Autoantibodies in myasthenia gravis

Autoimmune Myasthenia Gravis (MG) is a disease characterized by fatigable muscle weakness and autoantibodies. It can be divided by the presence of serum autoantibodies into two major categories where Immunoglobulin G (IgG) against either the acetylcholine receptor (AChR), or muscle specific kinase (MuSK) causes fatigable muscle weakness. The clinical relevance of Low-density lipoprotein-receptor related protein-4 IgG (LRP4) is debated. These antibodies disrupt neuromuscular transmission via different mechanisms: AChR antibodies, mostly of IgG1 and IgG3 subclass, can activate complement leading to a simplification of the NMJ architecture, block acetylcholine binding to its receptor to prevent channel opening, and internalize AChR. By contrast, MuSK antibodies, mostly of the IgG4 subclass, impair MuSK-LRP4 interactions, and LRP4 antibodies may interfere with agrin-induced clustering. Once these antibody targets were identified the development of antibody assays began. Patrick and Lindstrom made the landmark discovery that antibodies against soluble AChR caused acute flaccid paralysis in immunized rabbits which kickstarted test development. The first, and until recently, most useful test was the radioimmunoassay (RIA) where AChR radiolabeled with toxin from venomous snakes allowed quantitative measurement of AChR-IgG. Most recently the clustered AChR cell-based assays (CBA) provide a significant improvement in test sensitivity over all other methods. MuSK assays followed a similar but shorter path. The accurate detection of AChR and MuSK antibodies has a crucial role in supporting the clinical diagnosis and management of MG which includes a diverse population of patients with a wide range of clinical manifestations, disease severity and response to standard and new therapies. In this chapter we highlight how distinct target-specific IgG autoantibodies cause neuromuscular transmission defects, and subsequently shape disease manifestations in the different MG antibody subgroups. We review the evolution of diagnostic assays, from early RIA to modern CBA, and addresses interpretative pitfalls, particularly in borderline or "seronegative" cases. Finally, the authors address the significance of accurate autoantibody detection in the diagnosis and management of patients with one of the antibody MG subtypes, as well as in patients with other autoimmune conditions and thymic malignancies.