http://id.medscape.com/reuters/prof/2001/07/07.30/20010727scie001.html
Virus-Induced
Multiple Sclerosis Supports Molecular Mimicry Model
WESTPORT, CT (Reuters Health) Jul 27 - A
virus-induced model of multiple sclerosis in mice supports molecular mimicry as
a mechanism for infection-induced autoimmunity, according to a report in the
July issue of the Journal of Clinical Investigation.
Molecular mimicry, in which autoreactive T cells are activated secondary to
an encounter with a pathogen bearing epitopes cross-reactive with self
antigens, is the main postulated mechanism by which infections might trigger
autoimmune tissue damage, the authors explain.
Dr. Stephen Miller and colleagues, from Northwestern University Medical
School, in Chicago, Illinois, constructed a nonpathogenic virus encoding a
sequence encompassing the encephalitogenic myelin proteolipid protein
(PLP139-151) epitope to study the potential of virus-induced molecular mimicry
to induce autoimmune demyelination in mice.
Mice infected with the engineered virus developed severe clinical signs of
demyelinating disease within 7 to 10 days of infection, the authors report,
significantly earlier than seen in the standard multiple sclerosis model.
Similarly, engineered viruses containing substitutions at the secondary
T-cell receptor recognition site (H147A) caused a similar early-onset disease,
the report indicates, though viruses with substitutions at the primary T cell
receptor recognition site (W144A) exhibited a delayed-onset disease course.
Spinal cords from mice infected with virus containing PLP139-151 or H147A
showed areas of infiltrating immune cells and demyelination at 14 days, the
researchers note, whereas spinal cords from mice infected with W144A-containing
virus did not.
Moreover, clinically affected mice infected with the PLP139-151 virus
developed CD4+ T-cell responses cross-reactive with PLP139-151 early in the
course of infection, the results indicate, as did mice infected with the H147A
virus.
PLP139-151-specific CD4+ T cells from mice with early-onset demyelinating
disease showed a Th1 profile, secreting IFN-gamma and TNF-alpha at 28 days, the
investigators observe.
In addition, mice infected with virus expressing a bacterial mimic of
PLP139-151 (from Hemophilus influenzae) developed early clinical disease along
with cross-reactive CD4+ Th1 responses, the report indicates.
"The findings are to our knowledge the first real demonstration that
infection with a virus encoding mimics of a self antigen can induce a CNS
autoimmune disease by inducing T cells, which crossreact with myelin
antigens," Dr. Miller told Reuters Health.
"As such, the findings indicate in an experimental animal model of MS
that autoimmune induction via molecular mimicry is possible, but don't prove
that it actually takes place in the human disease," he continued.
"The results suggest that treatments aimed at specific regulation (ie,
immune tolerance induction) of the autoreactive T cells is the best method to
treat the disease," Dr. Miller added. "In fact, our follow-up paper
(in preparation) shows that induction of tolerance to the native mouse
PLP139-151 epitope can inhibit the induction of the disease induced by
infection with the Theiler's virus encoding the mimic H. influenzae
epitope."
J Clin Invest 2001;108:311-318.