title: Complement is activated in progressive multiple sclerosis cortical grey matter lesions.
abstract: The symptoms of multiple sclerosis (MS) are caused by damage to myelin and nerve cells in the brain and spinal cord. Inflammation is tightly linked with neurodegeneration, and it is the accumulation of neurodegeneration that underlies increasing neurological disability in progressive MS. Determining pathological mechanisms at play in MS grey matter is therefore a key to our understanding of disease progression.
  
  
  
  We analysed complement expression and activation by immunocytochemistry and in situ hybridisation in frozen or formalin-fixed paraffin-embedded post-mortem tissue blocks from 22 progressive MS cases and made comparisons to inflammatory central nervous system disease and non-neurological disease controls.
  
  
  
  Expression of the transcript for C1qA was noted in neurons and the activation fragment and opsonin C3b-labelled neurons and glia in the MS cortical and deep grey matter. The density of immunostained cells positive for the classical complement pathway protein C1q and the alternative complement pathway activation fragment Bb was significantly increased in cortical grey matter lesions in comparison to control grey matter. The number of cells immunostained for the membrane attack complex was elevated in cortical lesions, indicating complement activation to completion. The numbers of classical (C1-inhibitor) and alternative (factor H) pathway regulator-positive cells were unchanged between MS and controls, whilst complement anaphylatoxin receptor-bearing microglia in the MS cortex were found closely apposed to cortical neurons. Complement immunopositive neurons displayed an altered nuclear morphology, indicative of cell stress/damage, supporting our finding of significant neurodegeneration in cortical grey matter lesions.
  
  
  
  Complement is activated in the MS cortical grey matter lesions in areas of elevated numbers of complement receptor-positive microglia and suggests that complement over-activation may contribute to the worsening pathology that underlies the irreversible progression of MS.
authors.affiliation: Institute of Life Sciences, Swansea University School of Medicine, Swansea, SA2 8PP, UK.
authors.forename: Lewis M
authors.initials: LM
authors.lastname: Watkins
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: James W
authors.initials: JW
authors.lastname: Neal
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK.
authors.forename: Sam
authors.initials: S
authors.lastname: Loveless
authors.affiliation: Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Iliana
authors.initials: I
authors.lastname: Michailidou
authors.affiliation: Department of Genome Analysis, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramaglia
authors.affiliation: Institute of Life Sciences, Swansea University School of Medicine, Swansea, SA2 8PP, UK.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rees
authors.affiliation: Division of Brain Sciences, Imperial College London, London, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Reynolds
authors.affiliation: Institute of Psychological Medicine and Clinical Neuroscience, Cardiff University, Cardiff, UK.
authors.forename: Neil P
authors.initials: NP
authors.lastname: Robertson
authors.affiliation: Institute of Infection and Immunity, Cardiff University, Cardiff, UK.
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Institute of Life Sciences, Swansea University School of Medicine, Swansea, SA2 8PP, UK. o.w.howell@swansea.ac.uk.|Division of Brain Sciences, Imperial College London, London, UK. o.w.howell@swansea.ac.uk.
authors.forename: Owain W
authors.initials: OW
authors.lastname: Howell
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002490:Central Nervous System / Q000473:pathology*; D051152:Clusterin / Q000378:metabolism; D015331:Cohort Studies; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein; D003165:Complement System Proteins / Q000235:genetics / Q000378:metabolism*; D004660:Encephalitis / Q000473:pathology*; D005260:Female; D066128:Gray Matter / Q000473:pathology*; D006681:HLA-D Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000378:metabolism; D055815:Young Adult
chemical_list: D051152:Clusterin; D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D006681:HLA-D Antigens; D063308:Myelin-Oligodendrocyte Glycoprotein; C469952:SERPING1 protein, human; D003165:Complement System Proteins
keywords: Complement; Grey matter lesion; Innate immunity; Multiple sclerosis; Neurodegeneration