title: Complement C3 on microglial clusters in multiple sclerosis occur in chronic but not acute disease: Implication for disease pathogenesis.
abstract: Microglial clusters with C3d deposits are observed in the periplaque of multiple sclerosis (MS) brains and were proposed as early stage of lesion formation. As such they should appear in the brain of MS donors with acute disease but thus far this has not been shown. Using postmortem brain tissue from acute (n = 10) and chronic (n = 15) MS cases we investigated whether C3d+ microglial clusters are part of an acute attack against myelinated axons, which could have implications for disease pathogenesis. The specificity of our findings to MS was tested in ischemic stroke cases (n = 8) with initial or advanced lesions and further analyzed in experimental traumatic brain injury (TBI, n = 26), as both conditions are primarily nondemyelinating but share essential features of neurodegeneration with MS lesions. C3d+ microglial clusters were found in chronic but not acute MS. They were not associated with antibody deposits or terminal complement activation. They were linked to slowly expanding lesions, localized on axons with impaired transport and associated with neuronal C3 production. C3d+ microglial clusters were not specific to MS as they were also found in stroke and experimental TBI. We conclude that C3d+ microglial clusters in MS are not part of an acute attack against myelinated axons. As such it is unlikely that they drive formation of new lesions but could represent a physiological mechanism to remove irreversibly damaged axons in chronic disease. GLIA 2017;65:264-277.
authors: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105, The Netherlands.
authors: Iliana
authors: I
authors: Michailidou
authors: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105, The Netherlands.
authors: Daphne M P
authors: DM
authors: Naessens
authors: Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna, 1090, Austria.
authors: Simon
authors: S
authors: Hametner
authors: Department of Anatomy and Neurosciences, VU University Medical Center, De Boelelaan 1118, Amsterdam, 1081, The Netherlands.
authors: Willemijn
authors: W
authors: Guldenaar
authors: Department of Anatomy and Neurosciences, VU University Medical Center, De Boelelaan 1118, Amsterdam, 1081, The Netherlands.
authors: Evert-Jan
authors: EJ
authors: Kooi
authors: Department of Anatomy and Neurosciences, VU University Medical Center, De Boelelaan 1118, Amsterdam, 1081, The Netherlands.
authors: Jeroen J G
authors: JJ
authors: Geurts
authors: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105, The Netherlands.
authors: Frank
authors: F
authors: Baas
authors: Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Spitalgasse 4, Vienna, 1090, Austria.
authors: Hans
authors: H
authors: Lassmann
authors: Department of Genome Analysis, Academic Medical Center, Meibergdreef 9, Amsterdam, 1105, The Netherlands.
authors: Valeria
authors: V
authors: Ramaglia
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001344:Autopsy; D002135:Calcium-Binding Proteins; D002908:Chronic Disease; D003176:Complement C3 / Q000235:genetics / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D016489:Head Injuries, Closed / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D009185:Myelin Proteins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000473:pathology; D020521:Stroke / Q000473:pathology
chemical_list: C112986:AIF1 protein, human; C038245:C3 protein, human; D002135:Calcium-Binding Proteins; D003176:Complement C3; D016207:Cytokines; D004268:DNA-Binding Proteins; D008840:Microfilament Proteins; D009185:Myelin Proteins; D009419:Nerve Tissue Proteins
keywords: lesions; microglia; pathology