Molecular MimicryMadeleine White Cunningham, University of Oklahoma Health Sciences Center,

Oklahoma City, Oklahoma, USA

Molecular mimicry is structural, functional or immunological similarities shared

between macromolecules found on infectious pathogens and in host tissues. Molecular

mimicry plays an important role in immune responses to infection and in autoimmune

diseases. Infection may induce autoimmune responses which attack and destroy body

tissues or organs. Normally, the body is tolerant to self-antigens which are present in

individual tissues. In autoimmune disease, tolerance is abrogated to self-antigens, and

tissues or organs are destroyed by the immune system. Molecular mimicry of a

self-antigen by an infectious pathogen, such as bacteria and viruses, may trigger

autoimmune disease due to a crossreactive immune response against the infection.

Crossreactive antigen–antibody and T cell–antigen reactions are used to identify the

mimicking macromolecules on the pathogen and in tissues or organs. These parameters

define the concept of molecular mimicry.

Introduction

Disruption of immune tolerance and development of auto-immune disease is not based solely on mimicry between aninfectious pathogen and host tissues. The factors leading toautoimmune sequelae and disease are complex includingprior infections, host susceptibility genes and familial pat-terns of disease, alterations in B- and T-cell tolerance, ac-tivation of dendritic cells and stability of regulatory T cellswhich all play a role in allowing B or T cells which mimickhost andmicrobial antigens to become overstimulated andgrow into disease producing clones. The disease mostclearly associated with molecular mimicry and a definedinfection is rheumatic fever, an autoimmune sequela ofgroup A streptococcal pharyngitis. Mimicry between car-diac myosins, other a helical proteins such as laminin andtubulin, the streptococcal carbohydrate and M protein isthemost likely aetiologyof the disease (Cunningham, 2000;Galvin et al., 2000; Kirvan et al., 2003, 2007). Other auto-immune diseases associated with a potential infectiousaetiologies include insulin-dependent diabetes mellitus(Tian et al., 1994; von Herrath et al., 2003), ankylosingspondylitis (Fielder et al., 1995), Guillain–Barre syndrome(Oomes et al., 1995; Willison et al., 1997, 2008; Goodyearet al., 1999; Hartung et al., 2002; Jacobs et al., 2002, 2008),primary biliary cirrhosis (Shimoda et al., 1995) and

multiple sclerosis (Wucherpfennig and Strominger, 1995;von Herrath et al., 2003). The rheumatic autoimmune dis-eases include systemic lupus erythematosus (James et al.,1997;Arbuckle et al., 2003), rheumatoid arthritis (Holoshitzet al., 1986), Sjogren syndrome (Talal, 1990) and others arepotentially due to an infectious aetiology. Recent studieshave suggested that viral delivery of an epitope from thebacteria Haemophilus influenzae induced central nervoussystemdisease bymolecularmimicry (Croxford et al., 2005).Theiler’s virus was engineered to encode a mimic peptidefrom protease IV of H. influenzae, sharing 6 of 13 aa withthe dominant encephalitogenic proteolipid protein (PLP)epitope PLP (139–151). Infection of mice with the virus ex-pressing the Haemophilus mimic sequence induced a rapid-onset, nonprogressive paralytic disease characterized bycrossreactive PLP (139–151)-specific CD4(+) Th1 respo-nses. These studies have implications in diseases such asmultiple sclerosis and in animal models of experimental al-lergic encephalomyelitis. In autoimmune diseases, molecu-larmimicry, bystander activationorviral persistencemayallbe factors associated with infections and development ofautoimmune diseases (Tsunoda et al., 2004, 2006; Libbeyet al., 2005; Fujinami et al., 2006). See also: AutoimmuneDisease; Autoimmune Disease: Animal Models; Autoim-mune Disease: Pathogenesis; Immunological Discrimina-tion Between Self and Nonself; Immunological Tolerance:Mechanisms; Rheumatoid ArthritisHowever, intensive efforts to identify a single microbial

or viral agent in diseases such as diabetes or multiple scle-rosis have proven difficult (von Herrath et al., 2003). Inautoimmune diseases the single organism paradigm that iscentral to Koch’s postulates may not always apply to mi-crobially induced autoimmune disease (von Herrath et al.,2003). In these cases, the fertile-field hypothesis has beenproposed to explain how a single autoimmune diseasecould be induced and exacerbated by many different

Advanced article

Article Contents

. Introduction

. Molecular Mimicry to Avoid Recognition

. Mimicry of T- and B-cell Epitopes

. Internal Image Anti-idiotypes

. Peptide Mimic Vaccines

Online posting date: 15th September 2009

ELS subject area: Immunology

How to cite:Cunningham, Madeleine White (September 2009) Molecular Mimicry.

In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd:Chichester.

