Evidence for Immunopathogenic Heterogeneity in Multiple Sclerosis

Pathological studies suggest that the immune factors associated with multiple different effector mechanisms contribute to the inflammation, demyelination, and tissue injury observed in MS lesions. Binding T cells to myelin epitopes leads to macrophage activation and secondary myelin destruction. T cells and microglia macrophages release a variety of toxic mediators including cytokines, proteases, reactive oxygen, and nitrogen species or excitotoxins, which result in direct tissue damage....

Molecular Effectors of Axon Injury 421 Perforin and Granzymes

The dominant mechanism for NK cell- and CTL-mediated killing of target cells is the release of cytolytic granules containing the pore-forming protein perforin, the prote-oglycan serglycin, and a family of serine proteases known as the granzymes 145, 251, 258 . Granzyme B, a known mediator of caspase-dependent apoptosis, is packaged within the cytolytic granule in complex with serglycin. Following T cell receptor recognition of the appropriate peptide MHC class I complex on target cells and the...

Currenttopics In Microbiology And Immunology

Advances in Multiple Sclerosis and Demyelinating Diseases Current Topics in Microbiology and Immunology Volume 318 Emory University School of Medicine, Department of Microbiology and Immunology, 3001 Rollins Research Center, Atlanta, GA 30322, USA Howard Hughes Medical Institute, 378 Wallace Tumor Institute, 1824 Sixth Avenue South, Birmingham, AL 35294-3300, USA Department of Medical Chemistry, Kyoto University, Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan Thomas Jefferson...

Stress and the Naked Axon A Hypothesis

Simply stated, our current working hypothesis is that the stress of demyelination, manifested as retrograde transport defects, intra-axonal protein aggregation, retrograde trophic support withdrawal, mitochondrial dysfunction, and electrical dysregulation and silencing, results in the induction of aberrant neuronal and axonal expression of MHC class Ia and Ib molecules that serve as molecular recognition cues for the engagement of CTL- and NK cell-dependent attack, injury, transection, and...

Magnetic Resonance Imaging and Spectroscopy Evidence 321 Atrophy

White matter in the brain and spinal cord consists of 46 axons, 24 myelin, 17 glia, and 13 vasculature, by volume 162 , which means that axonal loss will significantly impact tissue volume. Indeed, atrophy is presently one of the most robust imaging parameters, revealing that the brain and spinal cord of MS patients atrophies at a rate that is two to ten times faster than in healthy age-matched controls 162 . Obviously, gross measurement of atrophy lacks fine resolution and may overestimate...

Retrograde Transport Defects

2.4.1 Normal Control of the Axon Cytoskeleton by Myelin While intra-axonal and interneuronal factors such as cytoskeletal protein synthesis, electrical activity, patterns of synaptic connectivity, and retrograde transmission of neurotrophic support clearly establish critical regulatory parameters for the maintenance of the axon cytoskeleton and determination of axonal caliber, recent studies have provided evidence that myelination crucially influences axon structural biology. The peripheral...