Bacterial molecular mimicry in autoimmune diseases
Current Bioscience. 2021;1(1):e01
Palma, M. (2021). Bacterial molecular mimicry in autoimmune diseases. Current Bioscience, 1(1). https://doi.org/10.51959/cb.2021.v1n1.e01
* Independent researcher, Torrevieja, Spain
^ Corresponding author: Marco Palma, email@example.com
Bacterial molecular mimicry in autoimmune diseases is one of the leading mechanisms by which microorganisms may induce autoimmunity and survive in the host. The main purpose of the current study was to determine the main microbes that elicit autoimmune reactions through molecular mimicry and identify the most relevant approaches to investigate this mechanism. A classic example is the M protein of Streptococcus pyogenes, which induces antibody cross-reactivity with a cardiac protein and causes rheumatic fever. Another notable example is the protein from Porphyromonas gingivalis that closely resembles the human heat shock protein and accelerates atherosclerotic. There is evidence that antibodies against Helicobacter pylori CagA interact with different parts of smooth muscle and endothelial cells enhancing atherosclerotic vascular disease. Recently, one cause of infertility has been associated with Staphylococcus aureus molecular mimicry that triggers an antibody response that cross-reacts with human spermatozoa proteins. Further examples of bacterial molecular mimicry are associated with Chlamydia pneumoniae, Escherichia coli, Yersinia, and Salmonella. From the literature, the most widely used methods in this field are Basic Local Alignment Search Tool (BLAST), serological assays, and phage display. The subjects of particular concern are vaccine cross-reactivity and immunosuppressive drugs side-effects, therefore alternative approaches are needed. Such an approach is phage display where therapeutic antibody fragments obtained by this technique have been used in the treatment of autoimmune diseases by neutralizing the pathological effects of autoantibodies. Phage display libraries are constructed from the antibody repertoires of autoimmune disease patients. Antibody fragments without the Fc domain can not interact with Fc receptors and proteins of the complement system and trigger autoimmune diseases. Another approach is to block the Fc receptors. In conclusion, this review highlights key aspects of bacterial molecular mimicry to better understand the factors associated with autoimmune diseases and encourage further research in this field.
Keywords: bacterial molecular mimicry, molecular mimicry, autoimmune diseases, autoantibody, cross-reactivity, phage display, blast.
Bacterial molecular mimicry mechanisms are implicated in several types of autoimmune diseases. They are a frequent cause of morbidity and mortality affecting over 3–5% of our population (1). They are triggered by the loss of immunological tolerance to self-antigens, which can cause systemic or organ-specific damages. Microorganisms have often appeared as one of the main factors and on many occasions, an autoimmune disease is considered a consequence of infection (2).
One of the leading mechanisms by which infectious agents may induce autoimmunity is molecular mimicry. Several studies have demonstrated that microorganisms contain proteins that are similar enough to host proteins that make B and T cells respond to self -proteins. Production of large quantities of autoantibodies by B lymphocytes may be important in antibody and complement deposition in tissues, leading to inflammation and subsequently to tissue damage (3). Molecular mimicry has been implicated in the pathogenesis of many autoimmune diseases including multiple sclerosis, Guillain-Barré syndrome, type 1 diabetes, rheumatoid arthritis, and cardiovascular diseases (4). Many bacterial species can induce an autoimmune response by molecular mimicry mechanism, including Streptococcus pyogenes, Porphyromonas gingivalis, Helicobacter pylori, Chlamydia pneumoniae, Staphylococcus aureus, Escherichia coli, Yersinia, Campylobacter jejuni, and Salmonella. The main purpose of this study is to describe the main pathogenic bacteria that cause autoimmune diseases and their mechanisms of molecular mimicry. We comment on certain aspects of possible methods to identify immunogenic epitopes and therapeutic approaches.
Sources of information
An extensive literature review was conducted in PubMed’s databases on autoimmune diseases, autoantibodies, and molecular mimicry in combination with the keywords bacteria and pathogen.
Bacterial molecular mimicry as a cause of autoimmune diseases
Streptococcus pyogenes generally inhabits epithelial surfaces, especially of the throat and skin, but it can cause severe conditions, including rheumatic fever, which is a serious autoimmune sequela of pharyngitis (5). The onset of rheumatic fever usually occurs about two to four weeks after a streptococcal throat infection. It is estimated that around 30 million people are currently affected by rheumatic heart disease globally (6), with 300,000 deaths each year, of which 60% occurred prematurely.
Rheumatic fever is a classic example of molecular mimicry where S. pyogenes M‐protein shares an α‐helical coiled structure similar to a heart protein (e.g., myosin). The antibodies from patients with acute rheumatic fever (ARF) cross‐react with both M‐protein and the cardiac tissue (7). Variability in the N-terminal of M proteins generates distinct M serotypes which makes it difficult to make a vaccine with good protection. Of the more than 130 M-protein types identiﬁed, M types such as 1, 3, 5, 6, 14, 18, 19, and 24 have been associated with rheumatic fever (8).
