Pathology Suggests An Autoimmune Etiology

MS tissue pathology suggests an immune-driven reaction to a myelin antigen. The pathology indicates a complex disorder that involves all arms of the immune system including cellular immunity, humoral immunity, and complement (8,9). Structures of the nervous system other than myelin, such as the axon and the oligodendrocyte cell body, may be lost or injured, thus making it difficult to identify the initial target. Even at very early stages, MS lesions demonstrate axonal as well as myelin damage (10). The pathology in MS appears to be heterogeneous (9), signifying variation in the innate immune response(s) and/or the inciting event(s).

Active MS lesions are characterized by immune cell infiltration, predominantly by T-cells and macrophages (11), as well as the presence of immune mediators such as adhesion molecules, chemokines, cytokines, and matrix metalloproteinases (MMPs). CNS vascular endothelium from MS patients expresses surface antigens such as ICAM-1, VCAM-1, E-selectin, and MHC II, all of which facilitate leukocyte adhesion and migration from the peripheral blood into the CNS (12). MHC II-associated antigens, essential for T-cell activation, have also been demonstrated on astrocytes within acute, chronic, and silent plaques (13-15). MMPs are enzymes that contribute to the breakdown of the extracellular matrix, facilitating trafficking of immune cells through the neuropil (16). MMPs may also be directly toxic to CNS structures (17). Histologic studies have noted that endothelial cells in MS lesions express MMP-3 and -9. Messenger RNA expression for MMP-7 and -9 is upregulated throughout the brain of MS patients (18). Macrophages in active lesions express MMP-1, -2, -3, -7, -9, and -12 (19-21). Studies of serum and CSF show increased expression of MMP-9 (22-25) during MS disease activity.

Many different chemokines, including IP-10 and Mig, have been found within the MS plaque. Some macrophages and CD3+ T-cells within MS-affected CNS express the CXCR3 receptor for these chemokines (26,27). CXCR3 positive T-cells are increased in CSF during relapses (28,29). CCR1 and CCR5 positive cells have been found in some MS lesions (30). One study suggested that primary progressive

MS patients have higher CCR5 mRNA expression by peripheral blood mononuclear cells than other forms of MS, but the surface protein expression of CCR5 on CD4+ T-cells from PBMC was similar in all MS subtypes and in controls (31). Both "pro-" inflammatory (IL-2, IFNy, TNFa and-) and "anti-" inflammatory (TGF-p, IL-4, IL-10) cytokines are expressed by infiltrating cells, astrocytes, and microglia within MS lesions (32-35). The presence of both Thl and Th2 cytokines in active and chronic lesions suggest a finely orchestrated response of the immune system to some unknown stimulus. Activated macrophages are a prominent component of the MS lesion (36,37), and can be seen adjacent to the axon apparently stripping it of myelin (38,39). Antibodies and complement that coat myelin in some MS lesions have been implicated as opsonins in this phagocytic process (38,40).

Although MS pathology does not prove an autoimmune cause of MS, it confirms that the immune system plays a central role in the disease process. It also reveals that immune system activity continues for decades in the absence of a recognizable pathogen. The animal model, EAE, which is autoimmune and initiated by T-cells, mimics MS in many aspects of the gross and microscopic pathology.

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