Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis.
Epidemiological studies indicate that infectious agents are important in the pathogenesis of multiple sclerosis (MS). Our previous reports showed that the infection of SJL mice with a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV) engineered to express a naturally occurring Haemophilus influenzae-encoded molecular mimic (HI574-586) of an immunodominant self-myelin proteolipid protein epitope (PLP139-151) induced a rapid-onset demyelinating disease associated with the activation of PLP139-151-specific Th1 responses. The current results extend our previous findings in four critical respects. We show that disease initiation by the H. influenzae mimic is prevented by tolerance to the self PLP139-151 epitope, definitively proving the occurrence of infection-induced molecular mimicry. We demonstrate that the H. influenzae mimic epitope can be processed from the flanking sequences within the native mimic protein. We show that the H. influenzae mimic epitope only induces an immunopathologic self-reactive Th1 response and subsequent clinical disease in the context of the TMEV infection and not when administered in complete Freund's adjuvant, indicating that molecular mimicry-induced disease initiation requires virus-activated innate immune signals. Lastly, we show that the infection of SJL mice with TMEV expressing the H. influenzae mimic can exacerbate a previously established nonprogressive autoimmune disease of the central nervous system. Collectively, these findings illustrate the evolving mechanisms by which virus infections may contribute to both the initiation and exacerbation of autoimmune diseases, and they have important implications for MS pathogenesis.
Croxford
J Ludovic
JL
Department of Microbiology and Immunology and Interdepartmental Immunobiology Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, Illinois 60611, USA.
Olson
Julie K
JK
Anger
Holly A
HA
Miller
Stephen D
SD
D000595:Amino Acid Sequence; D000818:Animals; D001327:Autoimmune Diseases / Q000453:epidemiology / Q000821:virology; D018076:DNA, Complementary / Q000235:genetics; D003711:Demyelinating Diseases / Q000453:epidemiology / Q000821:virology*; D005260:Female; D007108:Immune Tolerance; D051379:Mice; D008815:Mice, Inbred Strains; D018716:Molecular Mimicry / Q000276:immunology; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000453:epidemiology / Q000821:virology*; D010446:Peptide Fragments / Q000737:chemistry
D018076:DNA, Complementary; D010446:Peptide Fragments