Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry
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 Most interestingly, our preliminary results (unpublished observations) indicate that SJL mice immunized with the core HI574–586 mimic peptide in complete Freund’s adjuvant did not develop EAE-like clinical disease.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)
- et al.
Virus encoding an encephalitogenic peptide protects mice from experimental allergic encephalomyelitis
J. Neuroimmunol.
(1996) Can virus infections trigger autoimmune disease?
J. Autoimmun.
(2001)- et al.
Persistent anti-myelin basic protein IgG antibody response in multiple sclerosis cerebrospinal fluid
J. Neuroimmunol.
(1990) - et al.
Innate immunity: impact on the adaptive immune response
Curr. Opin. Immunol.
(1997) - et al.
Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice
Cell
(1991) - et al.
Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response
Cell
(1991) - et al.
Molecular mimicry in T cell-mediated autoimmunity: viral peptides activate human T cell clones specific for myelin basic protein
Cell
(1995) - et al.
T cells responsive to myelin basic protein in patients with multiple sclerosis
Science
(1990) - et al.
Immunopathological recognition of autoantigens in multiple sclerosis
Acta Neurol.
(1991) - et al.
Expansion by self antigen is necessary for the induction of experimental autoimmune encephalomyelitis by T cells primed with a cross-reactive environmental antigen
J. Immunol.
(1998)
Amino acid homology between the encephalitogenic site of myelin basic protein and virus: mechanism for autoimmunity
Science
Molecular mimicry and multiple sclerosis: degenerate T-cell recognition and the induction of autoimmunity
Ann. Neurol.
Identification of high potency microbial and self ligands for a human autoreactive class II-restricted T cell clone
J. Exp. Med.
Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry
Nat. Med.
Epidemiologic evidence for multiple sclerosis as an infection
Clin. Microbiol. Rev.
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