Molecular mimicry
Encyclopedia
Molecular mimicry is defined as the theoretical possibility that sequence similarities between foreign and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the promiscuity of several peptide sequences which can be both foreign and self in nature, a single antibody
or TCR (T cell receptor
) can be activated by even a few crucial residues which stresses the importance of structural homology
in the theory of molecular mimicry. Upon the activation of B or T cells, it is believed that these “peptide mimic” specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity
). Molecular mimicry is a phenomenon that has been just recently discovered as one of several ways in which autoimmunity can be evoked. A molecular mimicking event is, however, more than an epiphenomenon despite its low statistical probability of occurring and these events have serious implications in the onset of many human autoimmune disorders.
In the past decade the study of autoimmunity, the failure to recognize self antigens as “self," has grown immensely. Autoimmunity is a result of a loss of immunological tolerance, the ability for an individual to discriminate between self and non-self. Growth in the field of autoimmunity has resulted in more and more frequent diagnosis of autoimmune diseases. Consequently, recent data show that autoimmune diseases affect approximately 1 in 31 people within the general population. Growth has also led to a greater characterization of what autoimmunity is and how it can be studied and treated. With an increased amount of research, there has been tremendous growth in the study of the several different ways in which autoimmunity can occur, one of which is molecular mimicry. The mechanism by which pathogens have evolved, or obtained by chance, similar amino acid
sequences or the homologous three-dimensional crystal structure of immunodominant epitopes remains a mystery.
. Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Autoimmunity is evoked when this tolerance to self antigen is broken. Tolerance within an individual is normally evoked as a fetus
. This is known as maternal-fetal tolerance where T cells expressing receptors specific for a particular antigen enters the circulation of the developing fetus via the placenta.
After pre-T cells leave the bone marrow where they are synthesized, they are moved to the thymus
where the maturation of T cells occurs. It is here where the first wave of T cell tolerance arises. Within the thymus, pre-T cells will encounter various self and foreign antigens present in the thymus that enter the thymus from peripheral sites via the circulatory system
. Within the thymus, pre-T cells undergo a selection process where they must be positively selected and should avoid negative selection. T cells that bind with low avidity
to self-MHC receptors are positively selected for maturation, those that do not die by apoptosis
. Cells that survive positive selection, but bind strongly to self-antigens are negatively selected also by active induction of apoptosis. This negative selection is known as clonal deletion, one of the mechanisms for T cell tolerance. Approximately 99 percent of pre-T cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity.
However, there is only a limited repertoire of antigen that T cells can encounter within the thymus. T cell tolerance then must occur within the periphery after the induction of T cell tolerance within the thymus as a more diverse group of antigens can be encountered in peripheral tissues. This same positive and negative selection mechanism, but in peripheral tissues, is known as clonal anergy
. The mechanism of clonal anergy is important to maintain tolerance to many autologous antigens. Active suppression is the other known mechanism of T cell tolerance. Active suppression involves the injection of large amounts of foreign antigen in the absence of an adjuvant
which leads to a state of unresponsiveness. This unresponsive state is then transferred to a naïve recipient from the injected donor to induce a state of tolerance within the recipient.
Tolerance is also produced in B cells. There are also various processes which lead to B cell tolerance. Just as in T cells, clonal deletion and clonal anergy can physically eliminate autoreactive B cell clones. Receptor editing is another mechanism for B cell tolerance. This involves the reactivation or maintenance of V(D)J gene recombination in the cell which leads to the expression of novel receptor specificity through V region gene rearrangements which will create variation in the heavy and light immunoglobulin (Ig) chains.
(MHC) class I or II molecules. There are several ways in which a pathogen can cause an autoimmune response. 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 which 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 1970’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.
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 1.5 X 107 residues. The probability of finding a perfect match with a motif of 5 amino acids in length is 1 in 3.7 X 10−7 (0.055). Therefore, within the SwissProt database, one would expect to find 1.5 X 107 X 3.7 X 10−7 = 5 matches. However, there are sequence motifs within the database that are overrepresented and are found more than 5 times. For example, the QKRAA sequence is an amino acid motif in the third hypervariable region of HLA-DRB1*0401. This motif is also expressed on numerous other proteins, such as on gp110 of the Epstein-Barr virus
and in E. coli. This motif occurs 37 times in the database. This would suggest that the linear amino acid sequence may not be an underlying cause of molecular mimicry since it can be found numerous times within 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.
