Markers For Different Glial Cell Responses In Multiple Sclerosis: Clinical And Pathological Correlations
Petzold A, Eikelenboom MJ, Gveric D, Keir G, Chapman M, Lazeron RH, Cuzner ML, Polman CH, Uitdehaag BM, Thompson EJ, Giovannoni G
Brain 2002 Jul;125(Pt 7):1462-73
Institute of Neurology, Department of NeuroInflammation, Queen Square, London, UK; and VU Medical Center, Department of Neurology, Amsterdam, The Netherlands
PMID# 12076997; UI# 22071585
Disease progression in Multiple Sclerosis occurs within the interface of Glial activation and Gliosis.
This study aimed to investigate the relationship between biomarkers of different Glial Cell responses to:
- Disease dynamics and the clinical subtypes of Multiple Sclerosis
- Cross-validate these findings in a post-mortem study
To address the first goal, 51 patients with Multiple Sclerosis [20 Relapsing/Remitting (RR), 21 Secondary/Progressive (SP) and 10 Primary/Progressive (PP)] and 51 Neurological control patients were included.
Disability was assessed using the Ambulation Index (AI), the Expanded Disability Status Scale score (EDSS) and the 9-Hole PEG Test (9-HPT). Patients underwent Lumbar Puncture within 7 days of clinical assessment.
Post-mortem Brain tissue (12 Multiple Sclerosis and eight control patients) was classified Histologically and adjacent sites were homogenized for protein analysis.
S100B, Ferritin and Glial-Fibrillary Acidic Protein (GFAP) were quantified in CSF and Brain-tissue homogenate by ELISA (Enzyme-Linked Immunosorbent Assay) techniques developed in-house.
There was a significant trend for increasing S100B levels from PP to SP to RR Multiple Sclerosis (P < 0.05).
S100B was significantly higher in RR Multiple Sclerosis than in control patients (P < 0.01), while Ferritin levels were significantly higher in SP Multiple Sclerosis than in control patients (P < 0.01).
The S100B : Ferritin ratio discriminated patients with RR Multiple Sclerosis from SP, PP or control patients (P < 0.05, P < 0.01 and P < 0.01, respectively).
Multiple Sclerosis patients with poor Ambulation (AI >/=7) or severe disability (EDSS >6.5) had significantly higher CSF GFAP levels than less disabled Multiple Sclerosis or control patients (P < 0.01 and P < 0.001, respectively).
There was a correlation between GFAP levels and Ambulation in SP Multiple Sclerosis (r = 0.57, P < 0.01), and between S100B level and the 9-HPT in PP Multiple Sclerosis patients (r = -0.85, P < 0.01).
The post-mortem study showed significantly higher S100B levels in the acute than in the subacute plaques (P < 0.01), while Ferritin levels were elevated in all Multiple Sclerosis lesion stages.
Both GFAP and S100B levels were significantly higher in the Cortex of Multiple Sclerosis than in control Brain homogenate (P < 0.001 and P < 0.05, respectively).
We found that S100B is a good marker for the Relapsing phase of the disease (confirmed by post-mortem observation) as opposed to Ferritin, which is elevated throughout the entire course.
GFAP correlated with Disability Scales and may therefore be a marker for irreversible damage.
The results of this study have broad implications for finding new and sensitive outcome measures for treatment trials that aim to delay the development of Disability. They may also be considered in future classifications of Multiple Sclerosis patients.
Pender MP, Rist MJ.
Glia 2001 Nov;36(2):137-44
University of Queensland, Department of Medicine, Brisbane, Australia
The elimination of inflammatory cells within the Central Nervous System (CNS) by Apoptosis plays an important role in protecting the CNS from Immune-mediated damage. T-Cells, B-Cells, Macrophages, and Microglia all undergo Apoptosis in the CNS.
The Apoptotic elimination of CNS-reactive T-Cells is particularly important, as these cells can recruit and activate other Inflammatory Cells.
