibition as a therapeutic avenue to impede cDC2 activity in pSS.

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Circulating small non-coding RNAs reflect IFN status and B cell hyperactivity in patients with primary Sjögren’s syndrome

Cited by 11 publications

References 29 publications

Causes and Consequences of miR-150-5p Dysregulation in Myasthenia Gravis

Causes and Consequences of miR-150-5p Dysregulation in Myasthenia Gravis

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

MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1

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