Molecular Mimicry as a Mechanism of Autoimmune Disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266166/
Chronic autoimmune diseases are the byproduct of the immune system recognizing self-antigens as foreign, which can lead to inflammation and destruction of specific tissues and organs (immunopathology) [1]. The impact of these diseases is global and heterogeneous with over 100 million people afflicted with more than 80 different autoimmune diseases [2]. While the etiology of autoimmune diseases is not fully elucidated, the causes are likely based on a combination of hereditary and environmental factors [3]. Although host genetic background contributes to the induction of an immune response to self, epidemiological and molecular evidence implicates infectious agents (viral and bacterial) as the principal environmental insults responsible for the induction of autoimmune diseases (reviewed in [4–6]). Prolonged proinflammatory responses to infections have been associated with the initiation and exacerbation of autoimmune diseases (reviewed in [4, 7, 8]). Inflammation is facilitated by proinflammatory cytokines such as type I interferon (IFN), interleukin (IL)-1β, IL-12, IFNγ, IL-17 and tumor necrosis factor (TNF) α (reviewed in [7, 9, 10]). However, these proinflammatory cytokines are critical for clearance of pathogens, suggesting that environmental factors are able to divert the immune response towards immunopathogenesis. Although a number of immune cells are responsible for secreting proinflammatory cytokines, the primary cell types implicated in a vast majority of autoimmune disorders are autoreactive B and T cells, or antibody recognition of self [11]. Although a number of viruses and bacteria have been linked to the initiation of certain autoimmune diseases, identifying a particular virus or bacteria that is solely responsible for the induction of an autoimmune response is rare. This occurrence is due to the potential for multiple infections being involved in priming the immune system and other infections triggering disease, which could explain why no one viral infection has been conclusively linked to the development of immune mediated autoimmune diseases [7]. However, there are a variety of examples of bacterial infections initiating and exacerbating autoimmune diseases. Streptococcus pyogenes is a gram-positive bacterium which causes group A streptococcal infection that is responsible for a number of diseases. The complications associated with S. pyogenes are rheumatic fever and glomerulonephritis. The infection causes the production of cross-reactive antibodies in response to the bacteria. Antibodies recognize the M protein (virulence factor) and the N-acetyl-β-D-glucosamine (GLcNAc) of S. pyogenes and cross-react with myosin leading to heart damage (reviewed in [8, 12, 13]). Further evidence of molecular mimicry due to the production of cross-reactive antibody includes infection with gram-negative bacteria, such as Klebsiella pneumonia and Campylobacter jejuni. Infection with K. pneumonia or C. jejuni leads to the production of cross-reactive antibodies able to recognize the self-antigens histocompatibility leukocyte antigen (HLA)-B27 and gangliosides, which induces ankylosing spondylitis and Guillan-Barre′ syndrome, respectively (reviewed in [8, 14]). Examples of human autoimmune diseases with possible links with molecular mimicry are presented in Table 1.
Table 1
Examples of Human Autoimmune Diseases with Possible Molecular Mimicry as a Mechanism
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266166/table/T1/
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Unfortunately, there are a variety of mechanisms including molecular mimicry, bystander activation, exposure of cryptic antigens, and superantigens by which pathogens can aid in the expression of an autoimmune disease [16–21]. Inflammation induced by exposure to a foreign antigen can lead to autoimmune diseases from cross-reactive epitopes (molecular mimicry). These epitopes are segments of foreign antigens which, when presented to either T or B cells in the context of the MHC, can activate CD4+ or CD8+ T cells. The induction of the immune response and subsequent proinflammatory cytokine release is critical for clearance of a virus or bacteria. However, a sustained proinflammatory response against specific host tissues can occur when there is sequence or structural homology between foreign antigens and self-antigens, termed molecular mimicry [18]. Although this concept has been associated with autoimmunity, there are instances where mimicry (cross-reactivity) provides protection for the host, termed heterologous immunity [22]. Cross-reactivity or mimicry between various strains of viruses or bacteria could help explain how protective immunity arises in certain individuals even in the absence of prior exposure to an emerging pathogen. This example of sequence homology in which molecular mimicry between viruses leads to protective immunity is in contrast to a pathogen mimicking host epitopes.