. 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. Similarly, there has been evidence that even gross features such as acidic/basic and hydrophobic/hydrophilic interactions have allowed foreign peptides to interact with an antibody or MHC and TCR. 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. 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.
(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. Astrocytes are cells of the CNS which are used to regulate the concentrations of K+ and neurotransmitter
which enter the cerebrospinal fluid
(CSF) to contribute to the blood brain barrier. A twelve amino acid sequence (Leu-Gly-Ile-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys) on gp41 of the HIV-1 virus (immunodominant region) shows sequence homology with a twelve amino acid protein on the surface of human astrocytes. 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 contributes to many CNS complications found in AIDS
patients.
Theiler’s murine encephalomyelitis virus (TMEV) leads to the development of a progressive CD4+ T cell-mediated response after these cells have infiltrated the CNS. This virus has been shown to cause multiple sclerosis
, which is another autoimmune disease. It results in the gradual destruction of the myelin
sheath coating axons of the CNS. TMEV shares a thirteen amino acid sequence (His-Cys-Leu-Gly-Lys-Trp-Leu-Gly-His-Pro-Asp-Lys-Phe) (PLP (proteolipid protein) 139-151 epitope) with that of a human myelin-specific epitope. Bystander myelin damage is caused by virus specific Th1 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. As a result, there was a CD4+ T cell response and autoimmune demyelination was initiated by infection with a TMEV peptide ligand. In humans, it has recently been shown that there are other possible targets for molecular mimicry in patients with multiple sclerosis. 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).
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
. The receptor contains a seven amino acid sequence (Trp-Thr-Tyr-Asp-Gly-Thr-Lys) in the α-subunit that demonstrates immunological cross-reactivity with a shared immunodominant domain of gpD of the herpes simplex virus
(HSV). Similar to HIV-1, gpD also aids in binding to chemokines on the cell surface of the host to gain entry into the host. Cross-reactivity of the self epitope (α-subunit of the receptor) with antibodies produced against HSV suggests that the virus is associated with the initiation of myasthenia gravis. Not only does HSV cause immunologic cross-reactivity, but the gpD peptide also competitively inhibits the binding of antibody made against the α-subunit to its corresponding peptide on the α-subunit. 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.
and azathioprine
has also been used as a possible solution. However, in many cases this has been shown to be ineffective because cells and tissues have already been destroyed at the onset of the infection.
The concept of molecular mimicry is a useful tool in understanding the etiology
, pathogenesis
, treatment, and prevention of autoimmune disorders. Molecular mimicry is, however, only one mechanism by which an autoimmune disease can occur in association with a pathogen. Understanding the mechanisms of molecular mimicry may allow future research to be directed toward uncovering the initiating infectious agent as well as recognizing the self determinant. This way, future research may be able to design strategies for treatment and prevention of autoimmune disorders. The use of transgenic models such as those used for discovery of the mimicry events leading to diseases of the CNS and muscle disorders has helped evaluate the sequence of events leading to molecular mimicry.
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
or TCR (T cell receptor
T cell receptor
The T cell receptor or TCR is a molecule found on the surface of T lymphocytes that is responsible for recognizing antigens bound to major histocompatibility complex molecules...
) can be activated by even a few crucial residues which stresses the importance of structural homology
Homology (chemistry)
In chemistry, homology refers to the appearance of homologues. A homologue is a compound belonging to a series of compounds differing from each other by a repeating unit, such as a methylene group, a peptide residue, etcetera....
in the theory of molecular mimicry. Upon the activation of B or T cells, it is believed that these “peptide mimic” specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity
Autoimmunity
Autoimmunity is the failure of an organism to recognize its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease...
). Molecular mimicry is a phenomenon that has been just recently discovered as one of several ways in which autoimmunity can be evoked. A molecular mimicking event is, however, more than an epiphenomenon despite its low statistical probability of occurring and these events have serious implications in the onset of many human autoimmune disorders.
In the past decade the study of autoimmunity, the failure to recognize self antigens as “self," has grown immensely. Autoimmunity is a result of a loss of immunological tolerance, the ability for an individual to discriminate between self and non-self. Growth in the field of autoimmunity has resulted in more and more frequent diagnosis of autoimmune diseases. Consequently, recent data show that autoimmune diseases affect approximately 1 in 31 people within the general population. Growth has also led to a greater characterization of what autoimmunity is and how it can be studied and treated. With an increased amount of research, there has been tremendous growth in the study of the several different ways in which autoimmunity can occur, one of which is molecular mimicry. The mechanism by which pathogens have evolved, or obtained by chance, similar amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequences or the homologous three-dimensional crystal structure of immunodominant epitopes remains a mystery.
