What Is The Pathogenic Role Of Inflammation In Ms

Proven MS Treatment By Dr Gary

Multiple Sclerosis Free Forever

Get Instant Access

Focal areas of myelin destruction observed in MS occur on a background of an inflammatory process dominated by the infiltration of T-lymphocytes, recruitment of hematogenous macrophages, the local activation of microglia, and the presence of relatively few B-lymphocytes or plasma cells (Figure 5). This inflammatory reaction is associated with the upregulation of a variety of cytokines within the MS

Figure 5 (See color insert.) Inflammation in multiple sclerosis lesions. The inflammatory infiltrate within an active multiple sclerosis lesion contains variable numbers of perivascular and parenchymal CD3+ T-lymphocytes (A), cytotoxic CD8+ T-lymphocytes (B), macrophages (C; KiMIP), CD20+ B-lymphocytes (D), and plasma cells (H&E).

Figure 5 (See color insert.) Inflammation in multiple sclerosis lesions. The inflammatory infiltrate within an active multiple sclerosis lesion contains variable numbers of perivascular and parenchymal CD3+ T-lymphocytes (A), cytotoxic CD8+ T-lymphocytes (B), macrophages (C; KiMIP), CD20+ B-lymphocytes (D), and plasma cells (H&E).

lesion, including interleukin-1,2,4,6,10,12, gamma-interferon (y-IFN), tumor necrosis factor alpha (TNF-a), and transforming growth factor beta (TGF-p) (16,17). Activated endothelial cells in active lesions express adhesion molecules, fibronectin, urokinase plasmin activator receptor, major histocompatibility complex (MHC) molecules, chemokines and their receptors, and stress proteins (18). In some MS patients, immunodominant peptides of MBP become complexed with DR2 molecules at sites of demyelination (19), and T-cell clones with receptors specific for MBP have been found in MS lesions (20). These observations, coupled with the pathologic similarities between MS and experimental autoimmune encephalomyelitis (EAE), suggest that MS is an autoimmune disease, initiated by MHC-class II-restricted CD4+ Th1 lymphocytes that produce pro-inflammatory Th1 cytokines. This leads to the recruitment and activation of hematogenous macrophages, which destroy myelin sheaths, either via toxic effectors or in co-operation with specific autoantibodies. The expression of these immune-associated molecules, however, is not specific for MS and can be seen in other T-cell driven processes of the nervous system, such as viral infections. Furthermore, the evidence that MS is a Th1-mediated disease remains indirect and circumstantial. Therapeutic strategies that are beneficial in EAE have often yielded ineffective, or at times, unexpected aggravation of MS (21). A likely explanation for this discrepancy may be that the pathogen-esis of MS is more complex when compared with that of a pure Th1-mediated CNS autoimmune disease. Cells other than classical Th1 T-cells may contribute to MS pathology.

There is accumulating evidence that MHC class I-restricted T-cells may play an important role. The inflammatory infiltrates in MS lesions are dominated by class I MHC restricted CD8+ T-lymphocytes (13), and clonal expansions of T-lymphocytes are more pronounced for CD8+ compared with CD4+ T-lymphocytes (22). Myelin-specific CD8+ T-cells may even evoke EAE under certain conditions (23,24). Because antigen recognition by CD8+ T-lymphocytes requires the presentation of respective peptides in the context of MHC class I molecules, the expression of these molecules is most pronounced in acute lesions, followed by chronic active lesions and inactive lesions. Overall, all MS patients show more MHC class I expression compared with controls (25). Double staining and confocal laser microscopy reveals that in active MS lesions, class I expression is present not only on inflammatory cells, microglia, and endothelial cells, but also on astrocytes, oligodendrocytes, and some neurons and axons (25). These data suggest that all cell types in active MS lesions may become targets for class I restricted T-cell cytotoxicity (26). In support of these observations, axonal destruction in MS lesions correlates better with CD8+ T-cells and macrophages than CD4+ T-cells (27).

There is also evidence that Th2 cells can participate in pathologic autoimmune processes. Th2 polarized T-cells, directed against MBP, have been shown to induce destructive brain inflammation in immunodeficient mice (28). Similarly, circulating Th2 cells could drive the formation of antibodies in both MOG and MBP (29), which are present in MS lesions and in the serum of MS patients (30,31).

Despite the universal presence of inflammation in MS lesions, the pathogenic role of the inflammatory response is not clear. Neuropathologic studies reveal that inflammatory cells are not always present in areas of active demyelination, and persistent inflammation is a frequent and typical feature of chronic inactive MS lesions. In addition, active demyelination has been observed in immuno-suppressed patients with little or no evidence of perivascular inflammation in the lesions (32). Finally, the abundance of inflammation in inactive cases, together with recent observations on the local production of neurotrophic factors, such as brain-derived neurotrophic factor by leukocytes, may indicate an important role for inflammation in the repair of MS lesions (33). Interestingly, neurotrophin receptors are expressed on glial cells and neurons in or near actively demyelinating MS lesions (34). Autoimmune T-cells can protect optic nerve neurons after crush injury (35). Macrophages stimulate remyelination in tissue culture (36), while depletion of macrophages is associated with diminished remyelination (37). Therefore, there is likely a delicate balance between pathogenic and reparative factors that determine the final outcome of the MS lesion. Conceivably, the complete blockage of all inflammatory responses in the MS lesion could be counterproductive.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book

Post a comment