T-Cell Apoptosis contributes to the resolution of CNS inflammation and clinical recovery from attacks of Experimental AutoImmune Encephalomyelitis (EAE), an animal model of the DeMyelinating Disease Multiple Sclerosis (MS).
T-Cell Apoptosis in the CNS in EAE occurs in both an Antigen-specific and an Antigen-nonspecific manner. In Antigen-specific T-Cell Apoptosis, it is proposed that T-Cells that recognize their Antigen in the CNS.
Such as CNS-reactive T-Cells, are deleted by the process of activation-induced Apoptosis after activation of the T-Cell Receptor.
This may result from the Ligation of T-Cell Death Receptors (such as CD95 (Fas) or Tumor Necrosis Factor (TNF) Receptor 1) by CD95 Ligand (CD95L) or TNF expressed by the same T-Cell or possibly by Microglia, Astrocytes or Neurons.
Inadequate Costimulation of the T-Cell by Antigen-Presenting Glial Cells may render T-Cells susceptible to activation-induced Apoptosis.
T-Cells expressing CD95 may also die in an Antigen-nonspecific manner after interacting with Glial Cells expressing CD95L.
Other mechanisms for Antigen-nonspecific T-Cell Apoptosis include the endogenous release of GlucoCorticoSteroids, deprivation of InterLeukin-2, and the release of Nitric Oxide by Macrophages or Glia.
Apoptosis of AutoReactive T-Cells in the CNS is likely to be important in preventing the development of AutoImmune CNS diseases such as MS.
Copyright 2001 Wiley-Liss, Inc.
Immune Function Of Microglia
Glia 2001 Nov;36(2):165-79
Istituto Superiore di Sanita, Laboratory of Organ and System Pathophysiology, NeuroPhysiology Unit, Roma, Italy
During the past decade, mechanisms involved in the Immune surveillance of the Central Nervous System (CNS) have moved to the forefront of NeuroPathological research.
Mainly because of the recognition that most Neurological Disorders involve activation and, possibly, dysregulation of Microglia, the intrinsic Macrophages of the CNS.
Increasing evidence indicates that, in addition to their well-established Phagocytic function, Microglia may also participate in the regulation of non specific inflammation as well as Adaptive Immune Responses.
This article focuses on the signals regulating Microglia Innate Immune Functions, the role of Microglia in Antigen presentation, and their possible involvement in the development of CNS ImmunoPathology.
Copyright 2001 Wiley-Liss, Inc.
NeuroInflammation In The Rat CNS Cells And Their Role In Regulation Of Immune Reactions
Piehl F, Lidman O
Immunol Rev 2001 Dec;184:212-25
Karolinska Hospital, NeuroImmunology Unit, Department of Medicine, Stockholm, Sweden
Recent discoveries suggest that the resident cells of the Central Nervous System (CNS) the Nerve Cells and Glia, play a more Immunologically active role than was previously assumed.
NeuroGlial communication is of central interest in virtually all types of pathological conditions that affect the Brain and several features of the activation that results from Nerve Cell damage resemble the type of Innate Immune Reactions that occur in other parts of the body.
In particular, the characteristics of the activation of these CNS cells will affect both the interaction with cells of the Immune System as well as processes related to NeuroDegeneration and Regeneration.
We here review data regarding 3 different aspects of local inflammatory activation in the rat Nervous System:
- The genetic heterogeneity of Glial activation across inbred strains after Nerve injury
- Expression of MHC Class I Genes in the CNS
- NeuroProtective effects of CNS Antigen AutoReactive Immune reactions
Apart from NeuroImmune Diseases such as Experimental AutoImmune Encephalomyelitis & Multiple Sclerosis, these features are also of relevance for a wider range of Neurological Diseases which present pathological signs of inflammation, such as Alzheimer's Dementia, CerebroVascular Diseases and CNS Trauma.
