children with febrile seizures (Petrovski et al., 2009; Sadleir and Scheffer, 2007; Schlachter et al., 2009).

Molecular Mimicry

Molecular mimicry is sequence and/or conformational homology between an exogenous agent (foreign antigen) and self-antigen leading to the development of tissue damage and clinical disease from antibodies and T cells directed initially against the exogenous agent that also react against self-antigen. Molecular mimicry as a mechanism that can cause pathologic damage and disease has been demonstrated in several animal models, most notably experimental allergic encephalomyelitis (EAE) in mice and rabbits (Oldstone, 2005).

Evidence Needed to Conclude That Molecular Mimicry Is Operative in a Clinical Case or an Animal Model of Disease

Essential to concluding molecular mimicry contributes to a clinical case or animal model of disease are the following: (1) a susceptible host whose genetic background and adaptive immune responses allows emergence of self-reactive immunity, (2) exposure to an exogenous agent which expresses antigens that are immunologically similar to self-antigen(s), and (3) a host immune response to the exogenous agent that cross-reacts with biologically relevant host tissue structures and causes tissue damage and clinical disease.

Proving that a particular human autoimmune disease is due to molecular mimicry is problematic (Albert and Inman, 1999; Rose and Mackay, 2000). A realistic and consistent temporal relationship between exposure to exogenous antigen and development of disease must be documented. This can be difficult in the case of a natural exposure to pathogen where infection may have been subclinical, making it impossible to define an exact temporal relationship.

Linear amino acid sequence homology or even similar conformational structure between an exogenous agent and a self-antigen alone are not sufficient to prove that molecular mimicry is the pathogenic mechanism for a disease. Many such homologies exist, and the vast majority of these are not associated with biologically relevant autoimmune phenomena or actual human disease (Albert and Inman, 1999).

Finding a tissue-specific antibody response following exposure to an exogenous agent is also, by itself, not proof of molecular mimicry as the pathologic mechanism of disease (Albert and Inman, 1999). Both naturally occurring and postinfectious cross-reactive antibodies and T cells are relatively common and most frequently not pathogenic (Fujinami et al., 2006). Cross-reacting antibodies can also be secondary to nonspecific tissue injury

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