Myasthenia gravis (MG) is an autoimmune disorder affecting neuromuscular transmission. Patients suffer from muscle weakness and increased muscle fatigability due to diminished neuromuscular signaling (Abbas et al., 2022, Aguilo-Seara et al., 2017, Amanna et al., 2007). The impairment in autoimmune MG is caused by autoantibodies that target components of the neuromuscular junction (NMJ) (Abbas et al., 2022, Ashida et al., 2021, Aguilo-Seara et al., 2017). Different autoimmune MG subtypes are defined by distinct immunopathological features, primarily based on pathogenic autoantibodies. Post-synaptic membrane-targeted subtypes include MG with autoantibodies to the nicotinic acetylcholine receptor (AChR) (Vincent, 2002), muscle-specific tyrosine kinase (MuSK) (Hoch et al., 2001), and lipoprotein receptor-related protein 4 (LRP4) (Balasa and Sarvetnick, 2000, Battaglia et al., 2005).

AChR autoantibodies, detected in approximately 85 % of MG patients, predominantly comprise the IgG1 and IgG3 subclasses. These autoantibodies mediate pathology through complement-mediated tissue damage, AChR internalization, blockade of the acetylcholine binding sites on AChR or interfering with channel activity, leading to NMJ dysfunction (Bouneaud et al., 2000, Cao et al., 2016). MuSK autoantibodies, which are mainly of the IgG4 subclass (Niks et al., 2008), have low affinity for C1q and Fc receptors and thus do not activate the complement cascade or initiate Fc receptor-mediated effector functions (Cebi et al., 2020, Chapman et al., 2019). Instead, MuSK-specific autoantibodies exert pathogenicity by blocking the interaction between MuSK and LRP4, a critical step for AChR clustering (Koneczny et al., 2013). LRP4 autoantibodies, generally of the IgG1 and IgG2 subclasses (Zisimopoulou et al., 2014), disrupt agrin-MuSK-LRP4 mediated AChR clustering (Cotzomi et al., 2019, Diaz-Manera et al., 2012). Most MG patients harbor autoantibodies specific to a single NMJ target, with cases involving autoantibodies to multiple targets being exceptionally rare. However, a distinct subset of patients lacks detectable autoantibodies to any known NMJ targets. This group, termed seronegative MG, is characterized by an unclear (Dresser et al., 2021, Duke and Cohen, 1986) underlying NMJ pathology, representing an active focus of ongoing research.

MG, like other autoimmune diseases, manifests when the immune system fails to recognize normal body tissues (termed self) and attacks and destroys them as if they were foreign pathogens. When the immune system develops, it ‘learns’ to differentiate between our own proteins, cells, tissues, and organs, and components of foreign intruders. This process enables the immune system to effectively target pathogens while preventing damaging immune responses against the body’s own tissues. This essential ‘educational’ process is broadly termed immune tolerance. Accordingly, the fundamental basis of autoimmunity is the failure of self-tolerance (Abbas et al., 2022). A breakdown in self-tolerance permits the survival and activation of autoreactive immune cells, ultimately driving the pathogenic processes in autoimmune diseases, including MG. While the direct effectors of MG pathology are autoantibodies targeting NMJ components, the production and persistence of these pathogenic antibodies require dysregulation within both the B and T cell compartments. Understanding the complementary roles of these immune cell populations is essential for dissecting the underlying mechanisms of MG. In the following section, we will explore how immune tolerance is maintained under physiological conditions, how its failure permits the emergence of autoreactive B and T cells, and how these processes contribute to MG pathogenesis.