Role Of Central Nervous System MicroVascular Pericytes In Activation Of Antigen-Primed Splenic T-Lymphocytes
Balabanov R, Beaumont T, Dore-Duffy P
J NeuroSci Res 1999 Mar 1;55(5):578-87
Wayne State University, School of Medicine, Department of Neurology, and; Detroit Medical Center, Michigan 48201, USA
The cellular constituents of the Blood-Brain Barrier (BBB) must make finely tuned, regulatory responses to maintain MicroVascular Homeostasis. The mechanisms by which this task is accomplished are largely unknown.
However, it is thought they involve a series of cross-talk mechanisms among Endothelial Cells (EC), Pericytes (PC), and Astrocytes.
During inflammation, the BBB is exposed to a number of Biological Response modifiers including Cytokines released by infiltrating Leukocytes.
The response to inflammatory Cytokines may alter the normal regulatory function of EC and PC. These changes may account for some of the pathological findings in Central Nervous System (CNS) Inflammatory Disease.
Previous studies have shown that PC and EC may have Immune potential. We have investigated the response of the PC to a variety of ProInflammatory Cytokines.
Primary rat PC constitutively express low levels of InterCellular Adhesion Molecule-1 (ICAM-1) and Major Histocompatibility Complex (MHC) Class I molecule.
Which can be upregulated in response to the Cytokine Interferon-gamma (IFN-γ). IFN-γ also induced the expression of MHC Class II molecule.
After induction of MHC Class II molecule, CNS PC acquired the capacity to present Antigen to primed syngeneic rat T-Lymphocytes. Antigen presentation by PC was comparable to that seen with classic Antigen-Presenting Cells.
A small number of primary PC constitutively express low levels of Vascular Cell Adhesion Molecule-1 (VCAM-1), which was increased on exposure to Tumor Necrosis Factor-alpha (TNF-).
Results suggest that CNS PC respond to Inflammatory Cytokines, are involved in T-Lymphocyte activation, and express Cell Surface Adhesion Molecules (VCAM-1, ICAM-1).
That may provide costimulatory activity. It is likely that CNS PC are important in NeuroImmune Networks at the BBB.
The Remedy May Lie In Ourselves: Prospects For Immune Cell Therapy In Central Nervous System Protection And Repair
Schwartz M, Cohen I, Lazarov-Spiegler O, Moalem G, Yoles E.
Journal of Molecular Medicine 1999 Oct;77(10):713-7
The Weizmann Institute of Science, Department of NeuroBiology, Rehovot, Israel
The irreversible loss of function after Axonal injury in the Central Nervous System (CNS) is a result of the lack of NeuroGenesis, poor regeneration, and the spread of damage.
Caused by toxicity emanating from the degenerating Axons to uninjured Neurons in the vicinity.
Now, 100 years after Ramon y Cajal's discovery that CNS Neurons - unlike Neurons of the Peripheral Nervous System - fail to regenerate, it has become evident that:
- CNS tissue is indeed capable of regenerating, at least in part,
- provided it acquires appropriate conditions for growth support
- The spread of damage can be stopped
- The PostInjury rescue of Neurons thus achieved
- If ways are found to neutralize the mediators of toxicity either by
- inhibiting their action
- or increasing tissue resistance to them
In most physiological systems the processes of tissue maintenance and repair depend on the active assistance of Immune Cells. In the CNS, however, communication with the Immune System is restricted.
The accumulated evidence from our previous studies suggests that the poor PostTraumatic repair and maintenance in the CNS is due at least in part to this restriction.
Key factors in the recovery of injured tissues, but missing or deficient in the CNS, are the processes of recruitment and activation of Immune Cells.
We therefore propose the development of Immune Cell therapies in which the injured CNS is exogenously provided with an adequate number of appropriately activated Immune Cells:
Macrophages for regrowth and AutoImmune T-Cells for maintenance controlled in such a way as to derive maximal benefit with minimal risk of disease.
It is expected that these self-adjusting cells will communicate with the damaged tissue, monitor tissue needs, and control the dynamic course of CNS healing.