Complement membrane attack is required for endplate damage and clinical disease in passive experimental myasthenia gravis in Lewis rats

Abstract

SummaryMyasthenia gravis (MG) is a debilitating and potentially fatal neuromuscular disease characterized by the generation of autoantibodies reactive with nicotinic acetylcholine receptors (AChR) that cause loss of AChR from the neuromuscular endplate with resultant failure of neuromuscular transmission. A role for complement (C) in the pathology of human MG has been suggested based upon identification of C activation products in plasma and deposited at the endplate in MG. In the rat model, experimental autoimmune MG (EAMG), C depletion or inhibition restricts clinical disease, further implicating C in pathology. The mechanisms by which C activation drives pathology in MG and EAMG are unclear. Here we provide further evidence implicating C and specifically the membrane attack complex (MAC) in the Lewis rat passive EAMG model of MG. Rats deficient in C6, an essential component of the MAC, were resistant to disease induction and endplate destruction was reduced markedly compared to C6-sufficient controls. After reconstitution with C6, disease severity and endplate destruction in the C6-deficient rats was equivalent to that in controls. The data confirm the essential role of the MAC in the destruction of the endplate in EAMG and raise the prospect of specific MAC inhibition as an alternative therapy in MG patients resistant to conventional treatments.

Effect of complement and its regulation on myasthenia gravis pathogenesis

“…Animal models, which induce EAMG either by administration of AChR antibodies or immunization with purified AChR, support the hypothesis: complement drives pathology in mouse and rat EAMG [49,50]; agents that block, inhibit or deplete complement protect animals from EAMG [51][52][53]; mice with a genetic deficit in complement components are resistant or less susceptible to EAMG [54]; inability to activate complement is associated with many immunological factors (e.g., in IL-12-deficient mice) [55], antibody, C3, C9 and MAC are uniformly found at the junctions of EAMG animals; and mice deficient in cell surface regulators of complement are particularly susceptible to EAMG induced by administration of AChR antibodies [50,56,57]. The following sections discuss the function of individual complement components as they relate primarily to EAMG pathogenesis.…”

“…Any of these may contribute to the pathology of disease [69]. In murine and rat EAMG [49] produced by AChR antibody administration, activation of the terminal lytic complement complex (C5b-C9) is required for AChR destruction. The role of MAC was investigated by in vivo inhibition with anti-C6 Fab [51].…”

A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis

“…Much data exist implicating complement as a major effector in neuromuscular junction damage in MG. [1][2][3][4][5][6][7][8][9][10][11][12][14][15][16] Knockout experiments have shown that complement regulators such as DAF, at least in the EAMG model, influences the severity of damage by complement-fixing antibodies at the muscle endplate. 2,15,16 Although basal complement regulatory protein (CRP) mRNA transcripts were lower in mouse EOMs compared with their diaphragm muscles, the induction of EAMG resulted in a further reduction of EOM CRP expression and particularly of DAF.…”

“…1,3,5 Animal models became resistant to the induction of EAMG when circulating complement was either depleted by cobra venom toxin or functionally inhibited by the administration of a monoclonal C5 antibody or soluble C1 receptor. [6][7][8] Rodent models either deficient in C4, critical for the generation of C3 convertase, or C6, an important constituent of the membrane attack complex, were more resistant to EAMG induction 9,10 and showed less endplate damage than control animals. 9 Complement-mediated damage at the muscle endplate has been shown to result in the loss of AChRs, alter the architecture of endplate folds and likely reduce Na þ channel density in these folds, all of which affects neuromuscular transmission.…”

“…[6][7][8] Rodent models either deficient in C4, critical for the generation of C3 convertase, or C6, an important constituent of the membrane attack complex, were more resistant to EAMG induction 9,10 and showed less endplate damage than control animals. 9 Complement-mediated damage at the muscle endplate has been shown to result in the loss of AChRs, alter the architecture of endplate folds and likely reduce Na þ channel density in these folds, all of which affects neuromuscular transmission. 11 Innate complement control mechanisms include complement regulatory proteins expressed on all serum-exposed cells, each of which intervenes at key points in the cascade, thereby protecting cell membranes against autologous complement damage.…”