Molecular mimikry

Mimicry in biology is a form of imitation of "visual, auditory, or olfactory signals" with the goal that the imitator gains advantages by deceiving the signal receiver. Two common variants illustrate this evolutionary process of adaptation:

• Protective mimicry: imitation of role models that deter potential predators, for example.
• Attraction mimicry: imitation of role models that are attractive to potential prey, for example.

The term "molecular mimicry" initially referred in its original sense to these well-known examples of nature. However, the "mimicking or imitating" now concerned molecular structures. For example, exogenous pathogens can evade the host's immune defenses by showing similarities to host structures (e.g. amino acid sequences in proteins) or by developing them (Benvenga S et al. 2016). In this way, they camouflage their origin so that the host immune system does not recognize and tolerate them as foreign. Thus, infections are thought to be potential triggers of autoimmune responses (Cusick MF et al 2012). Evidence suggests that antibodies or T-cells are able to recognize "self-antigens" as well as microbial antigens. If the mechanisms of self-tolerance are overcome, a B- and T-cell mediated immune response can develop that is directed against the body's own tissues. An autoimmunological response mechanism.

• A classic example of this is rheumatic fever, which occurs after infection with ß-hemolytic A streptococci. In the serum of the patients, antibodies are found against an M protein of the streptococcal membrane (mainly affecting the M5 protein), which cross-reacts with the myocardial myosin protein of the infected person.
• Other examples of a relationship between infection and autoimmunity are provided by B3 coxsackievirus and concordant myocarditis, Campylobacter bacteria and Guillain-Barré syndrome.
• Another example is Borrelia burgdorferi and Lyme arthritis, as well as autoimmune reactions triggered by Epstein-Barr virus (EBV) infection. Conversely, it is possible that EB virus is reactivated by an episode of systemic lupus erythematosus.

However, molecular mimicry can induce autoimmunity only if the 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 an immune response. The aspect of "similarity" as a condition for cross-reactivity has been addressed by searching for sequence homologies between pathogen and self antigens. However, many of the suspected peptides had no traceable correlation to the disease under investigation. Thus, for the development of autoimmunity by molecular mimicry, further protective functions of immune regulation must be overcome:

• microbial and "self-peptide" have to 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 APZs to produce proinflammatory cytokines leading to tissue damage
• T cells must have access to the tissue in which the self-antigen to be cross-reactively recognized is expressed

Hemolytic streptococci use a very different form of molecular mimicry to protect themselves from immune defenses in an unusual way. The bacteria bind parts of the cell envelope of previously destroyed red blood cells to their surface via the S-protein of their cell membrane. This "camouflage" prevents such armed streptococci from being recognized as pathogens by immune cells and eliminated(immune evasion; Wierzbicki IH et al 2019). However, by blocking the S protein, the body's own defenses can again be enabled to attack these pathogens. In summary, the term molecular mimicry requires further definition.

1. Benvenga S et al (2016) Molecular mimicry and autoimmune thyroid disease. Rev Endocr Metab Disord 17:485-498.
2. Cusick MF et al (2012) Molecular mimicry as a mechanism of autoimmune disease. Clin Rev Allergy Immunol 42:102-111.
3. Matsui M et al (1996): Recurrent demyelinating transverse myelitis in a high titer HBs-antigen carrier. J Neurol Sci139: 235-237.
4. Rodriguez Y et al (2018): Guillain-Barré syndrome, transverse myelitis and infectious diseases. Cell Mol Immunol 15: 547-562.
5. Segal Y et al. (2018) Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction. Cell Mol Immunol 15:586-594.
6. 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