Moreover, some antibodies recognize the N-acetyl-β-Dglucosamine (GLcNAc) of S. pyogenes and cross-react with myosin (9). Besides, S.pyogenes induces the production of collagen IV autoantibodies after that S. pyogenes binds to collagen IV, a major component of subendothelial basement membranes, intermediated by a collagen-binding octapeptide motif of M-protein (10). Cross-reactivity has been found of anti S.pyogenes antibodies with vimentin, laminin, tropomyosin (11), and fibronectin (12).
Even when comprehensive studies on ARF and autoantibodies exist, there is currently no single test to diagnose or prevent this disease. Diagnosis of ARF is done using clinical criteria (Jones criteria) and excluding other differential diagnostics. Possible future research areas may include a better understanding of the epidemiology of the disease to improve diagnosis and identify new avenues for therapeutic intervention and development of group A streptococcal vaccine.
Porphyromonas gingivalis is a gram-negative oral anaerobe that is involved in the pathogenesis of periodontitis, an inflammatory disease that destroys the tissues supporting the tooth which eventually may lead to tooth loss. Several studies show inflammatory mechanisms that link periodontal diseases to cardiovascular diseases (13).
It was suggested that the progression of atherosclerosis can be explained in terms of the immune response to bacterial heat-shock proteins (i.e. HSP60 or GroEL) (14) from P. gingivalis (15–17), a protein that closely resembles human heat shock protein. Also, the immune system may not be able to differentiate between self-HSP and bacterial HSP which is resulting in an autoimmune response (18). 91% of the periodontitis patients were seropositive for P. gingivalis GroEL but only 61% were for human HSP60 (19). However, nothing is known about autoantibodies against GroEL and hsp60 in cardiovascular disease patients with a prior history of periodontitis. P. gingivalis cardiolipin, a lipid found in the bacterial membrane, induces autoantibodies against protein β2glycoprotein 1 (β2GP1), a protein whose physiological function speculates to protect damaged surfaces of endothelial cells from promoting inappropriate coagulation. A variety of microbial pathogens are capable of inducing autoantibodies by cardiolipin due to its similarity to the peptide sequences in β2GP1 (i.e. TLRVYK). Other antibodies that link periodontitis to cardiovascular disease include anti-phosphorylcholine (anti-PC) and the antioxidant LDL (anti-oxLDL) (20,21).
Helicobacter pylori infections have been suggested to be associated with atherosclerotic vascular disease (22). Many mechanisms underlying the molecular mimicry between H. pylori and the host have been proposed. Antibodies against CagA protein from H. pylori interact with different parts of smooth muscle and endothelial cells present in the thin-layer sections of atherosclerotic vessels (23). H. pylori UreB subunit, with a high number of epitopes recognized by anti-urease antibodies (24,25), exhibits similarity to the human CCRL1 protein (CC chemokine receptor-like 1) expressed in heart tissue (26). Antibodies against H. pylori Hsp B heat shock protein cross-react with human Hsp60 facilitating inflammation in the vascular endothelium (27).
Most of the H. pylori vaccine clinical trials focused on the urease antigen with different adjuvants, routes, and delivery systems that are generally not been effective in humans (28). H. pylori has not a predominant outer membrane protein (OMP), rather multiple lower-abundance OMPs have been observed (29). The largest family is Family 1, comprised of the Hop (for H. pylori OMP, 21 members) and Hor (for Hop related, 12 members) proteins. Families 2 and 3 comprise the Hof (for Helicobacter OMP, 8 members) and Hom (for Helicobacter outer membrane, 4 members) proteins, respectively. Families 4 and 5 are composed of iron-regulated OMPs (6 members) and efflux pump OMPs (3 members), respectively. I need to check all these proteins closely to decide if there is a good candidate to be used in a vaccine.
Chlamydia pneumoniae is a widespread respiratory pathogen responsible for sinusitis, pharyngitis, and pneumonia and its transmission occurs via the aerial route (30). The relationship between C. pneumoniae and cardiovascular diseases was first suggested in 1988 (31). Cardiovascular diseases are one of the main causes of death globally. It is expected to surpass infectious diseases as the leading cause of mortality and the number of deaths is estimated to reach 23,3 million by 2030 (32). The mechanism by which C. pneumoniae causes cardiovascular diseases is unknown, but it is speculated that it is through molecular mimicry. C. pneumoniae induces the expression of autoantibodies by producing proteins that have similarities with human proteins including hHSP60, a peptide of the alpha-myosin heavy chain molecule (M7A motif; SLKLMATLFSTYASAD). It will be interesting to analyze autoantibodies (i.e. against human HSP60 and myosin) in sera from cardiovascular disease patients with a history of C. pneumoniae infection.
