Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity
- 276 Downloads
Although inflammatory responses increase stroke severity, the role of immune cells specific for central nervous system (CNS) antigens remains controversial. Disruption of the blood–brain barrier (BBB) during stroke allows CNS antigens to leak into the peripheral circulation and enhances access of circulating leukocytes to the brain, including those specific for CNS antigens such as myelin oligodendrocyte glycoprotein (MOG) that can induce experimental autoimmune encephalomyelitis (EAE). We here demonstrate for the first time that myelin reactive splenocytes specific for MOG transferred into severe combined immunodeficient (SCID) mice can migrate into the infarct hemisphere of recipients subjected to 60 min middle cerebral artery occlusion (MCAO) and 96 h reperfusion; moreover these cells exacerbate infarct volume and worsen neurological deficits compared to animals transferred with naïve splenocytes. These findings indicate that autoimmunity in the CNS can exert detrimental injury on brain cells and worsen the damage from ischemic stroke.
KeywordsExperimental stroke Myelin reactive splenocytes Inflammatory responses Neurologic deficit
We thank Dr. Heng Hu, Dr. Sushmita Sinha, Dr. Sheetal Bodhankar, Dr. Suzan Dziennis, Dr. Takeru Shimizu and Ms. Sandhya Subramanian for helpful discussions; Ms. Xiao Jing Nie for performing histological staining and Ms. Lisa Miller for help with experiments; and Ms. Eva Niehaus for assistance in preparing the manuscript. This work was supported by NIH Grants NR03521 (PDH), NS49210 (PDH) and the Collins Medical Trust (XR). This material is based upon work supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
Conflict of interest statement
The authors have no financial conflicts of interest.
- Akiyoshi K, Dziennis S, Palmateer J, Ren X, Vandenbark AA, Offner H, Herson PS, Hurn PD (2011) Recombinant T Cell Receptor Ligands Improve Outcome After Experimental Cerebral Ischemia. Transl Stroke Res 2:404–410Google Scholar
- Dziennis S, Mader S, Akiyoshi K, Ren X, Ayala P, Burrows GG, Vandenbark AA, Herson PS, Hurn PD, Offner HA (2011) Therapy with recombinant T-cell receptor ligand reduces infarct size and infiltrating inflammatory cells in brain after middle cerebral artery occlusion in mice. Metab Brain Dis 26(2):123–133PubMedCrossRefGoogle Scholar
- Khoury SJ, Hancock WW, Weiner HL (1992) Oral tolerance to myelin basic protein and natural recovery from experimental autoimmune encephalomyelitis are associated with downregulation of inflammatory cytokines and differential upregulation of transforming growth factor beta, interleukin 4, and prostaglandin E expression in the brain. J Exp Med 176(5):1355–1364PubMedCrossRefGoogle Scholar
- Kleinschnitz C, Schwab N, Kraft P, Hagedorn I, Dreykluft A, Schwarz T, Austinat M, Nieswandt B, Wiendl H, Stoll G (2010) Early detrimental T-cell effects in experimental cerebral ischemia are neither related to adaptive immunity nor thrombus formation. Blood 115(18):3835–3842PubMedCrossRefGoogle Scholar
- Miller A, Lider O, Roberts AB, Sporn MB, Weiner HL (1992) Suppressor T cells generated by oral tolerization to myelin basic protein suppress both in vitro and in vivo immune responses by the release of transforming growth factor beta after antigen-specific triggering. Proc Natl Acad Sci U S A 89(1):421–425PubMedCrossRefGoogle Scholar
- Miller SD, Karpus WJ, Davidson TS (2010) Experimental autoimmune encephalomyelitis in the mouse. Current protocols in immunology/edited by John E Coligan [et al] Chapter 15:Unit 15 11.Google Scholar
- Montecucco F, Lenglet S, Gayet-Ageron A, Bertolotto M, Pelli G, Palombo D, Pane B, Spinella G, Steffens S, Raffaghello L, Pistoia V, Ottonello L, Pende A, Dallegri F, Mach F (2010) Systemic and intraplaque mediators of inflammation are increased in patients symptomatic for ischemic stroke. Stroke 41(7):1394–1404PubMedCrossRefGoogle Scholar
- Ren X, Akiyoshi K, Vandenbark AA, Hurn PD, Offner H (2011b) Programmed Death-1 Pathway Limits Central Nervous System Inflammation and Neurologic Deficits in Murine Experimental Stroke. Stroke 42:2578–2583Google Scholar