Classical Complement Pathway in Experimental Autoimmune Myasthenia Gravis Pathogenesis

Abstract

Mice deficient for complement factors C3, C4, or C5 are resistant to experimental autoimmune myasthenia gravis (EAMG). Acetylcholine receptor (AChR) immune lymph node cells (LNC) of C3 deficient mice produce less interleukin 6 (IL-6), and EAMG-resistant IL-6 deficient mice have less serum C3. Increased serum C1q-circulating immune complex (CIC) levels correlated with EAMG disease severity in RIIIS/J mice. The CIC promotes EAMG severity by stimulating the production of LNC IL-6, serum C1q, and C3 via FCgammaR interaction. Therefore, EAMG/MG could be treated by blocking the activation of classical complement pathway (CCP) and/or IL-6. Anti-C1q antibody administration before and following AChR immunization suppressed EAMG by reducing LNC IL-6 production and neuromuscular junction deposits of IgG, C3, and C5b-C9 complexes. Treatment with low dose (10 microg) of anti-C1q antibody twice a week for 4 weeks in mice with ongoing clinical EAMG reduced the clinical severity of disease and LNC IL-6 production. Therefore, inhibitors of CCP factors C1q, C2, or C4 could treat MG and would preserve the alternate complement pathway activation. Our goal is to tailor MG therapy using anti-C2/C4 reagents in combination, with or without anti-cytokine (e.g., anti-IL-6) reagents.

Novel complement inhibitor limits severity of experimentally myasthenia gravis

“…We found that rats with M‐EAMG treated with rEV576 produced less IgG 1 , which in rat activates complement 33. The result is surprising given a lack of precedent for suppression of the C5 step of complement activation to influence humoral immunity; however, there is an emerging literature34 that demonstrates that alterations in complement or complement regulatory proteins may influence antibody profiles. The result suggests that complement activation, or perhaps rEV576 specifically, may have a direct effect on adaptive immunity.…”

Correlation of C3 level with severity of generalized myasthenia gravis

“…Therefore, EAMG/MG can be treated by blocking activation of the classical complement pathway. Inhibitors of classical complement pathway factors can be used to treat MG and preserve activation of the alternate complement pathway 36. Thus, regulation of complement activation may be one possible therapeutic approach for AChRab‐positive GMG.…”

Humanized cobra venom factor: Structure, activity, and therapeutic efficacy in preclinical disease models

“…Experimental autoimmune immune myasthenia gravis (EAMG) is a mouse model of myasthenia gravis, an autoimmune disease of unknown etiology characterized by the occurrence of auto-antibodies against the acetylcholine receptors (AChR) in the neuromuscular junctions (Christadoss et al, 2008;Conti-Fine et al, 2006). The symptoms of muscle weakness and paralysis are produced by complement-mediated destruction of AChR.…”