InterLeukin-1 in the Brain: Biology, Pathology And Therapeutic Target
Rothwell NJ, Luheshi GN
Trends NeuroSci 2000 Dec;23(12):618-25
Univ of Manchester, School of Biological Sciences, 1.124 Stopford Building, M13 9PT, Manchester, UK
PMID# 11137152; UI# 20580007
The Cytokine InterLeukin-1 (IL-1) has diverse actions in the Brain. In normal Brain the IL-1 system is expressed at low levels and is upregulated rapidly in response to local or peripheral insults.
IL-1 mediates host defence responses to local and Systemic Disease and injury: e.g. fever, slow-wave sleep, appetite suppression and NeuroEndocrine responses.
And, to NeuroInflammation and cell death in NeuroDegenerative conditions, such as Stroke and Head Injury.
It has also been implicated in Chronic Degenerative Diseases, in particular, Multiple Sclerosis, Parkinson's and Alzheimer's Diseases.
The mechanisms regulating the expression and action of IL-1 are poorly understood, but involve multiple effects on Neuronal, Glial and Endothelial Cell function.
Thus, the IL-1 system provides an attractive and intensely competitive target for therapeutic intervention.
Engelhardt B, Wolburg-Buchholz K, Wolburg H
Microsc Res Tech 2001 Jan 1;52(1):112-129
Max-Planck Institut fur physiologische und klinische Forschung, W. G. Kerckhoff-Institut, Bad Nauheim, Germany
During inflammatory conditions in the Central Nervous System (CNS), Immune Cells immigrate into the CNS and can be detected in the CNS Parenchyma and in the CerebroSpinal Fluid (CSF).
The most comprehensively investigated model for CNS inflammation is Experimental AutoImmune EncephaloMyelitis (EAE), which is considered the prototype model for the human disease Multiple Sclerosis (MS).
In EAE autoagressive CD4+, T-Cells gain access to the CNS and initiate the molecular and cellular events leading to Edema, Inflammation, and DeMyelination in the CNS.
The Endothelial Blood-Brain Barrier (BBB) has been considered the obvious place of entry for the circulating Immune Cells into the CNS.
A role of the Choroid Plexus in the PathoGenesis of EAE or MS, i.e., as an alternative entry site for circulating Lymphocytes directly into the CSF, has not been seriously considered before.
However, during EAE, we observed massive ultrastructural changes within the Choroid Plexus, which are different from changes observed during Hypoxia.
Using ImmunoHistoChemistry and in situ hybridization, we observed expression of VCAM-1 and ICAM-1 in the Choroid Plexus and demonstrated their upregulation and also de novo expression of MAdCAM-1 during EAE.
Ultrastructural studies revealed polar localization of ICAM-1, VCAM-1, and MAdCAM-1 on the apical surface of Choroid Plexus Epithelial Cells and their complete absence on the fenestrated Endothelial Cells within the Choroid Plexus Parenchyme.
Furthermore, ICAM-1, VCAM-1, and MAdCAM-1 expressed in Choroid Plexus Epithelium mediated binding of Lymphocytes via their known Ligands.
In vitro, Choroid Plexus Epithelial Cells can be induced to express ICAM-1, VCAM-1, MAdCAM-1, and, additionally, MHC Class I and II molecules on their surface.
Taken together, our observations imply a previously unappreciated function of the Choroid Plexus in the ImmunoSurveillance of the CNS.
Copyright 2001 Wiley-Liss, Inc.
A Correlative Study With Conventional MRI, HistoPathology And Clinical Phenotype
Nijeholt GJ, Bergers E, Kamphorst W, Bot J, Nicolay K, Castelijns JA, van Waesberghe JH, Ravid R, Polman CH, Barkhof F
Brain 2001 Jan;124(Pt 1):154-166
Dutch MR Center for MS Research, Vrije Universiteit Hospital, Depts of Radiology, Pathology and Neurology, and Image Sciences Institute, Univ, Medical Centre, Utrecht and Dutch Brain Bank, Amsterdam, The Netherlands
We used high-resolution MRI to study the post-mortem appearance of Spinal Cord Multiple Sclerosis in relation to HistoPathology and low-resolution images.
Fifty-nine 3 cm long formalin-fixed Spinal Cord specimens from 19 Multiple Sclerosis patients and three controls were studied. Clinical characteristics of each patient were reviewed.
High-field MRI consisted of Proton-Density weighted Spin-Echo imaging with an in-plane resolution of 80 mum. Specimens were also imaged at 1.0 T, with 1 mm pixel resolution.
After MRI, the specimens were cut at 5 mm intervals and stained for Myelin (Luxol fast blue/cresyl violet) and Axons (Bodian method).
Two observers scored the MRIs for abnormalities and divided them into:
- Cell-delineated areas of high Signal Intensity (SI)
- Poorly defined areas of mildly increased SI
Abnormalities were scored semiquantitatively, White Matter and Gray Matter separately. In 81 sections the total area of abnormalities per section was measured on both HistoPathology sections and on matched high-field MRIs.
Abnormalities ranged from just a few abnormal areas to complete involvement of the Spinal Cord specimen. Patients with an aggressive disease course had more abnormalities than patients with a mild or intermediate disease course.
Areas of mildly increased SI were seen in all specimens, and were often found around Focal high-SI lesions. However, in six patients, areas of mildly increased SI were the predominant finding on the MRIs, correlating with a Primary/Progressive disease course.
HistoPathologically, high-SI areas correlated with complete DeMyelination, while mildly increased SI corresponded with partial DeMyelination.
All areas scored as abnormal by the NeuroPathologist were also found on the MRIs, and sizes measured using both methods correlated well (r = 0.85, P: < 0.01).
On conventional MRIs, abnormalities could be recognized fairly well. However, better differentiation could be made between high-SI and mildly increased SI abnormalities on the 4.7 T images.
In conclusion, high-resolution MRI revealed a great range of abnormalities in Spinal Cord Multiple Sclerosis, which related to disease course during life.
Furthermore, we found very good correlation between the extent of abnormalities shown by HistoPathology and the SI changes on Proton-Density MRIs, mainly relating to DeMyelination revealed HistoPathologically.
Multiple Sclerosis With Very Late Onset
A report of a case with onset at age 82 years and review of the literature
Abe M, Tsuchiya K, Kurosa Y, Nakai O, Shinomiya K
J Spinal Disord 2000 Dec;13(6):545-9
Tokyo Medical and Dental University, Dept of Orthopaedic Surgery, Kudanzaka Hospital, Tokyo, Japan
PMID# 11132990; UI# 21019041
This is a report of a patient with late-onset Multiple Sclerosis at age 82 years. The lesion involved was located on the Spinal Cord.
Multiple Sclerosis mainly affects young adults, making late onset of Multiple Sclerosis a rarity, particularly for cases after age 80 years.
Common characteristics of late-onset Multiple Sclerosis reported in other publications are predominant involvement of the Spinal Cord and a progressively worsening course with a serious prognosis.
In this case, Magnetic Resonance Imaging revealed a large area of high signal intensity in the Cervical and upper Thoracic Spinal Cord on T2-weighted images.
An increased ImmunoGlobulin G level in CerebroSpinal Fluid also played a diagnostic role in ruling out Cervical Spondylotic Myelopathy.
Spontaneous improvement occurred 2 months after the onset. Unlike other patient described in the literature, the clinical course of this man was not as bleak.