The role of complement in the immunopathogenesis of acetylcholine receptor antibody-positive generalized myasthenia gravis: bystander or key player?

Abstract

The complement system is a key component of the innate immune system. In antiacetylcholine receptor (AChR) antibody-positive (Ab+) generalized myasthenia gravis (MG), complement activation has long been considered a principal driver of pathology. Understanding the role of complement in AChR-Ab+ generalized MG has gained increasing importance in recent years, as anticomplement drugs have been approved for clinical use or are undergoing phase II/III clinical trials. This review aims to discuss recent and previous findings on the role of complement in AChR-Ab+ MG pathology, including its interaction with pathogenic antibodies and mechanisms beyond the classical pathway activation.

Keywords: anti-acetylcholine receptor antibodies; complement system; membrane attack complex; myasthenia gravis; therapy.

Figure 1

The pathways of complement system activation. In the classical pathway, C1q, a subunit of the C1 complex, binds to an antibody-fixed cell. This binding activates the proteases C1r and C1s (also components of the C1 complex). C1s cleave the C4 protein into C4a and C4b. C4b binds covalently to the target and attracts C2, which is cleaved by C1s into C2a and C2b. C2b binds to C4b to form the C4b2b complex, also known as C3 convertase. C3 convertase cleaves C3 into C3a and C3b. C3b may bind to the C3 convertase, forming the C4b2b3b complex, also known as C5 convertase. C5 convertase cleaves C5 into C5a and C5b. C5b associates with C6, C7, C8, and C9 to form the final product of complement activation, the membrane attack complex (MAC). In the lectin pathway, mannose-binding lectin (MBL) or ficolins bind to carbohydrate patterns on the target cell, leading to the activation of MBL-associated serine proteases (MASP)1 and MASP2, which are complexed with MBL. MASPs cleave C4 and C2, forming C3 convertase. The pathway continues with the generation of the C5 convertase and the formation of MAC. In the alternative pathway, inactive C3 undergoes spontaneous hydrolysis, forming C3(H₂O). Factor B binds to C3(H₂O), leading to its cleavage by factor D into Ba and Bb, resulting in the formation of the fluid-phase C3 convertase, C3(H₂O)Bb. C3(H₂O)Bb converts C3 into C3a and C3b, with some C3b molecules binding to the target and associating with factor B, which is subsequently cleaved by factor D to form the C3 convertase C3bBb. The pathway progresses with the formation of the C5 convertase (C3bBb3b), cleavage of C5, and the assembly of the MAC. Selected regulators of the complement cascade that interfere with different steps of the cascade are illustrated. C1 inhibitor (C1INH) promotes the decomposition of the C1 complex. Decay-accelerating factor (DAF), membrane cofactor protein (MCP), and complement receptor 1 (CR1) accelerate the decay of the C3 and C5 convertases. CD59 inhibits the formation of MAC. Factor H (FH) prevents the assembly of the alternative pathway C3 and C5 convertases, while factor P (properdin) stabilizes the alternative pathway C3 convertase, thereby promoting the amplification loop. Created with BioRender.com.

Figure 2

The complement system in AChR-Ab+ generalized myasthenia gravis: C1q binds to autoantibodies attached to AChRs (1) and to precipitated immune complexes (2), when present, at the neuromuscular junction, thereby activating the classical pathway (CP). Hydrolysis of C3, either spontaneously (3) or triggered by precipitated immunocomplexes (4), induces activation of the alternative pathway (AP). CP activation results in the opsonization of the muscle membrane by C4b and C3b, which serve as potent activators of CR1- and CR2-bearing lymphocytes (a). Both the CP and the AP result in the release of C3a, a product of C3 cleavage, and C5a, a product of C5 cleavage, which may interact with immune cells bearing C3a and C5a receptors, respectively (b). Additionally, both pathways contribute to the formation of the membrane attack complex (MAC), composed of C5b, C6, C7, C8, and C9, which serves as the key driver of neuromuscular junction damage (c). CP, classical pathway; AP, alternative pathway. Created with BioRender.com.