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.
Copyright © 2001 Reuters Ltd
Copyright © 2001 Reuters Ltd