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Complement C5a/C5aR Signaling and CNS Lupus

Jessy J Alexander

Systemic lupus erythematosus is a devastating disease with a therapeutic regimen that has toxic side effects. It affects 1.5 million Americans, 80% of whom have neuropsychiatric symptoms and finding an effective therapeutic target is an urgent need. One of the key inflammatory pathways altered in lupus is the complement system that forms a part of the clinical profile. Our lab has been systematically studying the role of complement in CNS lupus. Our work showed that pan complement inhibition using Crry-Ig is protective in experimental lupus. Inhibition of signaling by the complement byproducts C5a and C3a alleviated the lupus pathology. C5a causes the blood-brain barrier to become ‘leaky’. Subsequent studies demonstrated that C5a caused the human brain microvascular endothelial cells to apoptose through the executioner caspases that could be prevented using the C5aR antagonist. These studies demonstrate the pharmacologic potential and clinical benefit of C5a receptor antagonist in lupus.