Infertility is a frequent health problem among 5-8% of couples in developed countries and 5.8% to 44.2% in developing countries (33). 30-40% of couples have female infertility while 60-70% of couples have male infertility. The immune reaction in spermatozoa causes 2-30% of infertility (34) and in 9-12.8% of infertile couples were found anti-sperm antibodies (35,36). Affected women of bacterial vaginitis caused by Staphylococcus aureus develop antibodies against S. aureus that cross-react with human spermatozoa proteins which could be a potential cause of infertility (37). A molecular modeling approach revealed 55 of 96 human spermatozoa proteins with homology to S. aureus proteins (identity 19-45%). The top five proteins that showed high sequence and structure homology, as well as high antigenicity, were Glyceraldehyde‐3‐phosphate dehydrogenase, L‐lactate dehydrogenase C, protein deglycase DJ‐1, sperm acrosome membrane‐associated protein‐4, and UDP‐N‐acetylhexosamine phosphorylase (38). Recently, it was demonstrated that amelioration of sperm immobilization factor-induced infertility by bacterial antigenic determinants cross-reacting with spermatozoa (39).
Escherichia coli has been associated with several autoimmune diseases, including primary biliary cirrhosis (PBS), autoimmune hepatitis, rheumatoid arthritis (40). E.coli expresses several proteins that have homology with human proteins. Antimitochondrial antibodies, typically found in PBC, recognized E2 components of pyruvate dehydrogenase complex (PDC) that are localized in the mitochondrial inner membrane. These antibodies react well against PDC‐E2 of E. coli (41). The E. coli type I Fim H that binds to Gp1‐anchored molecule CD48, thereby inducing bacterial phagocytosis, has homology to human CD2 (42). Rheumatoid arthritis is associated with the amino acid sequence QKRAA located in the third hypervariable region of the DR beta-1 chain of HLA‐DR4 which is recognized by the T-cell antigen receptor. This motif has been identified in the E.coli dnaJ (43,44).
Graves’ disease is the most common type of autoimmune thyroid disease (AITD) distinguished by the presence of anti-TSH receptor (TSHR) autoantibodies (TRAb) in the serum of more than 90% of patients with Graves’ disease. Some of these autoantibodies stimulate the thyroid resulting in hyperthyroidism. It was demonstrated that the outer membrane porin F protein (ompF) of Yersinia shared cross-immunogenicity with a leucine-rich domain of TSHR and these autoantibodies recognized the region between residues 190–197 of ompF (45). TSHR has also homology to Yersinia proteins YopM, Ysp, exopolygalacturonase, and SpyA(46). In addition, the envelope protein invasin from Yersinia pseudotuberculosis binds to the host‐cell β1 integrin surface receptors leading to the internalization of Yersinia. The invasin protein has structural similarity to fibronectin (47).
Campylobacter jejuni is the major infecting agent in patients with the autoimmune condition SLE (systemic lupus erythematosus) which causes glomerulonephritis, arthritic changes, and neurological alterations. It was demonstrated the presence of antibodies against an epitope of the human ganglioside GM1 in SLE patients (48) which is mimicked by bacterial LPS (49).
Gram-negative enteric pathogens, including Salmonella, have been associated with the autoimmune disease reactive arthritis (ReA). ReA followed outbreaks of Salmonella food poisoning (50). The titer and profiles of autoantibodies in the sera of patients with acute salmonellosis due to Salmonella enterica serovar Typhimurium (S. Typhimurium) or Salmonella enterica serovar Enteritidis (S. Enteritidis) infection, as well as in convalescent patients, indicate that anti-smooth muscle antibodies (ASMA) were the most prevalent in all salmonellosis (51).
Recently, it was demonstrated that Curli, thin amyloid fibers expressed on the surface of enteric bacterial cells, can induce inflammatory responses by stimulating pattern recognition receptors. The study showed that curli is expressed by S. Typhimurium in the cecum and colon of mice after natural oral infection, in both acute and chronic infection models. The infected mice generated increased levels of anti-dsDNA autoantibodies and joint inflammation. They hypothesized that the study provided the relation between bacterial amyloids like curli and human amyloids and their association with diseases such as Alzheimer’s Disease (52).
Methods to find similarity
Probably many more candidates have been discredited in literature for molecular mimicry that so far remained unexplored. A suitable technique that can help to identify such molecules is to run BLAST at National Center for Biotechnology Information (NCBI) against the homo sapiens database using pathogen sequences to find proteins with sequence similarities between two species.
