Non-Coding RNAs in Myasthenia Gravis: From Immune Regulation to Personalized Medicine

Abstract

Myasthenia gravis (MG) is an antibody-mediated autoimmune disorder characterized by altered neuromuscular transmission, which causes weakness and fatigability in the skeletal muscles. The etiology of MG is complex, being associated with multiple genetic and environmental factors. Over recent years, progress has been made in understanding the immunological alterations implicated in the disease, but the exact pathogenesis still needs to be elucidated. A pathogenic interplay between innate immunity and autoimmunity contributes to the intra-thymic MG development. Epigenetic changes are critically involved in both innate and adaptive immune response regulation. They can act as (i) pathological factors besides genetic predisposition and (ii) co-factors contributing to disease phenotypes or patient-specific disease course/outcomes. This article reviews the role of non-coding RNAs (ncRNAs) as epigenetic factors implicated in MG. Particular attention is dedicated to microRNAs (miRNAs), whose expression is altered in MG patients' thymuses and circulating blood. The long ncRNA (lncRNA) contribution to MG, although not fully characterized yet, is also discussed. By summarizing the most recent and fast-growing findings on ncRNAs in MG, we highlight the therapeutic potential of these molecules for achieving immune regulation and their value as biomarkers for the development of personalized medicine approaches to improve disease care.

Keywords: autoimmunity; long non-coding RNAs; microRNAs; myasthenia gravis.

Figure 1

MicroRNAs, long non-coding RNAs, and related mRNAs known to be dysregulated in MG. A number of microRNAs (miRNAs, black), long non-coding RNAs (lncRNAs, orange), and related mRNAs (sky blue) were found to be dysregulated in the thymus, peripheral blood mononuclear cells (PBMCs), and serum/plasma of MG patients. Up- and down-regulated miRNAs are reported with arrows pointing up or down, along with implications of their dysregulation for T and B cell function and immune response (italics writing). MiRNAs, LncRNAs, and mRNAs interacting with each other and forming a molecular axis/triplet are represented with the semicircle. The left section illustrates ncRNAs, and some related mRNAs, altered in the thymus of AChR-MG patients, including hyperplastic MG thymuses, characterized by a germinal center presence in the thymic medulla, and MG thymoma, of which miRNAs are dysregulated in the tumoral area or in the normal tumor-adjacent area, are shown. The right upper and lower sections show molecules altered in MG PBMCs and serum/plasma, respectively. Boxes within these sections enclose miRNAs specifically altered in distinct disease subgroups, including early- (<50 years) and late- (>50 years) onset MG. NcRNAs altered in serum are subdivided according to the autoantibody status of MG patients (AChR- and MuSK-MG patients).