These mechanisms are known by many to be intrinsic. However, there are pathogenic mechanisms for the generation of autoimmune disease.
Pathogens can induce autoimmunity by polyclonal activation of B or T cells, or increased expression of major histocompatibility complex MHC class I or II molecules. There are several ways in which a pathogen can cause an autoimmune response.
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A pathogen may contain a protein that acts as a mitogen to encourage cell division, thus causing more B or T cell clones to be produced. Similarly, a pathogenic protein may act as a superantigen which causes rapid polyclonal activation of B or T cells. Pathogens can also cause the release of cytokines resulting in the activation of B or T cells, or they can alter macrophage function. Finally, pathogens may also expose B or T cells to cryptic determinants, which are self antigen determinants that have not been processed and presented sufficiently to tolerize the developing T cells in the thymus and are presented at the periphery where the infection occurs.
Molecular mimicry has been characterized as recently as the s as another mechanism by which a pathogen can generate autoimmunity. Molecular mimicry is defined as similar structures shared by molecules from dissimilar genes or by their protein products. Either the linear amino acid sequence or the conformational fit of the immunodominant epitope may be shared between the pathogen and host.
This is also known as " cross-reactivity " between self antigen of the host and immunodominant epitopes of the pathogen. An autoimmune response is then generated against the epitope. Due to similar sequence homology in the epitope between the pathogen and the host, cells and tissues of the host associated with the protein are destroyed as a result of the autoimmune response. The prerequisite for molecular mimicry to occur is thus the sharing of the immunodominant epitope between the pathogen and the immunodominant self sequence that is generated by a cell or tissue.
However, due to the amino acid variation between different proteins, molecular mimicry should not happen from a probability standpoint. Assuming five to six amino acid residues are used to induce a monoclonal antibody response, the probability of 20 amino acids occurring in six identical residues between two proteins is 1 in 20 6 or 1 in 64,, However, there has been evidence shown and documented of many molecular mimicry events. To determine which epitopes are shared between pathogen and self, large protein databases are used.
The largest protein database in the world, known as the UniProt database formerly SwissProt , has shown reports of molecular mimicry becoming more common with expansion of the database. The database currently contains 1. The probability of finding a perfect match with a motif of 5 amino acids in length is 1 in 3.
Therefore, within the SwissProt database, one would expect to find 1. However, there are sequence motifs within the database that are overrepresented and are found more than 5 times. This motif is also expressed on numerous other proteins, such as on gp of the Epstein-Barr virus and in E. This motif occurs 37 times in the database. The possibility exists, then, for variability within amino acid sequence, but similarity in three-dimensional structure between two peptides can be recognized by T cell clones.
This, therefore, uncovers a flaw of such large databases. They may be able to give a hint to relationships between epitopes, but the important three-dimensional structure cannot yet be searched for in such a database. Despite no obvious amino acid sequence similarity from pathogen to host factors, structural studies have revealed that mimicry can still occur at the host level.
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In some cases, pathogenic mimics can possess a structural architecture that differs markedly from that of the functional homologues. Therefore, proteins of dissimilar sequence may have a common structure which elicits an autoimmune response. It has been hypothesized that these virulent proteins display their mimicry through molecular surfaces that mimic host protein surfaces protein fold or three-dimensional conformation , which have been obtained by convergent evolution.
It has also been theorized that these similar protein folds have been obtained by horizontal gene transfer , most likely from a eukaryotic host. This further supports the theory that microbial organisms have evolved a mechanism of concealment similar to that of higher organisms such as the African praying mantis or chameleon who camouflage themselves so that they can mimic their background as not to be recognized by others.
Despite dissimilar sequence homology between self and foreign peptide, weak electrostatic interactions between foreign peptide and the MHC can also mimic self peptide to elicit an autoimmune response within the host. For example, charged residues can explain the enhanced on-rate and reduced off-rate of a particular antigen or can contribute to a higher affinity and activity for a particular antigen that can perhaps mimic that of the host.
Similarly, prominent ridges on the floor of peptide-binding grooves can do such things as create C-terminal bulges in particular peptides that can greatly increase the interaction between foreign and self peptide on the MHC. It is now apparent that sequence similarity considerations are not sufficient when evaluating potential mimic epitopes and the underlying mechanisms of molecular mimicry. Molecular mimicry, from these examples, has therefore been shown to occur in the absence of any true sequence homology. There has been increasing evidence for mimicking events caused not only by amino acid similarities but also in similarities in binding motifs to the MHC.
