- Research article
- Open Access
Potential T cell epitopes of Mycobacterium tuberculosis that can instigate molecular mimicry against host: implications in autoimmune pathogenesis
- Sathi Babu Chodisetti†1,
- Pradeep K Rai†1,
- Uthaman Gowthaman†1,
- Susanta Pahari1 and
- Javed N Agrewala1Email author
© Chodisetti et al; licensee BioMed Central Ltd. 2012
Received: 1 October 2011
Accepted: 21 March 2012
Published: 21 March 2012
Molecular mimicry between microbial antigens and host-proteins is one of the etiological enigmas for the occurrence of autoimmune diseases. T cells that recognize cross-reactive epitopes may trigger autoimmune reactions. Intriguingly, autoimmune diseases have been reported to be prevalent in tuberculosis endemic populations. Further, association of Mycobacterium tuberculosis (M. tuberculosis) has been implicated in different autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. Although, in silico analyses have identified a number of M. tuberculosis specific vaccine candidates, the analysis on prospective cross-reactive epitopes, that may elicit autoimmune response, has not been yet attempted. Here, we have employed bioinformatics tools to determine T cell epitopes of homologous antigenic regions between M. tuberculosis and human proteomes.
Employing bioinformatics tools, we have identified potentially cross-reactive T cell epitopes restricted to predominant class I and II alleles of human leukocyte antigens (HLA). These are similar to peptides of mycobacterial proteins and considerable numbers of them are promiscuous. Some of the identified antigens corroborated with established autoimmune diseases linked with mycobacterial infection.
The present study reveals many target proteins and their putative T cell epitopes that might have significant application in understanding the molecular basis of possible T cell autoimmune reactions during M. tuberculosis infections.
Although, the immune system efficiently discriminates between self and non-self, the occurrence of autoimmune diseases is a testimony to the fact that such discrimination may be imprecise . Understanding the etiology of autoimmune diseases has been a great challenge to immunologists. The existence of central tolerance mechanism ensures the clonal deletion of autoreactive T cells and B cells. Nonetheless, there are ample evidences signifying that a considerable number of such cells can escape these "failsafe" mechanisms [1, 2]. Immunological insults like exposure to pathogenic bacteria, viruses, aberrant expression of self proteins and exposure to cryptic antigens, etc., have been implicated to trigger and amplify the immune reactions that culminate into autoimmune diseases [3–5]. Antigenic determinants/epitopes present in pathogens, which resemble the host proteins, can potentially be a threat in activating the cells of immune system, resulting in autoimmunity [3, 4]. This resemblance is popularly termed as molecular mimicry.
Many different autoimmune diseases have been hypothesized to be a result of this mistaken identity. As a result of molecular mimicry, the immune cells attack the host tissues [3, 5]. The sharing of similar epitopes between the host and the pathogens may instigate autoaggression by stirring autoreactive T cells and B cells. Usually, autoreactive T cells are quiescent in the periphery, since they may recognize cryptic or low affinity epitopes. Pathogenic organisms express pathogen associated molecular patterns (PAMPs) that are perceived by the immune system as "danger signals" through Toll Like Receptors (TLRs) . Hence, the "TLR licensed" antigen presenting cells (APCs) can potentially activate the self-reactive T cells, since they present antigens along with inflammatory signals. Antigenic presentation in such a context may result in high avidity interactions between autoreactive T cells and the APCs that eventually break tolerance . Antigens like the pulD protein from Klebsiella sp., nuclear antigen-1 from Epstein-Barr virus and OSP-A from Borrelia sp. have been associated with diseases like ankylosing spondylitis, systemic lupus erythematosus (SLE) and Lyme arthritis, respectively [7–9]. Importantly, T cells play a pivotal role in autoimmune reactions, since they may directly attack the host tissues or help B cells to produce autoantibodies . Molecular mimicry has been demonstrated in T cell specific autoimmune diseases such as multiple sclerosis (MS), myocarditis, diabetes, etc. One of the early, classic studies by Strominger's group showed that the T cells reacting to immunodominant peptide of myelin basic protein (MBP) could cross-react with viral antigens .
M. tuberculosis infects about two million people annually. In TB-endemic areas, it is estimated that almost one-third of the population is infected with M. tuberculosis. Interestingly, an abundant presence of autoimmune diseases has been reported in these populations [12, 13]. TB has been associated with many different autoimmune diseases like SLE, rheumatoid arthritis (RA), MS, etc [4, 13–21]. There are ample evidences to suggest that TB reactive T cells can potentially recognize self antigens [14, 17–19, 21]. This has been demonstrated in animal models and in TB affected individuals. For example, T cells responding to the 65 kDa antigen of M. tuberculosis have been shown to be present in the synovia of arthritis patients [14, 17]. Hence, during a chronic state of disease, T cells that cross-react with mycobacterial and self antigens are activated, leading to detrimental autoimmune responses. Identification of such cross-reactive epitopes may be of immense scope in understanding the pathogenesis of autoimmunity. In this era of informatics, in silico analyses have identified a number of M. tuberculosis specific T cell epitopes that could be potentially used as vaccines [22–25]. However, it warrants the information on prospective cross-reactive epitopes that may elicit autoimmune responses. Cytotoxic CD8 T cells and helper CD4 T cells recognize peptides in the context of HLA class I and class II molecules, respectively. Both the subsets have been implicated in mediating autoimmune responses. Here, we have used bioinformatics tools to identify M. tuberculosis and human cross-reactive T cell epitopes, restricted to predominant HLA class I and class II alleles [26, 27]. Interestingly, we could identify several epitopes exhibiting similarity between human and M. tuberculosis proteins that may be molecular triggers of autoimmunity.
