Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis

This study investigated the capacity of neurons and astrocytes to spontaneo usly activate the complement system and control activation by expressing co mplement regulators. Human fetal neurons spontaneously activated complement through the classical pathway in normal and immunoglobulin-deficient serum and Clq binding was noted on neurons but not on astrocytes, A strong stain ing for C4, C3b, iC3b neoepitope and C9 neoepitope was also found on neuron s. More than 40% of human fetal neurons were lysed when exposed to normal h uman serum in the presence of a CD59-blocking antibody, whereas astrocytes were unaffected. Significant reduction in neuronal cell lysis was observed after the addition of soluble complement receptor 1 at 10 mu g/ml. Fetal ne urons were stained for CD59 and CD46 and were negative for CD55 and CD35. i n contrast, fetal astrocytes were strongly stained for CD59, CD46, CD55, an d were negative for CD35, This study demonstrates that human fetal neurons activate spontaneously the classical pathway of complement in an antibody-i ndependent manner to assemble the cytolytic membrane attack complex on thei r membranes, whereas astrocytes ate unaffected. One reason for the suscepti bility of neurons to complement-mediated damage in vivo may reside in their poor capacity to control complement activation.