Autoantibody Specificities in Myasthenia Gravis; Implications for Improved Diagnostics and Therapeutics

Abstract

Myasthenia gravis (MG) is an autoimmune disease characterized by muscle weakness and fatiguability of skeletal muscles. It is an antibody-mediated disease, caused by autoantibodies targeting neuromuscular junction proteins. In the majority of patients (∼85%) antibodies against the muscle acetylcholine receptor (AChR) are detected, while in 6% antibodies against the muscle-specific kinase (MuSK) are detected. In ∼10% of MG patients no autoantibodies can be found with the classical diagnostics for AChR and MuSK antibodies (seronegative MG, SN-MG), making the improvement of methods for the detection of known autoantibodies or the discovery of novel antigenic targets imperative. Over the past years, using cell-based assays or improved highly sensitive immunoprecipitation assays, it has been possible to detect autoantibodies in previously SN-MG patients, including the identification of the low-density lipoprotein receptor-related protein 4 (LRP4) as a third MG autoantigen, as well as AChR and MuSK antibodies undetectable by conventional methods. Furthermore, antibodies against other extracellular or intracellular targets, such as titin, the ryanodine receptor, agrin, collagen Q, K v 1.4 potassium channels and cortactin have been found in some MG patients, which can be useful biomarkers. In addition to the improvement of diagnosis, the identification of the patients' autoantibody specificity is important for their stratification into respective subgroups, which can differ in terms of clinical manifestations, prognosis and most importantly their response to therapies. The knowledge of the autoantibody profile of MG patients would allow for a therapeutic strategy tailored to their MG subgroup. This is becoming especially relevant as there is increasing progress toward the development of antigen-specific therapies, targeting only the specific autoantibodies or immune cells involved in the autoimmune response, such as antigen-specific immunoadsorption, which have shown promising results. We will herein review the advances made by us and others toward development of more sensitive detection methods and the identification of new antibody targets in MG, and discuss their significance in MG diagnosis and therapy. Overall, the development of novel autoantibody assays is aiding in the more accurate diagnosis and classification of MG patients, supporting the development of advanced therapeutics and ultimately the improvement of disease management and patient quality of life.

Autoimmune Pathology in Myasthenia Gravis Disease Subtypes Is Governed by Divergent Mechanisms of Immunopathology

“…Some patients originally categorized as seronegative were later found to have detectable AChR, MuSK, or LRP4 autoantibodies due to either improved test sensitivity or increased titers above the lower limit reference on repeat measurement (133). Other SNMG patients remain defined by the absence of detectable autoantibodies.…”

Improving accuracy of myasthenia gravis autoantibody testing by reflex algorithm

“…[1][2][3][4] Serologic autoantibody testing provides added value especially where diagnostic uncertainty remains after clinical EDX assessement. 5,6 In 80%-90% of patients with MG, autoantibodies against muscle acetylcholine receptors (AChRs) are present, either acetylcholine receptor binding (AChR-Bi) or modulating (AChR-Mo). 7,8 Patients with MG negative for these autoantibodies most commonly (38%-70%) have muscle-specific receptor tyrosine kinase (MuSK) autoantibodies or convert to having AChR autoantibodies within 12 months.…”

“…9,10 Other autoantibodies against extracellular or intracellular neuromuscular junction targets have been described, including titin, the ryanodine receptor, agrin, collagen Q, Kv1.4 potassium channels, low-density lipoprotein receptor-related protein-4 (LRP4), and cortactin, but their clinical utility beyond testing AChR-Bi and AChR-Mo remains under investigation. 6 Patients with MG frequently (10%-20%) have thymoma (paraneoplastic phenomena) and occasionally other extrathymic cancers. [11][12][13][14] CT chest imaging has become a part of standard practice in MG-confirmed patients in evaluation for thymoma and in planning thymectomy.…”

From Traditional to Targeted Immunotherapy in Myasthenia Gravis: Prospects for Research

“…Specific autoantibodies impair neuromuscular transmission according to different mechanisms. Anti-AChR antibodies block the acetylcholine binding site of the AChR, increase internalization and degradation of AChRs and, since they belong to the IgG1 subclass, fix complement ultimately leading to destruction of the NMJ ( 2 ). Anti-MuSK antibodies belong mainly to the IgG 4 subclass and therefore do not activate complement, but impair neuromuscular transmission by interfering with agrin-related AChR clustering.…”

“…Anti-MuSK antibodies belong mainly to the IgG 4 subclass and therefore do not activate complement, but impair neuromuscular transmission by interfering with agrin-related AChR clustering. Anti-LRP4 antibodies belong to the IgG1 subclass, activate complement, and interfere with the LRP4-agrin interaction pathway ( 2 ). Whatever the mechanism and antibody specificity involved, the final outcome is the impairment of neuromuscular transmission leading to the typical muscle weakness and fatigability complained by MG patients.…”