title: Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis.
abstract: This study investigated the capacity of neurons and astrocytes to spontaneously activate the complement system and control activation by expressing complement regulators. Human fetal neurons spontaneously activated complement through the classical pathway in normal and immunoglobulin-deficient serum and C1q binding was noted on neurons but not on astrocytes. A strong staining for C4, C3b, iC3b neoepitope and C9 neoepitope was also found on neurons. More than 40% of human fetal neurons were lysed when exposed to normal human 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 microg/ml. Fetal neurons were stained for CD59 and CD46 and were negative for CD55 and CD35. In contrast, fetal astrocytes were strongly stained for CD59, CD46, CD55, and were negative for CD35. This study demonstrates that human fetal neurons activate spontaneously the classical pathway of complement in an antibody-independent manner to assemble the cytolytic membrane attack complex on their membranes, whereas astrocytes are unaffected. One reason for the susceptibility of neurons to complement-mediated damage in vivo may reside in their poor capacity to control complement activation.
authors.affiliation: Department of Medical Biochemistry, Brain Inflammation and Immunity Group, University of Wales College of Medicine, Heath Park, Cardiff, United Kingdom. singhrao@cardiff.ac.uk
authors.forename: S K
authors.initials: SK
authors.lastname: Singhrao
authors.forename: J W
authors.initials: JW
authors.lastname: Neal
authors.forename: N K
authors.initials: NK
authors.lastname: Rushmere
authors.forename: B P
authors.initials: BP
authors.lastname: Morgan
authors.forename: P
authors.initials: P
authors.lastname: Gasque
mesh_terms: D019138:Antibodies, Blocking / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000166:cytology / Q000196:embryology; D002478:Cells, Cultured; D003167:Complement Activation / Q000502:physiology*; D050577:Complement C3-C5 Convertases / Q000502:physiology; D003169:Complement Inactivator Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D003171:Complement Pathway, Classical / Q000502:physiology*; D005333:Fetus; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017403:In Situ Hybridization; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D012313:RNA / Q000032:analysis; D012333:RNA, Messenger / Q000378:metabolism; D011951:Receptors, Complement / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D019138:Antibodies, Blocking; D015703:Antigens, CD; C497857:CD46 protein, human; D003169:Complement Inactivator Proteins; D051916:Membrane Cofactor Protein; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D011951:Receptors, Complement; D012313:RNA; D050577:Complement C3-C5 Convertases