Multiple Sclerosis
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Lectures:   Etiology








 
  • Autoimmune Causes

In MS immune dysfunction can be detected locally in CNS & CSF as well as systemically in peripheral circulation (Table 1) Autoimmune nature of MS has long been suspected. It is known that patients with MS have inflammation and demyelination in their CNS and oligoclonal bands in their cerebrospinal fluid. These abnormal immunoglobulins are identified in a high percentage of patients with clinically definite MS during exacerbations of relapsing-remitting disease, or persistently in significant proportion of chronic-progressive patients. A dysregulated immune system no longer prevents memory T-cells from becoming activated against myelin, entering the CNS, and mediating damage associated with the disease.

Immunologic abnormalities in CSF, whole blood and serum in MS patients:
Cerebrospinal FluidSerumBlood
Increased IFN-gammaIncreased IFN-gammaIncreased IFN-gamma
Increased IgG and oligoclonal bandsIncreased TNFIncreased IL-2
Increased TNFIncreased IL-2Increased IL-4
Increased activated CD4+ cellsIncreased IL-2 receptorsIncreased IL-1
 Decreased PGE-2 release by macrophages 
 Decreased CD8+ 


Abbreviations:

IFN-gammainterferon gamma
IgG immunoglobulin G
TNFTumor necrosis factor alpha or alpha & beta;
CD4+MHC class II restricted T-cells
CD8+ MHC class I restricted T-cells
IL-2, IL-4, IL-1interleukins
PGE2prostaglandin E


The inflammatory response in MS consists of predominantly lymphocytic and mononuclear cells. A number of T-cell receptors and their recognition of antigens combined with Major Histocompatibility Complex Class II molecules (Trimolecular Complex) have been studied. Particularly interesting were investigations on the response of T-lymphocytes from patients with MS for reactivity with Myelin Basic Protein (MBP). However, no specific oligoclonality was found to help differentiate patients with MS. However, it remains possible that other myelin proteins such as myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), and others may also play a role in pathogenesis of MS.

MS also has been associated with certain Human Leukocyte Antigen (HLA). Different HLA associations are reported within ethnic groups and some associations remain very stable in patients with MS. It is confirmed that MHC molecules may contribute to genetic susceptibility to the disease. DR2, DR(1*1501), DQ(1*602), DQA102 and the DW2 haplotype are frequently associated with multiple sclerosis.





 
  • Viral Causes

Infectious agents have been proposed as inciters of the MS. Some viral isolates have been found in the CNS of the patients with MS. However, this data is not consistent and thus far there has not been a viral protein or a group of viruses reliably identified in the CSF of patients with MS.

There is a considerable interest in a theory that exposure to a virus may lead to immunopathologic condition resulting in MS. One possible explanation for this is molecular mimicry between viral and CNS proteins so that antiviral response is mediated against myelin. "Molecular mimicry" means shared molecular homology between viral proteins and some normal human proteins. In MS, homology between viral peptides and myelin antigens is established. Viral persistency, latency and periodic inactivation could be of possible significance. A recent investigation suggests that HHV6 (Roseola virus) is associated with areas of demyelination in MS patients. Viral infections also are known to provoke relapses of the disease.

Another possibility is that autoimmunity results from super antigenic stimulation of T-cells by viral or bacterial proteins. Super antigens may bind to specific T-cell receptor proteins, producing non-specific stimulation of a large number of T-cells. This may result in clonal expansion of T-cells reactive to myelin or oligodendrogliocyte antigens.





 
  • Illustrations