Alleles used in the study
Predominantly occurring MHC (major histocompatibility complex) alleles in human population for HLA class I (A*01:01, A*02:01, A*03:01, A*11:01, A*24:02, B*07:02, B*08:01) and HLA class II (DRB1*01:01, DRB1*03:01, DRB1*04:01, DRB1*07:01, DRB1*08:02, DRB1*11:01, DRB1*13:02, DRB1*15:01) were chosen for the study [26–30].
Programs and databases
NetMHC 2.2 server predicts binding of peptides to various human HLA class II alleles using artificial neural networks (ANNs) .
NetMHC 3.0 server predicts binding of peptides to a number of different HLA class I alleles using artificial neural networks and weight matrices .
HAMAP (High-quality Automated and Manual Annotation of microbial Proteomes) automatically annotates a significant percentage of proteins originating from microbial genome sequencing projects . HAMAP uses annotation templates for protein families to propagate annotations to all members of manually defined protein families.
Expasy (Expert Protein Analysis System), is a proteomics server and allows browsing through a number of data bases as well as other cross-referenced ones . It also allows access to many analytical tools for the identification of proteins, analysis of their sequence and the prediction of tertiary structure.
UniProt is the world's most comprehensive catalogue of information on proteins . It is a central repository of protein sequences and functions created by joining the information contained in UniProt/Swiss-Prot/TrEMBL. The UniProt knowledgebase (UniProtKB) is the central hub for the collection of functional information on proteins, with accurate, consistent and rich annotation.
Identification and analysis of homologous M. tuberculosis peptides in humans
Sequences of curated proteins of M. tuberculosis were obtained from UNIPROT database employing HAMAP search. A total of 444 well characterized proteins of M. tuberculosis H37Rv were selected from the database. The four classifications of the proteins of M. tuberculosis, namely structural, secretory, antigenic and metabolic have been directly adopted from UNIPROT database. The proteins chosen were compared for similarity with the human proteome using BLAST program  from ExPASY server. Based on the BLAST results, regions of nine or more amino acids (small peptides) that were similar between the human and M. tuberculosis proteins were selected for further analysis. The selected human peptides were assessed for binding to different predominant HLA class I and class II alleles by using the NetMHC server. IC50 values were selected based on the binding scores of peptide core regions (9 amino acids length) to each allele. The peptides were classified based on predicted IC50 values as strong binders (IC50 ≤ 500), weak binders (500 ≤ IC50 ≤ 5000) and non-binders (IC50 ≥ 5000) [35–37]. The results were then analyzed by considering the binding affinity of peptides to HLA alleles, nature of antigens, allelic associations of autoimmune diseases and tuberculosis.
Mycobacterial proteome contains T cell epitopes that cross-react with human proteins
Putative CD4 T cell epitopes of established antigens involved in autoimmune diseases that share similarity with M.tuberculosis proteins.
(known to be associated with autoimmunity)
T cell epitope
HLA Class II Alleles
HLA DRB1* 01:01
HLA DRB1* 01:01, 03:01,04:01,07:01,11:01,15:01
HLA DRB1*01: 01, 04: 01, 07: 01, 01: 01, 13: 01, 15: 01
HLA DRB1*01: 01, 03: 01, 04: 01, 07: 01, 08: 02, 11: 01,15: 01
60 kDa chaperonin (Fragment) [HSPD1]
HLA DRB1*01: 01, 03: 01, 04: 01, 07: 01, 08: 02, 11: 01, 13: 01, 15: 01
HLA DRB1*01: 01, 03: 01, 04: 01, 07: 01, 11: 01, 13: 01
Putative uncharacterized protein HSPD1
HLA DRB1*01: 01
HLA DRB1*01: 01, 03: 01, 04: 01, 07: 01, 08: 02, 11: 01, 13: 01, 15: 01
T-complex protein 1 subunit beta
HLA DRB1*01: 01, 07: 01, 13: 01, 15: 01
T-complex protein 1 subunit epsilon
HLA DRB1*01: 01, 07: 01
Molybdopterin biosynthesis Mog protein
Stiff Man's Syndrome 
HLA DRB1*01: 01, 04: 01, 07: 01, 11: 01, 13: 01, 15: 01
Highly similar to Gephyrin
HLA DRB1*01: 01, 04: 01, 07: 01, 11: 01, 15: 01
Serine/threonine-protein kinase pknD
Paraneoplastic Limbic Encephalitis 
BR serine/threonine-protein kinase-2
HLA DRB1*01: 01, 07: 01, 13: 01
HLA DRB1*01: 01, 15: 01
Molecular mimicry between antigenic determinants present in pathogenic organisms and host proteins could potentially trigger autoimmune reactions . Interestingly, many mycobacterial antigens have been associated with autoimmune diseases [14, 16, 17]. This prompted us to investigate the occurrence of peptides in mycobacteria that share sequence similarity with human antigens; and identify T cell epitopes that probably would be responsible for autoimmunity.
Although, in silico tools have been used in the past to examine molecular mimics in other diseases ; the knowledge of such epitopes from mycobacteria still needs to be explored. Here, utilizing in silico methods, we have identified potential autoreactive CD4 and CD8 T cell epitopes that may act as molecular mimics and result in autoimmune response during M. tuberculosis infection. The following major findings have emerged from the present study: (i) there is an extensive number of potentially autoreactive CD4 and CD8 T cell epitopes that are similar to peptides of mycobacterial antigens; (ii) the majority of such epitopes are similar to the antigens from the metabolic proteins of mycobacteria; (iii) a considerable number of promiscuous CD4 T cell epitopes could be detected; (iv) some of the identified antigens were corroborated with established autoimmune diseases linked with mycobacterial infection, thus validating the approach. We believe that this study would be a suggestive starting point for future investigation that whether mycobacterial infections and molecular mimics may elicit T cell autoimmune reactions.
Autoimmune reactions occur as a consequence of the breakdown of self-tolerance. Even though the immune system has central and peripheral tolerance mechanisms to deter the presence of autoreactive T cells, the very occurrence of autoimmune diseases signifies that this may not totally eliminate the presence or detrimental activity of host reactive T cells . Autoimmune diseases develop as a result of multifactorial influences like genetic, hormonal, and environmental factors [43, 44]. One of these key elements that substantially influence the development of autoimmunity is the occurrence of antecedent infections . Almost every autoimmune disease investigated is assumed to be linked to one or more such infections. One of the classical evidences arguing for this hypothesis is the autoimmune acute rheumatic fever, which is associated with the infection with Streptococcus pyogenes. Molecular resemblance between the bacterial M-protein and human glycoproteins results in a breakdown of self-tolerance . The molecular mimicry hypothesis proposes that shared epitopes between the host and pathogen can break tolerance and elicit autoreactivity. The degeneracy of antigen recognition by the T cell receptor may also help in such cross-reactivity . Similarly, pathogen specific antibodies also can cross-react with host proteins . Hence, molecular mimicry and consequent epitope spreading is now a generally accepted phenomenon influencing autoimmune reactions [3, 42, 45, 47]. The idea of molecular mimicry was strongly put forward by Fujinami and Oldstone, where they argued that molecular mimicry could contribute pathogenesis of MS . The criteria for this mechanism includes that the pathogen must be associated with the onset of the autoimmune reactions, the antigens from the pathogen must provoke an immune response that cross-reacts with host proteins. Further, the cross-reactive epitopes should induce disease, if tested in an animal model . There are many reports that act as evidences to satisfy each of these criteria [2, 7, 44, 45].
The presentation of certain antigenic epitopes (that are mimics of host antigens) to T cells by the pathogen encountered "TLR licensed" APCs may initiate the autoreactive responses . Thus, homologous antigens from pathogens can potentially "revive" the otherwise non-responding autoreactive T cells. The inflammatory cytokines present during such priming may also imprint tissue migratory properties. When such autoreactive T cells come across the "cognate" host antigens, they will destruct tissues by their effector mechanisms. Hence, infection not only activates the autoreactive T cells but also may empower them to migrate to distant tissues thus initiating a process that ultimately escalates in to a full-bloomed disease. Tuberculosis has been associated with autoimmune reactions [13, 16]. Classical studies have demonstrated the occurrence of mycobacterium reactive T cells that cross-react to antigens associated with MS, RA, etc [18–21]. Interestingly, in many cases the antigen was found to be HSP60 [14, 18, 20]. The present study also corroborates with these findings. In addition, our extensive comparative analysis of the proteomes of M. tuberculosis and humans followed by T cell epitope identification has revealed many more such possible target proteins and their putative epitopes. In the present scenario, where identifying the etiology of autoimmune diseases remains a great challenge, we believe that the outcome of the present study would open up extensive future investigations into molecular basis of possible T cell autoimmune reactions during mycobacterial infections.
In essence, this study indicates the existence of considerable number of potential cross-reactive T cell epitopes between M. tuberculosis and the human proteome, which may elicit molecular mimicry and result in autoimmune responses during M. tuberculosis infection. Some of the epitopes were promiscuously binding to predominantly occurring HLA alleles and corroborated well with established autoimmune diseases. The identified target proteins and their putative T cell epitopes may have significant implications that will open up extensive investigations in understanding the molecular basis of autoimmune reactions during M. tuberculosis infection.
The authors thank Council of Scientific and Industrial Research (CSIR) and Department of Biotechnology (DBT), India, for financial support. SBC and PKR are recipients of fellowship of CSIR, and UG of DBT.
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