Molecular mimicry is thus occurring between two recognized peptides that have similar antigenic surfaces in the absence of primary sequence homology.
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For example, specific single amino acid residues such as cysteine creates di-sulfide bonds , arginine or lysine form multiple hydrogen bonds , could be essential for T cell cross-reactivity. These single residues may be the only residues conserved between self and foreign antigen that allow the structurally similar but sequence non-specific peptides to bind to the MHC. Epitope spreading, also known as determinant spreading, is another common way in which autoimmunity can occur which uses the molecular mimicry mechanism.
Autoreactive T cells are activated de novo by self epitopes released secondary to pathogen-specific T cell-mediated bystander damage. Thus, inflammatory responses induced by specific pathogens that trigger pro-inflammatory T h 1 responses have the ability to persist in genetically susceptible hosts. This may lead to organ-specific autoimmune disease. The result of this is an autoimmune response that is triggered by exogenous antigen that progresses to a truly autoimmune response against mimicked self antigen and other antigens. The HIV-1 virus has been shown to cause diseases of the central nervous system CNS in humans through a molecular mimicry apparatus.
HIV-1 gp41 is used to bind chemokines on the cell surface of the host so that the virion may gain entrance into the host. Antibodies are produced for the HIV-1 gp41 protein. These antibodies can cross-react with astrocytes within human CNS tissue and act as autoantibodies. This virus has been shown to cause CNS disease in mice that resembles multiple sclerosis, an autoimmune disease in humans that results in the gradual destruction of the myelin sheath coating axons of the CNS.
Bystander myelin damage is caused by virus specific T h 1 cells that cross react with this self epitope. To test the efficacy in which TMEV uses molecular mimicry to its advantage, a sequence of the human myelin-specific epitope was inserted into a non-pathogenic TMEV variant. These involve the hepatitis B virus mimicking the human proteolipid protein myelin protein and the Epstein-Barr virus mimicking anti- myelin oligodendrocyte glycoprotein contributes to a ring of myelin around blood vessels.
Myasthenia gravis is another common autoimmune disease. This disease causes fluctuating muscle weakness and fatigue. The disease occurs due to detectable antibodies produced against the human acetylcholine receptor. Similar to HIV-1, gpD also aids in binding to chemokines on the cell surface of the host to gain entry into the host. Despite this, an autoimmune response still occurs. This further shows an immunologically significant sequence homology to the biologically active site of the human acetylcholine receptor.
There are ways in which autoimmunity caused by molecular mimicry can be avoided. While the interest in cancer vaccines is renewed by some results in vaccine-based clinical trials, the premise still suffers from the incomplete concept of a successful vaccine. Future progress may come from matching preclinical data with clinical expectations while taking a step back to understand the systems perspective. For instance, the accumulation over the last three decades of clear associations of T and B cell cross-reactivity between a set of host targets of autoimmunity and microbial antigens strongly supports a pathogenic role for molecular mimicry.
Mimicry on its turn invites the concept of networks of molecular interactions. The intentional and rational approach to exploit mimicry in cancer vaccine development, while littered with failure, has provided also some insight into success. Here, we visit successes and underlying rationale to lend to future development of mimetic vaccines in immune-oncology. Targeting malignancies through manipulating the immune system has seen success in a variety approaches ranging from whole cell vaccination, to autologous dendritic cell based vaccines and therapeutic immune-modulation [ 1 , 2 , 3 , 4 , 5 ].
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But a number of opportunities and challenges remain. While tumor antigen identification from sequencing the cancer genome continues to be a high priority we now know that tumor antigens arise from multiple mechanisms that include somatic mutations, translocations, and amplifications and post-translational modifications. The role of post-translational modification with tumor associated carbohydrate antigens TACA in the generation of novel cancer antigens is in particular an opportunity to be explored [ 6 , 7 , 8 , 9 ].
Characterizing and overcoming the immunosuppressive environment of the tumors has led to a focus on downstream checkpoints that regulate activated T cells, or on vaccination and T cell adoptive transfer to expand the T cell pool [ 10 , 11 , 12 ]. However, it is well known that cancer-signaling pathways play pivotal roles in the biologic behavior of tumor cells that creates an opportunity to rethink cancer in general [ 13 ] and rethink cancer targeting strategies with small molecules [ 14 , 15 ], with monoclonal antibodies [ 16 ] and induced antibodies [ 17 , 18 ].