It is necessary to analyze sera from patients with cardiovascular disease to study the profile of autoantibodies against human proteins (e.g. myosin) and bacterial proteins (e.g. H. pylori CagA, and UreB), and identify novel biomarkers by screening peptide libraries against patient serum. Serological studies can determine if patients with autoimmune diseases or individuals in the risk zone produce autoantibodies against human or bacterial proteins. The aim is to define these autoantibodies since there are studies that show that the specific autoantibodies are detected in asymptomatic individuals years before the presentation of autoimmune disorders (53–55). Therefore, they can be useful serological biomarkers to identify people with a predisposition to developing autoimmune diseases.
The phage display technique consists of the expression of peptides, proteins, or antibody fragments on the surface of phage particles (56). The nucleotide sequence encoding the target protein is found in the phage genome fused to the gene sequence of a coat protein. This fusion ensures that during phage assembly, the target protein will be exposed on the surface of the mature phage while the sequence encoding it is contained in the same phage particle. Using phage display, the analysis of a library of nucleotide sequences with a diversity of millions or billions becomes the study of the corresponding population of exposed protein sequences that can be selected according to the desired properties.
Analysis of phage display libraries typically includes a panning selection step in which phage populations are exposed to the targets of interest to selectively capture the phages that have bound to them. Through successive rounds of binding, washing, elution, and amplification, the initial population made up of a great diversity of phages are enriched in those that can bind to the target in question. Since the phenotype of each protein carries its genotype inside the phage particle, once the proteins of interest have been isolated, the sequence encoding them can be easily determined and altered to manipulate or refine their binding properties. Currently, natural and synthetic peptides, proteins, and protein domains, as well as recombinant antibodies, are routinely expressed by phage display (56). The phage display technique constitutes a good system for the selection of antibodies or peptides with specific binding properties among a wide number of variants.
Novel biomarkers can be identified by screening phage-display peptide libraries with sera from autoimmune disease patients. A complementary strategy is to construct a phage display library from B-cells from autoimmune disease patients to identify antibody sequences that recognize human epitopes.
Vaccinations are necessary to combat antibiotic resistance bacterial strains and more effectively control bacterial diseases. However, the increment of autoimmune diseases around the world raised the concerns of vaccination as one of the trigger factors.
An important example of this is the report of two cases with reactive arthritis associated with typhoid vaccination in travelers (57). This case reveals the need for further investigation in patients with autoimmune diseases related to vaccination.
Probably, some vaccines induce the production of antibodies against bacterial compounds that cross-react with compounds in the human body. This demonstrates the need for better therapeutic strategies for autoimmune diseases. Therefore, an alternative therapeutic approach is to neutralize the pathological effect of autoantibodies using antibody fragments isolated from phage display libraries constructed from B-cells from autoimmune disease patients. To accomplish this, Wang and colleagues used bullous pemphigoid (BP) as an example of a typical autoimmune disease. Specific Fab fragments to the non-collagenous 16th-A domain of type XVII collagen, the principal pathogenic target for autoantibodies in BP, were obtained from the antibody repertoires from patients with BP patients using phage display (58). The determination of the autoantibody profile represents a useful tool, not only helps to design neutralizing antibodies but also for both diagnosis and characterization of autoimmune diseases. Furthermore, peptides representing the epitopes identified by autoantibodies can be isolated from synthetic peptide phage display libraries. These peptides can then be used to neutralize autoantibodies and to design specific and safe vaccines that do not induce cross-reactivity.
This study highlights the importance of understanding the antibody or biomarker profiles to develop diagnostic tools to identify people who are in an early stage of the disease or individuals with a predisposition to developing an autoimmune disease in the future. Furthermore, these profiles are useful to develop antibodies or peptides to treat such patients by blocking the pathological action of autoantibodies. Such molecules can prevent complement activation through inhibition of autoantibody binding to the corresponding pathogenic autoantigen. Therapeutic antibody fragments with no Fc portion necessary to activate the complement pathway fail to initiate autoimmune disease. Several clinical studies have shown correlative evidence between autoimmune diseases and autoantibodies. Despite this, no current therapeutic approaches are designed to improve many autoimmune disease outcomes by reducing autoantibody production or activity. Another approach consists in treating autoimmune diseases with molecules from phage display libraries that target the Fc receptors. An example of this is the study carried out by Bril et al. in which shown encouraging results in phase 3 trials by blocking the neonatal Fc receptor (FcRn) in myasthenia gravis (ClinicalTrials.gov Identifier: NCT03971422) with the therapeutic Rozanolixizumab (59). Furthermore, a peptide derived from a phage display library could inhibit IgG- neonatal Fc receptor interaction reducing the IgG levels in vivo (60).
M.P. was the sole author of this article.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Declaration of competing interest
M.P. is Editor-in-Chief of Current Bioscience and a member of Current Bioscience editorial board. This article was reviewed by Current Bioscience editors and reviewers. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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