title: Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry.
abstract: Molecular mimicry is the main postulated mechanism by which infectious agents induce autoimmune disease. A number of animal models have been utilized to establish a link between molecular mimicry and autoimmunity. However, a model of infectious disease whereby a natural pathogen expressing a known mimic epitope can induce autoimmunity to a known self-antigen leading to clinical autoimmune disease is still lacking. We have engineered a recombinant Theiler's murine encephalomyelitis virus (TMEV) to express an encephalitogenic myelin proteolipid protein PLP139-151 epitope (PLP-TMEV) and a PLP139-151 mimic peptide naturally expressed by Haemophilus influenzae (HI-TMEV). Infection of mice with either PLP-TMEV or HI-TMEV induces early-onset disease that is associated with the activation of cross-reactive PLP139-151-specific immunopathologic CD4+ Th1 cells. Based on results from this model, we hypothesize, due to the considerable degeneracy in the T cell repertoire, that induction of full-blown autoimmune disease via molecular mimicry is a tightly regulated process requiring multiple factors related to the pathogen expressing the potential mimic epitope. In this review, we will discuss how various factors related to the infectious environment control whether or not autoimmune disease is initiated. Contributing factors include the nature of the innate immune response to the pathogen which determines the immunopathologic potential of the induced cross-reactive T cells, the capacity of the mimic epitope to be processed and presented from its natural flanking sequences in the pathogen-encoded protein, the site(s) of the primary infection in the host and the ability of the pathogen to persist, and the potential requirement for multiple infections with the same or different pathogens.
authors.affiliation: Department of Microbiology-Immunology and the Interdepartmental Immunobiology Center, Feinberg School of Medicine, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA.
authors.forename: Julie K
authors.initials: JK
authors.lastname: Olson
authors.forename: J
authors.initials: J
authors.lastname: Ludovic Croxford
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Miller
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D003141:Communicable Diseases / Q000150:complications / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D020278:Demyelinating Autoimmune Diseases, CNS / Q000209:etiology / Q000276:immunology*; D006801:Humans; D018716:Molecular Mimicry; D009103:Multiple Sclerosis / Q000209:etiology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology