Complement Activation Profile in Myasthenia Gravis Patients: Perspectives for Tailoring Anti-Complement Therapy

Abstract

The complement system plays a key role in myasthenia gravis (MG). Anti-complement drugs are emerging as effective therapies to treat anti-acetylcholine receptor (AChR) antibody-positive MG patients, though their usage is still limited by the high costs. Here, we searched for plasma complement proteins as indicators of complement activation status in AChR-MG patients, and potential biomarkers for tailoring anti-complement therapy in MG. Plasma was collected from AChR-MG and MuSK-MG patients, and healthy controls. Multiplex immunoassays and ELISA were used to quantify a panel of complement components (C1Q, C2, C3, C4, C5, Factor B, Factor H, MBL, and properdin) and activation products (C4b, C3b, C5a, and C5b-9), of classical, alternative and lectin pathways. C2 and C5 levels were significantly reduced, and C3, C3b, and C5a increased, in plasma of AChR-MG, but not MuSK-MG, patients compared to controls. This protein profile was indicative of complement activation. We obtained sensitivity and specificity performance results suggesting plasma C2, C3, C3b, and C5 as biomarkers for AChR-MG. Our findings reveal a plasma complement “C2, C3, C5, C3b, and C5a” profile associated with AChR-MG to be further investigated as a biomarker of complement activation status in AChR-MG patients, opening new perspectives for tailoring of anti-complement therapies to improve the disease treatment.

Complement activation profiles in anti‐acetylcholine receptor positive myasthenia gravis

“…Despite the clinical efficacy of its inhibition, roles of the complement system in MG are still poorly understood, but in vivo data on its activation in MG patients are increasing. Iacomino et al reported increased levels of C3, C3b and C5a in the plasmas of patients with AChR‐Ab + MG, but not in MuSK‐Ab + MG patients, which is in line with our findings [15]. Additionally, they also found no correlation of plasma levels of the altered complement components (C2, C3, C3b, C5 and C5a) with disease severity or AChR‐Ab titres.…”

“…Despite the clinical efficacy of its inhibition, roles of the com- which is in line with our findings [15]. Additionally, they also found no correlation of plasma levels of the altered complement compo- Studies in such larger series could additionally focus on the various AChR epitopes recognized by the patients' Abs, which can vary between MG subgroups [23] and might affect complement activation.…”

Activation of the classical complement pathway in myasthenia gravis with acetylcholine receptor antibodies

“…In fact, it has been reported that plasma C5 levels were significantly lower in anti-AChR-antibody-positive MG patients compared with those in controls. 10 C5 is located upstream of sC5b-9, 3 and lower C5 levels accompanied by high sC5b-9 levels observed in the patients with MG in the present study may indicate the decomposition of C5 after an elevation of sC5b-9, namely the activation of the terminal complement pathway. C5b is primarily involved in the formation of the membrane attack complex, whereas C5a shows potent biological activity in the development of inflammatory sequelae such as the promotion of leukocyte chemotaxis, enhancement of neutrophil-endothelial cell adhesion and vascular permeability, induction of granule secretion by phagocytes, and production of various cytokines.…”

“…Lacomino et al reported plasma C5a levels were higher in AChR-antibody-positive MG compared with those in controls, although C5a did not correlate with disease severity. 10 In a mouse model of autoimmune MG, the susceptibility to T A B L E 1 Relation between complement/their regulators and clinical profiles in MG C1q (μg/mL) C5 (μg/mL) C5a (ng/mL) sC5b-9 (μg/mL) Ba (μg/mL) CFH (mg/mL) Sex (female vs. male) 7.9 ± 3.4 vs. disease was comparable between the C5a receptor-knockout and wildtype mice based on antibody and lymphocyte proliferation responses to AChR. 17 Further studies are warranted to elucidate the role of C5a in the pathogenesis of human MG.…”

“…Eculizumab, which specifically binds to complement protein C5, has been approved for patients with MG. 9 The examination of complement and their regulators has become increasingly important in understanding the pathogenesis of MG. In previous studies, complement activation and alterations in the complement network were identified as possibly contributing to the inflammatory pathogenesis of MG. 2,[5][6][7]10 In this study, we examined the relationship of the levels of serum complement and complement regulators to clinical parameters in patients with anti-AChR-antibody-positive generalized MG, with a focus on other complement, including the components of the classical pathway.…”