Molecular mimikry

The term “molecular mimicry” was coined in 1964 by the American parasitologist Raymond T. Damian. Damian originally used the term to describe the phenomenon in which parasites possess or produce antigens that resemble the antigenic structures of their host. This “molecular camouflage” was thought to protect the parasites from the immune system.

The meaning that is particularly common today—an infection-induced autoimmune reaction caused by cross-reactivity between microbial and self-epitopes—was not experimentally elucidated until later (in the 1980s) by Michael B. A. Oldstone, Robert S. Fujinami, and their colleagues. They demonstrated that antibodies against viral proteins can recognize the body’s own tissues due to structural similarities with host proteins.

In biology, mimicry refers to a form of imitation of “visual, auditory, or olfactory signals” with the goal of providing the mimic with advantages by deceiving the signal recipient. Two common types illustrate this evolutionary adaptation process:  

• Protective mimicry: Imitation of models that, for example, deter potential predators
• Attractive mimicry: Imitation of models that are attractive to potential prey, for example.

The term “molecular mimicry” initially referred, in its original sense, to these well-known examples found in nature. However, “mimicry or imitation” now applied to molecular structures. Thus, exogenous pathogens can evade the host’s immune defense by exhibiting or developing similarities to the host’s own structures (such as amino acid sequences in proteins) (Benvenga S et al. 2016). In this way, they mask their origin so that the host’s own immune system does not recognize them as foreign and tolerates them. Thus, infections are suspected of being potential triggers of autoimmune reactions (Cusick MF et al. 2012). It has been demonstrated that antibodies or T cells capable of recognizing both “self-antigens” and microbial antigens are present in such cases. If the mechanisms of self-tolerance are overcome, a B- and T-cell-mediated immune response directed against the body’s own tissues can develop. This is an autoimmune reaction mechanism.

• A classic example of this is rheumatic fever, which occurs following infection with β-hemolytic Group A streptococci. Antibodies against an M-protein of the streptococcal membrane (primarily the M5 protein) are found in the patients’ serum; this protein cross-reacts with the myocardial myosin protein of the infected individual.
• Further examples of a relationship between infection and autoimmunity include the B3 Coxsackievirus and concomitant myocarditis, Campylobacter bacteria and Guillain-Barré syndrome.
• Other examples include Borrelia burgdorferi and Lyme arthritis, as well as the autoimmune reactions triggered by infection with the Epstein-Barr virus (EBV). Conversely, it is possible that the EB virus may be reactivated by a flare-up of systemic lupus erythematosus.

However, molecular mimicry can only induce autoimmunity if pathogen and host antigens are similar enough to be recognized as cross-reactive (Segal Y et al. 2018). At the same time, they must be sufficiently different to elicit a differentiated immune response. The aspect of “similarity” as a condition for cross-reactivity was addressed by searching for sequence homologies between pathogen and self-antigens. However, many of the suspected peptides no longer showed a discernible correlation with the disease under investigation. For autoimmunity to arise through molecular mimicry, therefore, additional protective functions of immune regulation must be overcome:

• Microbial and “self-peptides” must be processed and presented
• the “self-peptide” must be present in sufficiently high concentrations
• the cross-reactive T cells must be present in sufficient numbers and require costimulatory signals from professional APCs to produce proinflammatory cytokines that lead to tissue damage
• T cells must have access to the tissue in which the self-antigen to be recognized as cross-reactive is expressed 

Hemolytic streptococci use a completely different form of molecular mimicry to protect themselves from the immune system in an unusual way. Via the S protein on their cell membrane, the bacteria bind fragments of the cell membrane from previously destroyed red blood cells to their surface. This “camouflage” prevents streptococci armed in this way from being recognized as pathogens and eliminated by immune cells (immune evasion; Wierzbicki IH et al 2019). However, by blocking the S protein, the body’s own immune system can once again be enabled to attack these pathogens. In summary, the concept of molecular mimicry requires further clarification. See also epitope spreading. 

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3. Damian RT (1964). Molecular mimicry: antigen sharing by parasite and host and its consequences. The American Naturalist 98(900):129–149.
4. Fujinami RS et al. (19893) Molecular mimicry in viral infection: cross-reaction of measles virus phosphoprotein or herpes simplex virus protein with human intermediate filaments. Proceedings of the National Academy of Sciences USA 80:2346–2350.
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8. Wierzbicki IH et al. (2019) Group A Streptococcal S protein utilizes red blood cells as immune camouflage and is a critical determinant for immune evasion. *Cell Reports* 29: P2979–2989