Immunological tolerance
Tolerance is a fundamental property of the immune systemImmune system
An immune system is a system of biological structures and processes within an organism that protects against disease by identifying and killing pathogens and tumor cells. It detects a wide variety of agents, from viruses to parasitic worms, and needs to distinguish them from the organism's own...
. Tolerance involves non-self discrimination which is the ability of the normal immune system to recognize and respond to foreign antigens, but not self antigens. Autoimmunity is evoked when this tolerance to self antigen is broken. Tolerance within an individual is normally evoked as a fetus
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. This is known as maternal-fetal tolerance where T cells expressing receptors specific for a particular antigen enters the circulation of the developing fetus via the placenta.
After pre-T cells leave the bone marrow where they are synthesized, they are moved to the thymus
Thymus
The thymus is a specialized organ of the immune system. The thymus produces and "educates" T-lymphocytes , which are critical cells of the adaptive immune system....
where the maturation of T cells occurs. It is here where the first wave of T cell tolerance arises. Within the thymus, pre-T cells will encounter various self and foreign antigens present in the thymus that enter the thymus from peripheral sites via the circulatory system
Circulatory system
The circulatory system is an organ system that passes nutrients , gases, hormones, blood cells, etc...
. Within the thymus, pre-T cells undergo a selection process where they must be positively selected and should avoid negative selection. T cells that bind with low avidity
Avidity
In proteins, avidity is a term used to describe the combined strength of multiple bond interactions. Avidity is distinct from affinity, which is a term used to describe the strength of a single bond...
to self-MHC receptors are positively selected for maturation, those that do not die by apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
. Cells that survive positive selection, but bind strongly to self-antigens are negatively selected also by active induction of apoptosis. This negative selection is known as clonal deletion, one of the mechanisms for T cell tolerance. Approximately 99 percent of pre-T cells within the thymus are negatively selected. Only approximately 1 percent are positively selected for maturity.
However, there is only a limited repertoire of antigen that T cells can encounter within the thymus. T cell tolerance then must occur within the periphery after the induction of T cell tolerance within the thymus as a more diverse group of antigens can be encountered in peripheral tissues. This same positive and negative selection mechanism, but in peripheral tissues, is known as clonal anergy
Anergy
Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...
. The mechanism of clonal anergy is important to maintain tolerance to many autologous antigens. Active suppression is the other known mechanism of T cell tolerance. Active suppression involves the injection of large amounts of foreign antigen in the absence of an adjuvant
Adjuvant
An adjuvant is a pharmacological or immunological agent that modifies the effect of other agents, such as a drug or vaccine, while having few if any direct effects when given by itself...
which leads to a state of unresponsiveness. This unresponsive state is then transferred to a naïve recipient from the injected donor to induce a state of tolerance within the recipient.
Tolerance is also produced in B cells. There are also various processes which lead to B cell tolerance. Just as in T cells, clonal deletion and clonal anergy can physically eliminate autoreactive B cell clones. Receptor editing is another mechanism for B cell tolerance. This involves the reactivation or maintenance of V(D)J gene recombination in the cell which leads to the expression of novel receptor specificity through V region gene rearrangements which will create variation in the heavy and light immunoglobulin (Ig) chains.
Autoimmunity
Autoimmunity can thus be defined simply as exceptions to the tolerance "rules." By doing this, an immune response is generated against self-tissue and cells. 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 complexMajor histocompatibility complex
Major histocompatibility complex is a cell surface molecule encoded by a large gene family in all vertebrates. MHC molecules mediate interactions of leukocytes, also called white blood cells , which are immune cells, with other leukocytes or body cells...
(MHC) class I or II molecules. There are several ways in which a pathogen can cause an autoimmune response. A pathogen may contain a protein that acts as a mitogen
Mitogen
A mitogen is a chemical substance that encourages a cell to commence cell division, triggering mitosis. A mitogen is usually some form of a protein.Mitogenesis is the induction of mitosis, typically via a mitogen....
to encourage cell division, thus causing more B or T cell clones to be produced. Similarly, a pathogenic protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
may act as a superantigen
Superantigen
Superantigens are a class of antigens which cause non-specific activation of T-cells resulting in oligoclonal T cell activation and massive cytokine release...