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By the same token such pathways are also involved in developing therapeutic resistance, which requires alternative immunotherapeutic strategies. One such strategy is to develop polyclonal humoral immune responses by active immunotherapy. On the one hand the effect can be pursued by formulating a platform with multiple epitopes of target antigens [ 19 ].
On the other—making use of polyspecific pan-antigen mimetics to target simultaneously multiple antigens on cancer cells [ 17 , 18 ]. A polyclonal antibody approach would target more than two antigens on a single tumor cell, which is expected to have even higher potential.
This latter idea is a part of the conceptual evolution in immune-oncology harnessing polyclonal responses to cancer cells. The concept of mimetic vaccines in oncology. Carbohydrate specificity and anti-idiotype interactions are related more to the later compartment. Polyspecific vaccines based on carbohydrate mimotopes or idiotypes recruit B cell clones across that spectrum but their novel properties are related mostly to their capacity to elicit diversified responses from MZ and B1 cells including idiotypically connected clones.
In addition, the mimotopes capture only the most salient features of the carbohydrate epitopes and induce diversified responses targeting multiple antigens illustrated by diverse words sharing only partially the topology of the mimotope as compared to highly specific responses that match the shape of the epitope. Thus, mimetic vaccines both target polyspecific compartments of the B cell repertoire as well as they themselves function as polyspecific antigens.
Systems immunology is now in focus to understand the immune system [ 20 ], especially in the context of vaccinology [ 21 ]. This perspective is ushering in a new era in vaccine development [ 22 ]. For the future, it is argued that successful approaches will depend on the elucidation of the entire network of immune signaling pathways that regulate immune responses with an eye toward integrating advances in computational and systems biology, genomics, immune monitoring, bioinformatics and machine learning [ 22 , 23 ].
Systems immunology also teaches us that one antigen can substitute for another having the potential to regulate tolerance [ 24 , 25 , 26 , 27 , 28 ]. However, it is unclear why an immune system that is tolerant of its own self-antigens would respond to a self-antigen mimic in a vaccine. Antibodies referred to as anti-idiotypic are produced during the process of tolerization and demonstrated in tolerant animals [ 29 , 30 ] and in patients [ 31 ].
These antibodies may prevent a B cell receptor from interacting with the antigen. Jerne envisioned the immune system as a web of immunoglobulin V domains constituting an idiotypic network. Inherent to the idiotype network is that antibodies recognize antibodies. Jerne thought that regulatory processes governed by idiotypic interactions could explain the generation of the various immune states that include tolerance.
An extension of the network theory was that antibodies, by virtue of being recognized by antibodies, might function as mimics of antigens that would break tolerance instead of maintaining it—the so-called Ab2, used as antigen surrogates [ 32 ]. Thus a new context of molecular mimicry was born—one highlighted by the functionality of idiotypic antibodies in the context of the idiotype network theory [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Smaller fragments peptides of anti-idiotypes proved to translate successfully to vaccines too [ 40 ]. Peptides as mimics of antigens were clearly defined with the advent of phage screening technology [ 41 , 42 ] growing in its application in biomedical sciences [ 43 ].
Peptide mimics are well defined as B and T cell epitopes [ 44 ]. Now there is an unprecedented opportunity to unravel the intricacies of the human immune response to immunization.
Anti-Idiotypes, Receptors, and Molecular Mimicry
Yet, fundamentally, vaccine strategies across susceptible disease depend on the identification of immunogenic antigens that can serve as the best targets [ 45 , 46 , 47 ]. Tumor antigens present a special challenge. Except for small details defined by mutations or altered post-translational modifications, generally they are self-antigens and this poses a barrier to effective vaccination.
Tolerance is different from non-specific immunosuppression, and immunodeficiency. Like immune response, tolerance is specific existing both for T-cell and B cells and, like immunological memory tolerance is lasting longer at the T cell level than at the B cell level. Maintenance of immunological tolerance requires persistence of antigen. Tolerance can be broken naturally or artificially [ 48 , 49 ].