Brief history of molecular mimicry
Over 30 years ago, molecular mimicry by either a virus [18] or bacteria [23] was hypothesized to initiate and exacerbate an autoimmune response through sequence or structural similarities with self-antigens. Currently, molecular mimicry is the prevailing hypothesis as to how viral antigens initiate and maintain autoimmune responses which lead to specific tissue damage [18]. Initial work by Fujinami, Oldstone, and colleagues identified mouse antibodies to measles virus and herpes simplex virus (HSV-1) obtained from antibody-secreting B cell clones [18]. These antibodies were reactive to both intermediate filaments of normal cells and the proteins of measles virus and HSV-1, thereby demonstrating a relatedness between host and viral antigens [18]. Further work by Fujinami and Oldstone used myelin basic protein (MBP), a nerve sheath protein containing an encephalitogenic T cell epitope in rabbits. The hepatitis B virus polymerase (HBVP) protein was found through computer analysis to share six consecutive amino acids with the encephalitogenic MBP epitope [16] and when rabbits were sensitized with either MBP or HBV peptides, the rabbit's tissue serum reacted against MBP. Further, rabbits sensitized with the HBVP peptide developed central nervous system (CNS) pathology similar to rabbits sensitized with whole MBP protein or the MBP peptide [16]. Importantly, the rabbits sensitized with HBVP did not contract hepatitis but still developed encephalomyelitis and presented with a similar pathology as MBP sensitized mice. These experiments were the first experimental demonstration of molecular mimicry, whereby a microbial peptide with similar amino acid sequences to the self-peptide was able to activate autoreactive T cells and subsequently cause specific tissue damage.
Relationship between molecular mimicry and autoimmune diseases
Immune cells of the adaptive immune response are specifically activated, but the hallmark of autoimmunity is the dysregulation of the immune system, especially T and B cells recognizing self-antigens as foreign. The ability of T cells to evade central (thymic selection) and peripheral (Tregs) mechanisms of tolerance is evident by the large number of T cell mediated human autoimmune diseases, such as type-1 diabetes, systemic lupus erythematosus, rheumatoid arthritis and multiple sclerosis (MS) [24–28]. Molecular mimicry has been implicated in the pathogenesis of many of these autoimmune diseases including MS, spondyloarthropathies, Graves' disease, and diabetes mellitus [16, 29, 30]. In the case of MS, it has been hypothesized that certain viruses, such as Epstein-Barr virus (EBV), share sequence homology with antigenic structures in the CNS [31].
Activation of an autoimmune response could be enhanced by a variety of other, albeit, non-mutually exclusive non-specific mechanisms including bystander activation and superantigens. The difference between other non-specific mechanisms that initiate autoimmunity and molecular mimicry is that microbial mimics specifically direct the immune response towards a tissue and/or organ. Originally, T cell recognition was postulated to be highly specific and cross-reactivity was thought to be a rare phenomenon. However, the structural requirements for peptide binding by MHC class II molecules that are presented to T cells were found to be based on amino acid properties, and amino acids sharing similar chemical features were able to bind at the same peptide MHC binding groove, thereby demonstrating that binding motifs were degenerate with only a small sequence needed for TCR recognition [32–34].
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Linear sequence matches in amino acid motifs is not the only criteria for mimicry [32]. It has been hypothesized that self-reactive immune cells are primed by molecular mimicry and bystander activation, thereby sensitizing the immune cells and leading to a “fertile field” but no apparent disease. Subsequent environmental insults could induce these sensitized autoreactive cells to cause an autoimmune disease. Work from our laboratory demonstrated that recombinant viruses having molecular mimicry with self-CNS antigens were unable to initiate an autoimmune disease individually [38]. However, infected mice that were subsequently challenged, after viral clearance, with a non-specific immunologic insult developed disease [38]. Further, subsequent experiments showed that conventional inflammatory responses to specific pathogens were able to induce disease in animals primed with a molecular mimic to a CNS antigen [39]. Therefore, not only is the priming of the immune system necessary for an autoimmune disease but the milieu to which the primed immune cells are exposed is an important factor in initiating an autoimmune disease.