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
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
function. Finally, pathogens may also expose B or T cells to cryptic determinants which are self antigen determinants which 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 1970’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
Cross-reactivity
Cross-reactivity is the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity...
” 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.
Probability of mimicry events
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 206 or 1 in 64,000,000. 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
UniProt
UniProt is a comprehensive, high-quality and freely accessible database of protein sequence and functional information, many of which are derived from genome sequencing projects...
database (formerly SwissProt), has shown reports of molecular mimicry becoming more common with expansion of the database. The database currently contains 1.5 X 107 residues. The probability of finding a perfect match with a motif of 5 amino acids in length is 1 in 3.7 X 10−7 (0.055). Therefore, within the SwissProt database, one would expect to find 1.5 X 107 X 3.7 X 10−7 = 5 matches. However, there are sequence motifs within the database that are overrepresented and are found more than 5 times. For example, the QKRAA sequence is an amino acid motif in the third hypervariable region of HLA-DRB1*0401. This motif is also expressed on numerous other proteins, such as on gp110 of the Epstein-Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
and in E. coli. This motif occurs 37 times in the database. This would suggest that the linear amino acid sequence may not be an underlying cause of molecular mimicry since it can be found numerous times within 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.
Structural mimicry
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. 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 evolutionConvergent evolution
Convergent evolution describes the acquisition of the same biological trait in unrelated lineages.The wing is a classic example of convergent evolution in action. Although their last common ancestor did not have wings, both birds and bats do, and are capable of powered flight. The wings are...
. It has also been theorized that these similar protein folds have been obtained by horizontal gene transfer
Horizontal gene transfer
Horizontal gene transfer , also lateral gene transfer , is any process in which an organism incorporates genetic material from another organism without being the offspring of that organism...
, 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
Chameleon
Chameleons are a distinctive and highly specialized clade of lizards. They are distinguished by their parrot-like zygodactylous feet, their separately mobile and stereoscopic eyes, their very long, highly modified, and rapidly extrudable tongues, their swaying gait, the possession by many of a...
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. Similarly, there has been evidence that even gross features such as acidic/basic and hydrophobic/hydrophilic interactions have allowed foreign peptides to interact with an antibody or MHC and TCR. 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. For example, specific single amino acid residues such as cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
(creates di-sulfide bonds), arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
or lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
(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
Epitope spreading is another common way in which autoimmunity can occur which uses the molecular mimicry mechanism. This inducer of autoimmunity causes autoreactive T cells to be activated de novo by self epitopes released secondary to pathogen-specific T cell-mediated bystander damage. T cell responses to progressively less dominant epitopes are activated as a consequence of the release of other antigens secondary to the destruction of the pathogen with a homologous immunodominant sequence. Thus, inflammatory responses induced by specific pathogens that trigger pro-inflammatory Th1 responses have the ability to persist in genetically susceptible hosts. This may lead to organ-specific autoimmune disease. Conversely, epitope spreading could be due to target antigens being physically linked intracellularly as members of a complex to self antigen. 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. From these examples, it is clear that the search for candidate mimic epitopes must extend beyond the immunodominant epitopes of a given autoimmune response.Diseases of the central nervous system
The HIV-1 virus has been shown to cause diseases of the central nervous systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) in humans through a molecular mimicry apparatus. HIV-1 gp41
Gp41
gp41 is a subunit of the envelope protein complex of retroviruses, including Human immunodeficiency virus and Simian-Human immunodeficiency virus. This glycoprotein subunit remains non-covalently-bound to gp120, and provides the second step by which HIV enters the cell...
is used to bind chemokines on the cell surface of the host so that the virion may gain entrance into the host. Astrocytes are cells of the CNS which are used to regulate the concentrations of K+ and neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...
which enter the cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
(CSF) to contribute to the blood brain barrier. A twelve amino acid sequence (Leu-Gly-Ile-Trp-Gly-Cys-Ser-Gly-Lys-Leu-Ile-Cys) on gp41 of the HIV-1 virus (immunodominant region) shows sequence homology with a twelve amino acid protein on the surface of human astrocytes. 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 contributes to many CNS complications found in AIDS
AIDS
Acquired immune deficiency syndrome or acquired immunodeficiency syndrome is a disease of the human immune system caused by the human immunodeficiency virus...
patients.
Theiler’s murine encephalomyelitis virus (TMEV) leads to the development of a progressive CD4+ T cell-mediated response after these cells have infiltrated the CNS. This virus has been shown to cause multiple sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
, which is another autoimmune disease. It results in the gradual destruction of the myelin
Myelin
Myelin is a dielectric material that forms a layer, the myelin sheath, usually around only the axon of a neuron. It is essential for the proper functioning of the nervous system. Myelin is an outgrowth of a type of glial cell. The production of the myelin sheath is called myelination...
sheath coating axons of the CNS. TMEV shares a thirteen amino acid sequence (His-Cys-Leu-Gly-Lys-Trp-Leu-Gly-His-Pro-Asp-Lys-Phe) (PLP (proteolipid protein) 139-151 epitope) with that of a human myelin-specific epitope. Bystander myelin damage is caused by virus specific Th1 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. As a result, there was a CD4+ T cell response and autoimmune demyelination was initiated by infection with a TMEV peptide ligand. In humans, it has recently been shown that there are other possible targets for molecular mimicry in patients with multiple sclerosis. These involve the hepatitis B virus mimicking the human proteolipid protein (myelin protein) and the Epstein-Barr virus mimicking anti-myelin oligodendrocyte glycoprotein
Myelin oligodendrocyte glycoprotein
Myelin Oligodendrocyte Glycoprotein ' is a glycoprotein believed to be important in the process of myelinization of nerves in the central nervous system . In humans this protein is encoded by the MOG gene...
(contributes to a ring of myelin around blood vessels).
Muscle disorders
Myasthenia gravisMyasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
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
Acetylcholine receptor
An acetylcholine receptor is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.-Classification:...
. The receptor contains a seven amino acid sequence (Trp-Thr-Tyr-Asp-Gly-Thr-Lys) in the α-subunit that demonstrates immunological cross-reactivity with a shared immunodominant domain of gpD of the herpes simplex virus
Herpes simplex virus
Herpes simplex virus 1 and 2 , also known as Human herpes virus 1 and 2 , are two members of the herpes virus family, Herpesviridae, that infect humans. Both HSV-1 and HSV-2 are ubiquitous and contagious...
(HSV). Similar to HIV-1, gpD also aids in binding to chemokines on the cell surface of the host to gain entry into the host. Cross-reactivity of the self epitope (α-subunit of the receptor) with antibodies produced against HSV suggests that the virus is associated with the initiation of myasthenia gravis. Not only does HSV cause immunologic cross-reactivity, but the gpD peptide also competitively inhibits the binding of antibody made against the α-subunit to its corresponding peptide on the α-subunit. 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.
Control of molecular mimicry
There are ways in which autoimmunity caused by molecular mimicry can be avoided. Control of the initiating factor (pathogen) via vaccination seems to be the most common method to avoid autoimmunity. Inducing tolerance to the host autoantigen in this way may also be the most stable factor. The development of a downregulating immune response to the shared epitope between pathogen and host may be the best way of treating an autoimmune disease caused by molecular mimicry. Alternatively, treatment with immunosuppressive drugs such as ciclosporinCiclosporin
Ciclosporin , cyclosporine , cyclosporin , or cyclosporin A is an immunosuppressant drug widely used in post-allogeneic organ transplant to reduce the activity of the immune system, and therefore the risk of organ rejection...
and azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...
has also been used as a possible solution. However, in many cases this has been shown to be ineffective because cells and tissues have already been destroyed at the onset of the infection.
Conclusion
The concept of molecular mimicry is a useful tool in understanding the etiology
Etiology
Etiology is the study of causation, or origination. The word is derived from the Greek , aitiologia, "giving a reason for" ....
, pathogenesis
Pathogenesis
The pathogenesis of a disease is the mechanism by which the disease is caused. The term can also be used to describe the origin and development of the disease and whether it is acute, chronic or recurrent...
, treatment, and prevention of autoimmune disorders. Molecular mimicry is, however, only one mechanism by which an autoimmune disease can occur in association with a pathogen. Understanding the mechanisms of molecular mimicry may allow future research to be directed toward uncovering the initiating infectious agent as well as recognizing the self determinant. This way, future research may be able to design strategies for treatment and prevention of autoimmune disorders. The use of transgenic models such as those used for discovery of the mimicry events leading to diseases of the CNS and muscle disorders has helped evaluate the sequence of events leading to molecular mimicry.