Abstract
BackgroundA characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). However, the mechanisms that trigger and maintain thymic hyperplasia are poorly characterized. Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases. We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance.MethodsMG thymus samples were assessed by histology and grouped based upon the appearance of GC; GC positive and GC negative. A systems biology approach was used to study the differences between the groups. Our study included miRNA and mRNA profiling, quantitative real-time PCR validation, miRNA target identification, pathway analysis, miRNA-mRNA reciprocal expression pairing and interaction.ResultsThirty-eight mature miRNAs and forty-six annotated mRNA transcripts were differentially expressed between the two groups (>1.5 fold change, ANOVA p<0.05). The miRNAs were found to be involved in immune response pathways and identified in other autoimmune diseases. The cellular and molecular functions of the mRNAs showed involvement in cell death and cell survival, cellular proliferation, cytokine signaling and extra-cellular matrix reorganization. Eleven miRNA and mRNA pairs were reciprocally regulated. The Regulator of G protein Signalling 13 (RGS13), known to be involved in GC regulation, was identified in specimens with GC and was paired with downregulation of miR-452-5p and miR-139-5p. MiRNA target sites were validated by dual luciferase assay. Transfection of miRNA mimics led to down regulation of RGS13 expression in Raji cells.ConclusionOur study indicates a distinct miRNA and mRNA expression pattern in ectopic GC in MG thymus. These miRNAs and mRNAs are involved in regulatory pathways common to inflammation and immune response, cell cycle regulation and anti-apoptotic pathways suggesting their involvement in support of GC formation in the thymus. We demonstrate for the first time that miR-139-5p and miR-452-5p negatively regulate RGS13 expression.
Highlights
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder mediated by antibodies against neuromuscular junction proteins, primarily the acetylcholine receptor (AChR) [1]
A large proportion of AChR antibody positive early onset myasthenia gravis (EOMG) patients have thymic lymphofollicular hyperplasia with ectopic germinal centers (GC) [2] that are rarely observed in thymus of normal individuals
We demonstrate 1) miRNA and transcriptional profiles of MG thymus segregate based on the presence of germinal centers, 2) differently regulated transcripts fall into categories related to immune response, cell proliferation and cell communication/movement, 3) signaling pathways that are differentially identified include cell death and survival as well as inflammation, while 4) differentially regulated miRNAs are primarily involved in immune response and cell proliferation/apoptosis, and 5) each of the profiles are consistent with other investigations which have identified miRNA and gene transcripts involved in GC formation and maintenance in non-thymic, secondary lymphatic structures
Summary
Myasthenia gravis (MG) is an autoimmune neuromuscular disorder mediated by antibodies against neuromuscular junction proteins, primarily the acetylcholine receptor (AChR) [1]. A large proportion of AChR antibody positive early onset myasthenia gravis (EOMG) patients have thymic lymphofollicular hyperplasia with ectopic germinal centers (GC) [2] that are rarely observed in thymus of normal individuals. Removal of the thymus improves the clinical course of EOMG patients [8]. These observations make the thymus a likely site of disease initiation and maintenance in MG. A characteristic pathology of early onset myasthenia gravis is thymic hyperplasia with ectopic germinal centers (GC). Dysregulation of small, non-coding microRNAs (miRNAs) and their target genes has been identified in the pathology of several autoimmune diseases. We assessed the miRNA and mRNA profiles of the MG thymus and have investigated their role in GC formation and maintenance.
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