Mimicry might impact on an already existing autoimmune process rather than precipitate novel disease by breaking of tolerance from the beginning [ 50 ]. While molecular mimicry is proposed as a basis for potential pathogenesis of some human disease, there are examples also of its exploitation in vaccine development. It is also acknowledged that these preexisting antibodies can be affected by the presence of exogenous antigen since they recognize in a polyspecific manner evolutionarily fixed epitopes present in foreign antigens as well as on self-antigens [ 53 ].
Because of their constitutive expression, responses by natural antibodies are generally excluded from vaccine strategies. Among approaches that can modulate the natural antibody repertoire are immunizations affecting idiotypic interactions. Once acclaimed, idiotypy—the theory that the B lymphocyte repertoire forms a highly connected network of mutually recognizing and stimulating clones [ 54 , 55 ]—unfortunately predated the discovery of many more levels of immune system complexity. The daunting task of attuning to the new knowledge prevented this theory from maintaining a support that would match its intellectual attractiveness.
Almost, because many immune system phenomena like a self-assertive rather than ignorant tolerance or the immune memory ultimately do not need to be explained by emergent properties of the immune network. Now it is accepted that specific cell populations and genetic programs rather than the dynamics of a network of functionally equivalent agents clones are responsible for almost all of the observed immune phenomena.
In fact, recent development in our understanding of swarms of simple agents uncovers the limits of such systems where complexity of the behavior of the agents and the size of the system have Goldilocks conditions for optimal behavior [ 57 ]. While the natural antibodies in a strict sense are produced by a particular subset of B1 cell derived plasma cells in the bone marrow without external stimulus there are B1 cells e.
Thus, focusing on the naturally autoreactive compartment of the repertoire did not answer all questions but also added another dimension of uncertainty. Natural antibodies are known to bind to a variety of antigens that are both self and exogenous and thereby providing one of the first lines of defense against both bacterial and viral pathogens [ 53 , 59 ].
Antibodies reactive to self-antigens play a key role in both healthy individuals and patients with autoimmune disorders [ 60 , 61 , 62 ]. Hence, such antibodies are intrinsically multifaceted in their regulatory roles in immune responses and tolerance. While the immune response activated against self can be detrimental when triggered in an autoimmune genetic background, tuning immune activity with natural antibodies is a potential therapeutic strategy. One conceptual approach in this tuning is using naturally occurring anti-idiotype anti-Id antibodies to stimulate multifaceted natural antibodies.
Anti-idiotypic based vaccines have a long history of generating immune responses in experimental animals and in humans [ 27 , 28 , 63 , 64 , 65 ]. One of the first demonstrations for the basis of molecular mimicry observed between proteins and anti-idiotypes for proteins was dissected in the TEPC idiotype system [ 66 ]. They suggested that the minimal stretch of homology 8—10 amino acid residues was responsible for the cross-reactive nature of the TEPC idiotype and the acute-phase protein C-reactive protein CRP from the horseshoe crab Limulus polyphemus limulin.
Of no less importance, it was shown that T helper cells could recognize a shared determinant that is present on idiotypically different myeloma proteins [ 67 ]. These findings collectively showed that T helper cells, induced by priming with antigen, can recognize shared idiotypic determinates, suggesting that peptides derived from anti-idiotypes can be processed as immunogens [ 40 , 68 ].
The early studies of anti-idiotypes made clear the idea that functional mimicry of ligands of biological receptors is a matter of just binding to an antibody-binding site. This functional or antigenic mimicry ushered in concepts and a technology. It was evident that structural and immunological rules governing molecular mimicry require definition for its successful exploitation whether anti-idiotypes, small fragments derived from them or peptide mimetics [ 69 , 70 ]. It was suggested that ligand-based pharmacophore design principles could be applied to designing peptides that can mimic ligands reactive with antibodies [ 69 , 71 ].
Often times it was stated that there were no observable structural correlations to explain the mimicry [ 72 ]. Yet it seemed that antibodies could mimic antigens at the molecular level whereby the antigen and anti-idiotype could bind essentially the same combining-site residues of the Ab1 antibody [ 73 ]. Historically, clinical trials with anti-idiotypes in the cancer space have proved to be of mixed success [ 74 , 75 ] but, clearly showing that humoral and cellular immune reactivity against a tumor can be enhanced upon active anti-id vaccination [ 76 ].
Other studies with anti-ids in humans have included those associated with tumor associated carbohydrate antigens TACAs , [ 77 , 78 , 79 , 80 ]. These examples are representative for other anti-Id vaccine trials.
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