title: Systemic autoimmunity in TAM triple knockout mice causes inflammatory brain damage and cell death.
abstract: The Tyro3, Axl and Mertk (TAM) triply knockout (TKO) mice exhibit systemic autoimmune diseases, with characteristics of increased proinflammatory cytokine production, autoantibody deposition and autoreactive lymphocyte infiltration into a variety of tissues. Here we show that TKO mice produce high level of serum TNF-α and specific autoantibodies deposited onto brain blood vessels. The brain-blood barrier (BBB) in mutant brains exhibited increased permeability for Evans blue and fluorescent-dextran, suggesting a breakdown of the BBB in the mutant brains. Impaired BBB integrity facilitated autoreactive T cells infiltrating into all regions of the mutant brains. Brain autoimmune disorder caused accumulation of the ubiquitin-reactive aggregates in the mutant hippocampus, and early formation of autofluorescent lipofuscins in the neurons throughout the entire brains. Chronic neuroinflammation caused damage of the hippocampal mossy fibers and neuronal apoptotic death. This study shows that chronic systemic inflammation and autoimmune disorders in the TKO mice cause neuronal damage and death.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Qiutang
authors.initials: Q
authors.lastname: Li
authors.forename: Qingjun
authors.initials: Q
authors.lastname: Lu
authors.forename: Huayi
authors.initials: H
authors.lastname: Lu
authors.forename: Shifu
authors.initials: S
authors.lastname: Tian
authors.forename: Qingxian
authors.initials: Q
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism; D001925:Brain Damage, Chronic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D056654:CA3 Region, Hippocampal / Q000098:blood supply / Q000276:immunology / Q000473:pathology*; D002199:Capillary Permeability / Q000276:immunology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D018891:Dentate Gyrus / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D002479:Inclusion Bodies / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000276:immunology / Q000378:metabolism; D009474:Neurons / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D057149:Ubiquitinated Proteins / Q000378:metabolism; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D001323:Autoantibodies; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D057149:Ubiquitinated Proteins; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse