Restricted immune responses lead to CNS demyelination and axonal damage.
Although autoreactive T-cells have a pivotal role in initiating the inflammatory process in experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS), recent evidence suggests a relevant role for autoantibodies specific for myelin proteins as well. To examine the role of B-cells in the cerebrospinal fluid of patients with MS, we analyzed the V(H) gene usage in ten MS patients by PCR technologies. Analysis of HCDR3 length revealed an oligoclonal accumulation of B-cells. Sequence analysis of the V(H)3 and V(H)4 gamma transcripts of two MS individuals demonstrated that this accumulation was related to the expansion and somatic diversification of a limited groups of B-cell clones. These findings are indicative of a chronic and intense antigenic stimulation occurring in the CNS. Animal models, such as EAE, are of particular importance in order to elucidate the pathogenetic effector mechanisms in autoimmune demyelination. In a non-human primate model of EAE, we describe that the immunodominant T-cell epitope is presented exclusively by a monomorphic DRB1 allele, suggesting that susceptibility to EAE may be linked to this unique restriction and, therefore, providing a possible mechanism for MHC linkage to diseases. Moreover, we report on the presence of inflammation, sharp demyelination and axonal damage in EAE induced with whole myelin as well as with recombinant myelin oligodendrocyte glycoprotein (MOG), but not with myelin basic protein alone. The presence of axonal pathology was supported by immunohistochemistry with anti-amyloid precursor protein and anti-non phosphorilated neurofilaments monoclonal antibodies within early active demyelinated plaques. These findings suggest that axonal damage may be an early event in the pathogenesis of autoimmune demyelinating diseases of the CNS and highlights the importance of animal models in which therapies targeting repair and axonal survival may be exploited.
Mancardi
G
G
Department of Neurological Sciences and Vision, University of Genova, Via De Toni 5, 16132, Genoa, Italy. neurolab@cisi.unige.it
Hart
B A
BA
Capello
E
E
Brok
H P
HP
Ben-Nun
A
A
Roccatagliata
L
L
Giunti
D
D
Gazzola
P
P
Dono
M
M
Kerlero de Rosbo
N
N
Colombo
M
M
Uccelli
A
A
D000818:Animals; D001369:Axons / Q000276:immunology* / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology*