Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides.
Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR (T cell receptor).
Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity).
One possible cause of autoimmunity, the failure to recognize self antigens as "self", is a loss of immunological tolerance, the ability for the immune system to discriminate between self and non-self.
The mechanism by which pathogens have similar amino acid sequences or the homologous three-dimensional crystal structure of immunodominant epitopes remains a mystery.
This is known as maternal-fetal tolerance where B cells expressing receptors specific for a particular antigen enter the circulation of the developing fetus via the placenta.
Active suppression involves the injection of large amounts of foreign antigen in the absence of an adjuvant which leads to a state of unresponsiveness.
This involves the reactivation or maintenance of V(D)J recombination in the cell which leads to the expression of novel receptor specificity through V region gene rearrangements which will create variation in the heavy and light immunoglobulin (Ig) chains.
Pathogens can induce autoimmunity by polyclonal activation of B or T cells, or increased expression of major histocompatibility complex (MHC) class I or II molecules.
Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products.
Either the linear amino acid sequence or the conformational fit of the immunodominant epitope may be shared between the pathogen and host.
However, due to the amino acid variation between different proteins, molecular mimicry should not happen from a probability standpoint.
[11] This would suggest that the linear amino acid sequence may not be the single underlying cause of molecular mimicry since it can be found numerous times within the database.
The possibility exists, then, for similarity in three-dimensional structure between two peptides to be recognized by T cell clones when there is variability within the amino acid sequence.
It is now apparent that sequence similarity considerations may not be sufficient when evaluating potential mimic epitopes and the underlying mechanisms of molecular mimicry.
Molecular mimicry is thus occurring between two recognized peptides that have similar antigenic surfaces in the absence of primary sequence homology.
Autoreactive T cells are activated de novo by self epitopes released secondary to pathogen-specific T cell-mediated bystander damage.
[16] T cell responses to progressively less dominant epitopes are activated as a consequence of the release of other antigens secondary to the destruction of the pathogen with a homologous immunodominant sequence.
[1] The HIV-1 virus has been shown to cause diseases of the central nervous system (CNS) in humans through a molecular mimicry apparatus.
Astrocytes are cells of the CNS which are used to regulate the concentrations of K+ and neurotransmitter which enter the cerebrospinal fluid (CSF) to contribute to the blood brain barrier.
[19] Theiler's murine encephalomyelitis virus (TMEV) leads to the development in mice of a progressive CD4+ T cell-mediated response after these cells have infiltrated the CNS.
The receptor contains a seven amino acid sequence (Trp-Thr-Tyr-Asp-Gly-Thr-Lys)[21] in the α-subunit that demonstrates immunological cross-reactivity with a shared immunodominant domain of gpD of the herpes simplex virus (HSV).
Cross-reactivity of the self epitope (α-subunit of the receptor) with antibodies produced against HSV suggests that the virus is associated with the initiation of myasthenia gravis.
This further shows an immunologically significant sequence homology to the biologically active site of the human acetylcholine receptor.
The development of a downregulating immune response to the shared epitope between pathogen and host may be the best way of treating an autoimmune disease caused by molecular mimicry.
[5] The concept of molecular mimicry is a useful tool in understanding the etiology, pathogenesis, treatment, and prevention of autoimmune disorders.
Understanding the mechanisms of molecular mimicry may allow future research to be directed toward uncovering the initiating infectious agent as well as recognizing the self determinant.