In 1962, Melvin Kaplan released his revolutionary article describing a case of an 11-year-old boy who died of heart failure due to rheumatic fever. Pathology revealed immunoglobulin deposits in the cardiac muscle of the patient, leading Kaplan to explore the role of these antibodies. He examined the reaction of sera from rabbits immunized with group A streptococcal cells to samples of human heart tissue, conjuring the first established description of what is today a well-accepted paradigm—that structural similarity between bacteria and human protein may lead to the development of cardiac injury in rheumatic fever.1

In another canonical article published that same year, Rowley and Jenkin2 described a novel theory, concerning a possible immune crossreaction between infectious agents and host antigens, causing the development of autoimmunity.

These two articles may be viewed as harbingers to a mass of scientific publications that followed, all exploring the concept of immune crossreactivity due to structural homology between pathogens and self-proteins, a concept commonly termed molecular mimicry.3,4,5,6

Molecular mimicry is a term originally referring to the ability of an organism to evade detection by its predator through assuming features of a non-edible object,7 yet the concept was expanded to address the significant homology between microbial agents and the human host. Interestingly, the theoretical consequences of such similarities may vary depending on the interpreter. Thus, almost simultaneous with the publication by Rowley and Jenkin,2 a fundamentally opposite view of molecular mimicry was presented by Damian.8 Damian addressed naturally occurring parasitic antigenic determinants that were found to elicit little or no immune reaction. He attributed this feature to the similarity of these determinants to host proteins, suggesting that molecular mimicry may facilitate immune tolerance rather than immune autoreactivity.

Nevertheless, these two seemingly rivaling hypotheses may actually coexist, explaining the ostensibly paradoxical induction of autoimmunity in the unique setting created by vaccination.

During the past two decades, the similarity of viral and bacterial proteins to the human proteome was extensively researched. Noteworthy are the papers of Kanduc9 and Kanduc and colleagues10 who described a massive overlap of the different proteomes, ranging up to 90% of viral pentapeptides, as well as an astonishing 99.7% of bacterial heptapeptides, which were shared by the human proteome. Kanduc11 suggested that this massive overlap supports the notion that microbial elements bearing similarity to human proteins would likely not elicit an immune response, owing to tolerogenic mechanisms inherent to our immune system. However, in the setting of impaired tolerogenicity, exposure to those similar elements may induce autoimmunity.

The importance of tolerogenic mechanisms in preventing autoimmunity has been widely explored. A prominent illustration is the process of stimulation and clonal expansion of lymphocytes upon exposure to antigens: both T cells and B cells exposed to foreign antigens depend on a second signal to generate an effective immune response. It is believed that the goal of this duplicity is to minimize immune reactiveness against self-antigens.12

A crucial question is therefore, what factors are involved in attenuating immune tolerance?

The answer, as may be expected, is comprised of two chief pillars: environmental and genetic.

With regards to the role of genetics in predisposing individuals to autoimmunity, the body of evidence is constantly expanding. One central example is the association between certain major histocompatibility complex (MHC) alleles and autoimmune diseases.13,14 The mechanisms behind this association are poorly understood as yet. However, it was suggested that aberrant presentation of antigens via MHC class II to autoreactive T cells may lead to breakdown of immune tolerance.15 In fact, it is hypothesized that this genetic susceptibility to autoimmunity represents a natural evolutionary toll, as it may have provided a survival advantage for those with an overactive immune system, which would be more effective in fighting infections.16,17

The second pillar in attenuation of immune response is environmental effects. The role of environmental factors in the pathogenesis of autoimmunity has supplied grounds to a vast body of research, with data accumulating on the contribution of various elements such as nutrition, sun exposure, exercise, smoking and gut microbiota.18,19,20,21 Nonetheless, attention is rarely drawn to a significant environmental factor applied regularly with the sole purpose of impairing immune tolerance—Adjuvants.

The term adjuvant refers to a variety of compounds used to stimulate immune response. In fact, research of immune responses is dependent on these compounds since inducing a significant ‘researchable’ immune response to pathogenic elements is possible almost solely when injecting these element along with an adjuvant.12

Kanduc11 suggested the need for adjuvants stems from the inherent tolerance of the human immune system to many pathogenic motifs, which are repeatedly shared with the human proteome. Therefore, she offered that upon exposure of the immune system to these shared motifs, while impairing immune tolerance (by adding an adjuvant), a reasonable outcome may be the development of crossreactivity and autoimmunity.11

This application of the molecular mimicry theory may serve to explain potential development of autoimmune phenomena post vaccination (as illustrated in Figure 1).

Figure 1 Schematic illustration of the process leading to the development of immune crossreactivity in genetically prone individuals upon exposure to vaccines. Full size image

Herein, we present principle examples of vaccines associated with autoimmunity, in which molecular mimicry has been implicated as a plausible mechanism.