Perforin-dependent neurologic injury in a viral model of multiple sclerosis.

نویسندگان

  • P D Murray
  • D B McGavern
  • X Lin
  • M K Njenga
  • J Leibowitz
  • L R Pease
  • M Rodriguez
چکیده

In this study we demonstrate perforin-mediated cytotoxic effector function is necessary for viral clearance and may directly contribute to the development of neurologic deficits after demyelination in the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. We previously demonstrated major histocompatability complex (MHC) class I-deficient (beta2m-deficient) mice with an otherwise resistant genotype develop severe demyelination with minimal neurologic disease when chronically infected with TMEV. These studies implicate CD8(+) T cells as the pathogenic cell in the induction of neurologic disease after demyelination. To determine which effector mechanisms of CD8(+) T cells, granule exocytosis or Fas ligand expression, play a role in the development of demyelination and clinical disease, we infected perforin-deficient, lpr (Fas mutation), and gld (Fas ligand mutation) mice with TMEV. Perforin-deficient mice showed viral persistence in the CNS, chronic brain pathology, and demyelination in the spinal cord white matter. Perforin-deficient mice demonstrated severely impaired MHC class I-restricted cytotoxicity against viral epitopes, but normal MHC class II-restricted delayed-type hypersensitivity responses to virus antigen. Despite demyelination, virus-infected perforin-deficient mice showed only minimal neurologic deficits as indicated by clinical disease score, activity monitoring, and footprint analysis. Perforin- and MHC class II-deficient mice (with functional CD8(+) T cells and perforin molecules and an H-2(b) haplotype) had comparable demyelination and genotype, however, only the latter showed severe clinical disease. Gld and lpr mice demonstrated normal TMEV-specific cytotoxicity and maintained resistance to TMEV-induced demyelinating disease. These studies implicate perforin release by CD8(+) T cells as a potential mechanism by which neurologic deficits are induced after demyelination.

برای دانلود رایگان متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

CD8 T cell-initiated vascular endothelial growth factor expression promotes central nervous system vascular permeability under neuroinflammatory conditions.

Dysregulation of the blood-brain barrier (BBB) is a hallmark feature of numerous neurologic disorders as diverse as multiple sclerosis, stroke, epilepsy, viral hemorrhagic fevers, cerebral malaria, and acute hemorrhagic leukoencephalitis. CD8 T cells are one immune cell type that have been implicated in promoting vascular permeability in these conditions. Our laboratory has created a murine mod...

متن کامل

O 8: Tenasin-C as a New Target for Multiple Sclerosis Treatment

Multiple Sclerosis (MS) is an autoimmune disease, which is characterized by demyelination and neuroinflammation. Extracellular Matrix (ECM) have important role in the central nervous system (CNS). Alterations are happening to the ECM after the CNS disorder like MS, Alzheimer and other neural injury. Tenasin-C (TnC) is a glycoprotein that is highly expressed in inflammatory conditions of the CNS...

متن کامل

IFN-gamma is required for viral clearance from central nervous system oligodendroglia.

Infection of the central nervous system (CNS) by the JHM strain of mouse hepatitis virus (JHMV) is a rodent model of the human demyelinating disease multiple sclerosis. The inability of effective host immune responses to eliminate virus from the CNS results in a chronic infection associated with ongoing recurrent demyelination. JHMV infects a variety of CNS cell types during the acute phase of ...

متن کامل

O 9: Immunomodulatory Effects of Neural Stem Cell on Multiple Sclerosis: A Systematic Review

Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are chronic inflammatory demyelinating disorders of central nervous system (CNS). While the cause is unclear, the fundamental mechanism is thought to be destruction of myelin sheaths of neurons through immune system. One of the approaches being proposed in EAE therapy is neural stem cells (NSCs) trans...

متن کامل

CD8+ T Cells Cause Disability and Axon Loss in a Mouse Model of Multiple Sclerosis

BACKGROUND The objective of this study was to test the hypothesis that CD8+ T cells directly mediate motor disability and axon injury in the demyelinated central nervous system. We have previously observed that genetic deletion of the CD8+ T cell effector molecule perforin leads to preservation of motor function and preservation of spinal axons in chronically demyelinated mice. METHODOLOGY/PR...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

عنوان ژورنال:
  • The Journal of neuroscience : the official journal of the Society for Neuroscience

دوره 18 18  شماره 

صفحات  -

تاریخ انتشار 1998