Increased complement biosynthesis by microglia and complement activation on neurons in Huntington's disease.
In this study complement activation and biosynthesis have been analysed in the brains of Huntington's disease (HD) (n = 9) and normal (n = 3) individuals. In HD striatum, neurons, myelin and astrocytes were strongly stained with antibodies to C1q, C4, C3, iC3b-neoepitope and C9-neoepitope. In contrast, no staining for complement components was found in the normal striatum. Marked astrogliosis and microgliosis were observed in all HD caudate and the internal capsule samples but not in normal brain. RT-PCR analysis and in-situ hybridisation were carried out to determine whether complement was synthesised locally by activated glial cells. By RT-PCR, we found that complement activators of the classical pathway C1q C chain, C1r, C4, C3, as well as the complement regulators, C1 inhibitor, clusterin, MCP, DAF, CD59, were all expressed constitutively and at much higher level in HD brains compared to normal brain. Complement anaphylatoxin receptor mRNAs (C5a receptor and C3a receptor) were strongly expressed in HD caudate. In general, we found that the level of complement mRNA in normal control brains was from 2 to 5 fold lower compared to HD striatum. Using in-situ hybridisation, we confirmed that C3 mRNA and C9 mRNA were expressed by reactive microglia in HD internal capsule. We propose that complement produced locally by reactive microglia is activated on the membranes of neurons, contributing to neuronal necrosis but also to proinflammatory activities. Complement opsonins (iC3b) and anaphylatoxins (C3a, C5a) may be involved in the recruitment and stimulation of glial cells and phagocytes bearing specific complement receptors.
Singhrao
S K
SK
Department of Pathology, University of Wales College of Medicine, Heath Park, Cardiff, CF4 4XN, UK.
Neal
J W
JW
Morgan
B P
BP
Gasque
P
P
D000328:Adult; D000368:Aged; D001253:Astrocytes / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology; D003167:Complement Activation; D003165:Complement System Proteins / Q000096:biosynthesis / Q000235:genetics*; D003342:Corpus Striatum / Q000276:immunology; D017931:DNA Primers; D005786:Gene Expression Regulation / Q000276:immunology*; D005911:Gliosis; D006801:Humans; D006816:Huntington Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017628:Microglia / Q000276:immunology*; D008875:Middle Aged; D009186:Myelin Sheath / Q000276:immunology; D009474:Neurons / Q000276:immunology*; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D003165:Complement System Proteins