Cytokines and immunity in multiple sclerosis: the dual signal hypothesis.
Multiple sclerosis (MS) is considered an immune-mediated disease of the central nervous system (CNS) sustained by a chronic inflammatory process leading to patchy demyelination and axonal loss. However, the inflammatory triggering event as well as the target of the pathogenic process in MS are still partially unknown. We report evidence that a 'local' inflammatory process occurring in the CNS (considered as a reaction of blood vessels in vascularized living tissue to a local injury leading to the accumulation of fluid and blood cells) along with a concomitant, but possibly unrelated, peripheral inflammatory event may trigger a CNS-specific autoimmune reaction cascade sustaining the MS pathogenesis. In the CNS, inflammatory mediators (mainly cytokines) act either as regulatory (i.e. activation of glial cells, shaping the autoimmune response) or effector molecules (i.e. myelinotoxicity, oligodendrotoxicity). In the periphery, inflammatory cytokines induce, in a bystander fashion, activation of monocytes and T cells. Among this latter cell population there are myelin-specific T cells belonging to the normal 'autoimmune' repertoire that home to the CNS where they may trigger the continuous recruitment of effector cells (macrophages) from the periphery. The concept that two concomitant, but possibly unrelated, inflammatory events, occurring in the CNS and in the periphery, represent the crucial elements sustaining MS, might reveal a more comprehensive view (dual signal hypothesis) of the entire etiopathogenic process underlying this disease.
Martino
G
G
Neuroimmunology Unit, DIBIT, San Raffaele Scientific Institute, Via Olgettina 58, 20132, Milano, Italy. g.martino@hsr.it
Furlan
R
R
Brambilla
E
E
Bergami
A
A
Ruffini
F
F
Gironi
M
M
Poliani
P L
PL
Grimaldi
L M
LM
Comi
G
G
D000818:Animals; D001921:Brain / Q000276:immunology; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000209:etiology; D018836:Inflammation Mediators / Q000502:physiology; D008213:Lymphocyte Activation; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D016207:Cytokines; D018836:Inflammation Mediators