Pathogenesis of multiple sclerosis.
OBJECTIVE
The aim of this article is to describe recent observations regarding the basis for the initiation and disease evolution of multiple sclerosis.


RESULTS
A current debate is where and what initiates the neuroinflammatory reaction that characterizes the acute multiple sclerosis lesion. Immune sensitization to neural antigens could develop within the systemic compartment consequent to exposure to cross-reacting, possibly viral derived, peptides (molecular mimicry). Although CD4 T cells are considered central to initiating central nervous system inflammation, the actual extent and specificity of tissue injury reflects the array of adaptive (CD8 T cells and antibody) and innate (microglia/macrophages) immune constituents present in the lesions. Neuropathologic studies indicate that lethal changes in neural cells (oligodendrocytes) could also be the initiating event, reflecting as yet unidentified acquired insults (e.g. exogenous virus or reactivated endogenous retrovirus) or intrinsic abnormalities ('neurodegenerative' hypothesis). Recurrence or persistence of the disease process can reflect events occurring at multiple sites including expansion of the immune repertoire in response to neural antigens transported to regional lymph nodes (determinant spreading), especially if immune regulatory mechanisms are defective; alterations in blood-brain barrier properties consequent to initial cellular transmigration; and participation of endogenous (microglia, astrocytes) or long lived infiltrating cells (macrophages, B cells in ectopic germinal centers) in regulating and effecting immune functions within the central nervous system. Accumulating neurologic deficit reflects the balance between injury and repair; the latter also being negatively or positively (trophic support and clearance of tissue debris) impacted by inflammatory processes.


CONCLUSIONS
Understanding the full spectrum of multiple sclerosis presents a continuing challenge for both immunology and neurobiology.
Prat
Alexandre
A
Neuroimmunology Laboratory and Multiple Sclerosis Clinic, CHUM Notre-Dame Hospital, Montreal, Quebec, Canada.
Antel
Jack
J
D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology*