Elsevier

Molecular Immunology

Volume 40, Issues 14–15, February 2004, Pages 1103-1108
Molecular Immunology

Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry

https://doi.org/10.1016/j.molimm.2003.11.010Get rights and content

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.

Section snippets

T cell degeneracy and infection-induced autoimmune disease

Multiple sclerosis (MS), one of the most prevalent neurological diseases, is characterized by a loss of the myelin sheath surrounding axons in the central nervous system (CNS) (Steinman, 1996). MS is generally considered to be an autoimmune disease as demyelination is associated with elevated levels of CD4+ T cells specific for major myelin proteins (Ota et al., 1990, Bernard and de Rosbo, 1991, Allegretta et al., 1990, Link et al., 1990, Sun et al., 1991). Although it is not known for certain

Virus-induced molecular mimicry model for MS

Initial studies addressing molecular mimicry as a possible way to induce autoimmunity were conducted using mice in which virus proteins expressed as transgenes were targeted as pseudo-self antigens causing tissue destruction following virus infection (Ohashi et al., 1991, Oldstone et al., 1991) and more recently with mimic peptides in complete Freund’s adjuvant (Madsen et al., 1999). These studies provided evidence that a cross-reactive immune response could be initiated by mimic sequences, but

Innate immune response to pathogens in molecular mimicry-induced autoimmune disease

The virus-induced model of molecular mimicry described above provides a model for addressing the requirement of the innate immune response to the infection on the development of the mimic T cell response. Most interestingly, our preliminary results (unpublished observations) indicate that SJL mice immunized with the core HI574–586 mimic peptide in complete Freund’s adjuvant did not develop EAE-like clinical disease. HI574–586 mimic peptide immunization induced a T cell proliferative response

Antigen processing and presentation in infection-induced molecular mimicry

Molecular mimicry-induced autoimmune disease is also dependent on antigen processing and presentation. Two important factors are required for proper antigen processing and presentation of mimic peptide to autoreactive T cells during an infection. The first factor is the type of antigen presenting cell that initiates the response to the mimic peptide during the infection. APCs in a tissue-specific autoimmune disease may be infiltrating professional APCs, such as macrophages, dendritic cells, and

Is infection of the target organ required for initiation of autoimmune disease via molecular mimicry?

Autoimmune diseases such as MS are organ-specific with the autoimmune T cell response developing to tissue-specific self antigens in the specific organ. For molecular mimicry-induced autoimmune disease, it is not known whether the infection must occur primarily in the target organ or whether it can occur in a distal site. Direct infection of the target organ may be important for providing an inflammatory environment for local activation of cross-reactive T cells and may be important for tissue

Multiple infections in autoimmune disease following induction by molecular mimicry

Epidemiological evidence suggests MS has a viral etiology based on migration studies, twin studies, and epidemics of MS in Iceland and the Faroe Islands (Kurtzke and Hyllested, 1986, Kurtzke et al., 1993, Kurtzke, 1997, Sadovnick et al., 1993). MS presents in most patients with symptoms between 20 and 40 years of age, and some MS patients have underlying clinical signs such as optic neuritis or fine limb tremor for years before the disease develops into more severe symptoms. Thus, one

Conclusions

Although many studies have provided evidence for the role of molecular mimicry-induced autoimmunity, further elucidation of the mechanisms involved are required. We have developed a virus infection model for molecular mimicry in which a virus encodes a mimic sequence. With the infection model, we have addressed and are continuing to address multiple questions related to molecular mimicry-induced autoimmune diseases. TCR recognition of the mimic epitope is the first identification point for

References (30)

  • R.S Fujinami et al.

    Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity

    Science

    (1985)
  • B Gran et al.

    Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity

    Ann. Neurol.

    (1999)
  • B Hemmer et al.

    Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone

    J. Exp. Med.

    (1997)
  • M.S Horwitz et al.

    Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry

    Nat. Med.

    (1998)
  • J.F Kurtzke

    Epidemiologic evidence for multiple sclerosis as an infection

    Clin. Microbiol. Rev.

    (1993)
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