Transgenic Expression of TNF by Astrocytes Increases Mechanical Allodynia In A Mouse Neuropathy Model
DeLeo JA, Rutkowski MD, Stalder AK, Campbell IL
Neuroreport 2000 Feb 28;11(3):599-602
Dartmouth-Hitchcock Medical Center, Dept of Anesthesiology, Lebanon, NH 03756, USA
PMID# 10718321; UI# 20181249
It has been hypothesized that increased expression of ProInflammatory Cytokines mediate a variety of Central Nervous System Disorders such as Multiple Sclerosis, Alzheimer's Disease, Cerebral Ischemia, Spinal Cord Injury, HIV Encephalopathy and Chronic Pain.
In order to further examine the central role of Tumor Necrosis Factor (TNF) in NeuroPathic Pain, transgenic mice were used in which expression of murine TNF was targeted to Astrocytes using a Glial Fibrillary Acidic Protein (GFAP)-TNF fusion gene.
Spinal Nerve (L5) transection was performed in either the GFAP-TNF transgenic or wild type mice. Mechanical Allodynia was significantly enhanced in the GFAP-TNF transgenic mice compared with the wild type mice.
These data support a central role of Glial expression of TNF in the generation of NeuroPathic Pain.
Green MH, Petit-Frere C, Clingen PH, Bentham G, Cole J, Arlett CF
J Epidemiol 1999 Dec;9(6 Suppl):S48-57
Univ of Sussex, MRC Cell Mutation Unit, Brighton, United Kingdom
PMID# 10709350; UI# 20174126
The human population is exposed to both the UltraViolet A (UVA) and B (UVB) regions of the solar spectrum. UVB induces mainly Dipyrimidine photoproducts in DNA by a direct photochemical mechanism, whereas UVA is absorbed by other cellular constituents and induces mainly Oxidative damage indirectly.
The proportions of the different Dipyrimidine photoproducts, and the ratio of Dipyrimidine to Oxidative damage depend on the exact Spectral output of a UV source.
Irradiation of human epidermal Keratinocytes induces release of Cytokines, with CycloButane Pyrimidine dimers playing a significant role in the process. These Cytokines may then modulate the activity of cells of the Immune System.
Freshly isolated human Lymphocytes are exquisitely sensitive to UVB irradiation, because of their low DeoxyriboNucleotide pools. They also have a separate defect in removal of CycloButane Pyrimidine dimers from their DNA.
We have observed that frequencies of mutations at the hprt locus in human T-Lymphocytes and translocations involving the bcl2 locus in B-Lymphocytes appear to be associated with sunlight levels over the period before the blood sample was taken.
This may be an indirect Cytokine-mediated effect, and may be relevant to the possible link between Non-Hodgkin's Lymphoma and sunlight. On the other hand, sunlight can have beneficial effects, and may protect against AutoImmune Diseases including type I Diabetes and Multiple Sclerosis.
Serial Magnetic Resonance Imaging In Multiple Sclerosis: Correlation With Attacks, Disability, And Disease Stage
Weiner HL, Guttmann CR, Khoury SJ, Orav EJ, Hohol MJ, Kikinis R, Jolesz FA
J NeuroImmunol 2000 May 1;104(2):164-173
Center for Neurologic Diseases, Brigham and Women's and Massachusetts General Hospitals, Partners Multiple Sclerosis Center, 77 Louis Pasteur Avenue, HIM 730, Boston, MA, USA
Serial MRI and clinical testing was performed on 45 well-defined untreated Multiple Sclerosis patients in different categories of Disease (Relapsing/Remitting, progressive, stable).
Up to 24 MRIs were scheduled over a 1-year period for each patient. Clinical evaluation was performed monthly and at times of attacks using the Expanded Disability Status Scale (EDSS) and the Ambulation Index (AI).
MRI scans were performed both with and without Gadolinium enhancement. MRI lesion volume was determined by computerized analysis and Gadolinium-enhancing lesions were counted by Radiologists.
We observed an increase in lesion volume over 1 year in all patient groups except those classified clinically as stable.
In Relapsing/Remitting patients there were correlations between increases in the number of Gadolinium enhancing lesions and increases in EDSS and the occurrence of attacks.
In Chronic/Progressive patients, increases in lesion volume were correlated with both increases in EDSS and AI.
These results demonstrate a linkage between MRI and clinical disease that depends both on the stage of MS and the MRI measures used and support the use of MRI as a surrogate marker of clinical disability in the study of Multiple Sclerosis.
T-Cells Specific For Soluble Recombinant Oligodendrocyte-Specific Protein Induce Severe Clinical Experimental AutoImmune EncephaloMyelitis In H-2(b) & H-2(s) Mice
Zhong M, Cohen L, Meshorer A, Kerlero de Rosbo N, Ben-Nun A
J NeuroImmunol 2000 Jun 1;105(1):39-45
The Weizmann Institute of Science, Dept of Immunology, Rehovot, Israel
To investigate the ImmunoGenicity and Encephalitogenicity of Oligodendrocyte-Specific Protein (OSP), recombinant soluble mouse OSP (smOSP) was produced from a synthetic Gene engineered to lack the sequences coding for the hydrophobic transmembrane domains of the native molecule.
SmOSP was ImmunoGenic and Encephalitogenic for SJL/J, C3H.SW and C57BL/6J mice, but not PL/J or BALB/c mice. SmOSP-specific T-Cells from SJL/J, C3H.SW and C57BL/6J mice induced severe chronic clinical Experimental AutoImmune EncephaloMyelitis upon transfer.
These findings indicate that AutoImmune T-Cell responses to OSP should be investigated in the context of Multiple Sclerosis.
van Noort JM, Bajramovic JJ, Plomp AC, van Stipdonk MJ
J NeuroImmunol 2000 Jun 1;105(1):46-57
TNO Prevention and Health, Division of Immunological and Infectious Diseases, P.O. Box 2215, 2301 CE, Leiden, Netherlands
Several findings indicate that infectious events play a role in the PathoGenesis of Multiple Sclerosis (MS). At the same time, T-Cell AutoImmunity to Myelin Antigens is widely believed to be crucial to the development of MS lesions.
Several mechanisms have been put forward to explain the presumed link between microbial infections and Myelin-directed AutoImmunity. These include Molecular Mimicry, bystander activation including Epitope spreading and superantigenic activation of T-Cells.
Evidence that either one of these mechanisms actually occurs in MS patients, however, is still weak. Also, none of the above mechanisms explain why MS is unique to humans.
We propose an alternative link between Microbial infection and Myelin AutoImmunity, which we refer to as *mistaken self*.
In this mechanism, peripheral Microbial infections of Lymphoid Cells prime the human T-Cell repertoire not only to Microbial Antigens but also to the Stress Protein alphaB-Crystallin that is expressed de novo in infected Lymphoid Cells.
Subsequently, stress-induced accumulation of this self Antigen in Oligodendocytes/Myelin can provoke pro-inflammatory responses as the recruited Memory T-Cell repertoire then mistakes the self protein for a Microbial Antigen.
In this paper we review the currently available evidence that *mistaken self* centering on alphaB-Crystallin represents a powerful source of Anti-Myelin AutoImmunity in a way that is unique to humans.