Abstract
Abstract: :
Purpose: Myasthenia gravis (MG) is an autoimmune neuromuscular transmission disorder characterized by acetylcholine receptor (AChR) loss due primarily to the production of anti–AChR autoantibodies with a predilection for extraocular muscle (EOM) involvement. We previously found that mice deficient in decay accelerating factor (DAF), an intrinsic inhibitor that circumvents cell surface assembly of C3/C5 amplification convertases, develop markedly more severe experimental autoimmune MG (EAMG) than wild type (WT) mice. We have also found that EOM has lower levels of complement regulator expression. In this study, we evaluated the extent to which CD59, an intrinsic inhibitor of cell surface assembly of membrane attack complexes (MAC), protects against EAMG development. Methods: We induced EAMG in Daf1–/–, CD59a–/–, Daf1–/–CD59a–/–, and WT mice by injection of rat anti–AChR mAb, McAb–3, and evaluated the mice 24 and 48 hours later by several methods. Results: Whereas the Daf1–/– exhibited marked weakness and the Daf1–/–CD59a–/– mice exhibited even more profound weakness requiring euthanasia, the CD59a–/– and WT mice retained normal strength. At 48 hr, the Daf1–/– mice remained much weaker than CD59a–/– animals which in turn were weaker than WT mice. Compared to Daf1–/– mice, immuno–histochemistry revealed further augmented C9 deposition in the Daf1–/–CD59a–/–mice localized at post–synaptic junctions, immunostaining showed greater macrophage infiltration, radioimmunoassays showed more profound reductions in AChR levels, and electron microscopy demonstrated markedly greater junctional damage. In contrast, the CD59a–/– and WT mice showed only minor changes. Conclusions: The results demonstrate that DAF plays a primary role in protection of neuromuscular junction from EAMG while CD59 diminishes endplate damage. Taken together, the study suggests that the low level of complement regulators in EOM could make them susceptible to MG and that in disease flares complement inhibitors should have therapeutic value.
Keywords: immunomodulation/immunoregulation • extraocular muscles: structure • eye movements