Although the avidity of the interactions between antigenic determinants and specific antibodies is considerably high, these antigen-binding sites can allow epitopes of similar shapes expressed on completely different microbial or animal cells to bind these antibodies, albeit with a lower binding avidity. These so-called crossreactive epitopes are made up of essentially the same amino acid and carbohydrate molecules, and such crossreactions are in fact common and may account for the undesirable production of antibodies against self-molecules which occurs in some autoimmune diseases.
Molecular mimicry or crossreactivity hypothesis proposes that an exogenous substance, mostly produced or possessed by infectious agents, may trigger an immune response against self-antigens. According to this theory susceptible individuals acquire an infection by a microbial agent that has antigenic similarity to self-antigens. As the result, these pathogen-specific antibodies bind to the host structures possessing crossreactive self-antigens and cause tissue damage and disease.
Molecular mimicry has been linked to the pathogenesis of several important diseases, such as rheumatic heart disease [87
], multiple sclerosis [88
], and type 1 diabetes mellitus [89
]. In rheumatic fever carditis, for example, the basic pathogenetic process involves production of antibodies against Streptococcus
which express high levels of M protein antigens, a molecule that shares structural similarities with those found in the heart valves and endocardial membrane. If antibodies to these bacterial proteins reach high levels, there may be sufficient binding to the host cells possessing these cross-reactive antigens with activation of the complement system and induction of the pathological damages at these sites.
The mechanism of molecular mimicry, however, can also be used in the explanation for the development of RA, AS, and CD after infections by the causative microbes. In AS, for example, after a preliminary gut mucosal activation by Klebsiella microbes and production of the secretory anti-Klebsiella IgA antibodies, recurrent bouts of subclinical Klebsiella infections in the large bowel of susceptible individuals carrying HLA-B27 will lead to production of increased levels of Klebsiella IgG antibodies. When the level of these antibodies reaches a certain limit, they will be able to activate the classical cascade of complement system and destroy tissues via the effect of end products of the complement components, mainly C8 and C9, “membrane attack complex.” At the same time, certain activated complement components such as C3a and C5a help in the propagation of the inflammatory process through recruitment (chemoattraction) and activation of the neutrophils and phagocytes with the release of cytotoxic and destructive enzymes by these cells. Other chemoattractants, such as leukotriene B4, can be released by the autoantibody targeted cells. Inflammatory cells are further activated by binding to autoantibody Fc regions and fixed complement C3 fragments on the tissue cells, thus causing further tissue injury via effects of the products of activated inflammatory cells.
There is a requirement for the presence of high levels of anti-Klebsiella
IgG antibodies in order that classical complement cascades will be activated and this will occur in patients with AS mainly during the active phases of the disease [90
]. The same pathogenetic process can also be applied to RA being caused by recurrent bouts of Proteus
asymptomatic urinary tract infections.