Immunopathology of Autoimmune Myasthenia Gravis: Implications for Improved Testing Algorithms and Treatment Strategies

Abstract

Myasthenia gravis (MG) is a heterogeneous condition, characterized by autoantibodies (Abs) that target functionally important structures within neuromuscular junctions (NMJ), thus affecting nerve-to-muscle transmission. MG patients are more often now subgrouped based on the profile of serum autoantibodies, which segregate with clinical presentation, immunopathology, and their response to therapies. The serological testing plays an essential role in confirming MG diagnosis and guiding disease management, although a small percentage of MG patients remain negative for antibodies. With the advancements in new highly effective pathophysiologically-specific immunotherapeutic options, it has become increasingly important to identify the specific Abs responsible for the pathogenicity in individual MG patients. There are several new assays and protocols being developed for the improved detection of Abs in MG patients. This review focuses on the divergent immunopathological mechanisms in MG, and discusses their relevance to improved diagnostic and treatment. We propose a comprehensive “reflex testing,” algorithm for the presence of MG autoantibodies, and foresee that in the near future, the convenience and specificity of novel assays will permit the clinicians to consider them into routine systematic testing, thus stimulating laboratories to make these tests available. Moreover, adopting treatment driven testing algorithms will be crucial to identify subgroups of patients potentially benefiting from novel immunotherapies for MG.

Autoantibody profile in myasthenia gravis patients with a refractory phase

“…We cannot exclude the possibility that DSNMG patients are a heterogeneous group. One can speculate that low levels of undetectable antibodies or the presence of unrecognized antibodies are associated with diverse immunopathological mechanisms and require novel targeting of treatment modalities 15 . A small sample size and a bias toward more severe and challenging cases at our center of excellence for MG are possible limitations of this study.…”

Comparative Analysis of BIOCHIP Mosaic-Based Indirect Immunofluorescence with Enzyme-Linked Immunosorbent Assay for Diagnosing Myasthenia Gravis

“…The diagnosis of MG is based on a multistep approach, which combines clinical features and laboratory criteria (Figure 3). The sensitive and specific detection of anti-AChR and anti-MuSK autoantibodies has become an essential laboratory investigation in evaluating patients with MG, because seropositivity has diagnostic, prognostic, and therapeutic implications [15][16][17][18][19]. Recent studies report that anti-MuSK positive patients have a worse prognosis with predominant bulbar and respiratory muscle involvement and frequent respiratory crises [3,[20][21][22].…”

Diagnosis of Myasthenia Gravis

“…Furthermore, LRP4-Ab are present in up to 23% of amyotrophic lateral sclerosis (ALS) patients, a percentage of patients with other neuroimmune disorders, and up to 20% of subjects with MuSK-MG (as defined by serological and clinical criteria) [2]. Thus, the detection of anti-LRP4-Ab is not a straightforward diagnostic, unlike that of AChR-Ab or MuSK-Ab; it should be interpreted strictly within the clinical context [6,24].…”