DOI: 10.1002/9780470015902.a0000958.pub2

ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 1

microbial infections which together lead to induction ofdiseases such as diabetes or multiple sclerosis (vonHerrathet al., 2003). There are three types ofmolecularmimicry. Inthe first type, identical amino acid sequences present indifferent proteinmolecules are recognized by amonoclonalantibody or T-cell clone. Examples of this first type of mol-ecular mimicry include (1) identical amino acid sequencesshared between the human leukocyte antigen (HLA) B27major histocompatibility complex (MHC) class I antigenand a nitrogenase ofKlebsiella pneumoniae and (2)mimicrybetween Theiler’s virus andmyelin basic protein (Fujinamiand Oldstone, 1985; Schwimmbeck and Oldstone, 1989).Themimicry between theHLAB27 class Imolecule and themicrobial nitrogenase is believed to play a role in ankylos-ing spondylitis, arthritis and Reiter syndrome which aresequelae of bacterial infections. Rats transgenic for theHLA B27 class I molecule develop arthritis, but undergerm-free conditions, they do not develop autoimmunedisease (Taurog et al., 1994). Mimicking molecular struc-tures among self-antigens and infectious pathogens such asviruses and bacteria are believed to be relevant to thedevelopment of autoimmune disease. In autoimmune dis-eases where microbial or viral infections may be an envi-ronmental trigger leading to disease, the foreign antigen onthe infectious agent is similar to cryptic or ‘hidden’ epitopesof the self-antigen but is different enough from self- tobreak tolerance. Activation of the immune system duringinfection results from the release of influential cytokineswhich affects the outcome of the response to the mimick-ing antigen. See also: Epitopes; Major HistocompatibilityComplex: Disease Associations; Major Histocompati-bility Complex: Human

A second type of molecular mimicry is due to structuralsimilarities, rather than amino acid sequence identities inthemimicking chemical structures. In this type of mimicry,similarities or homologies rather than identities of aminoacids can constitute mimicry between structurally similarmolecules. An example of this second type ofmimicry is thestructural similartities between cardiac myosins and thegroupA streptococcalM proteins. These molecules form ahelical coiled–coiled structures from a seven amino acidresidue periodicity that limits the conformation of the pro-tein to an a helical coiled-coil molecule (Cunningham,2000). Other a helical coiled-coil self-proteins which shareimmunological and structural similarities with strepto-coccalM proteins include keratins, tropomyosin, vimentinand laminin (Cunningham, 2000) as well as a, b tubulin(Kirvan et al., 2007). Cardiac myosins which are mimickedby pathogens such as the group A streptococci and cox-sackieviruses are relevant in the development of rheu-matic carditis and autoimmune myocarditis, respectively(Cunningham et al., 1992; Gauntt et al., 1995). In animalmodels, the streptococcal M protein or its peptides aresimilar enough in amino acid sequence to epitopes on car-diacmyosin that they break tolerance to cryptic epitopes ofcardiac myosin and induce autoimmune heart disease,myocarditis or valvulitis (Huber and Cunningham, 1996;Cunningham et al., 1997). The most recent studies of

streptococcalM protein show that coiled-coil irregularitiesand instabilities in the groupA streptococcalMprotein arerequired for its major virulence, proinflammatory andantiphagocytic properties and also for the immunologicalcrossreactivity with human tissues and cardiac myosin(McNamara et al., 2008). The irregularities in the coiled-coil a helix cause the molecule to splay apart and interactwith the immune system. The crystal structure of the M1protein was recently resolved and demonstrated the im-portance of the splaying of the coiled-coil a helix. Whenmutants to stabilize the a helical coiled-coil were produced,the mutant M proteins lost their inflammatory propertiesto interact with the innate immune system and also lost theability to crossreact with antibodies against the heart, car-diac myosin and streptococcal M protein (McNamaraet al., 2008). See also: Myosin SuperfamilyThe second type of mimicry has been further delineated

using human T-cell clones demonstrating the reactivitywith peptides of streptococcal M protein and human car-diac myosin (Ellis et al., 2005; Fae et al., 2006). In multiplesclerosis, human T-cell clones specific for myelin basicprotein react with viral peptides that are structurally re-lated (Wucherpfennig and Strominger, 1995). The recog-nition of related peptides from different viral pathogens bya single T-cell receptor suggests that molecular mimicrypotentially has an important role in T-cell responses inautoimmunity. It is proposed that recognition of peptideantigens by the T-cell receptor induces large conformatio-nal changes in the T-cell receptor (Garcia et al., 1998). Thissuggests that the T-cell receptor can conform to a variety ofpeptide antigen structures.A third type of molecular mimicry is the recognition of

completely dissimilar chemical structures on separate mol-ecules by a single antibody (Kabat et al., 1986; Shikhmanet al., 1994; Cunningham, 2000; Galvin et al., 2000; Kirvanet al., 2003). Immunological mimicry between dissimilarepitopes on chemically different molecules has changed theconcept that an antibody molecule must recognize only asingle antigenic epitope. The hypothesis ofmolecular mim-icry and the identification of crossreactive or polyreactiveantibody was first met with scepticism, however, it is ev-ident that a single antibody molecule does not necessarilybind to a single antigen and may react with antigens ofdifferent chemical composition. Specific monoclonal anti-bodymolecules may recognize peptides and carbohydrates(Shikhman et al., 1994; Shikhman and Cunningham,1997), carbohydrates and deoxyribonucleic acid (DNA)(Kabat et al., 1986) or proteins and DNA (Cunninghamand Swerlick, 1986; Gaynor et al., 1997; Putterman andDiamond, 1998). Gangliosides are also found to be impor-tant targets of antibodies against the groupA streptococcalcarbohydrate (Kirvan et al., 2003) or lipopolysaccharidecomponents of Campylobacter jejuni in Guillain–Barresyndrome (Willison and Kennedy, 1993; Willison et al.,1997, 2008; Goodyear et al., 1999). The basis of thesediverse crossreactions may be due in part to structuralcharacteristics of the antigenic epitope as well as germ-line configurations of the antibody molecule. Antibody

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molecules make conformational changes to accomodatedifferent antigen structures (Wedemayer et al., 1997). Ex-amples include polyreactive antibodies present in autoim-mune diseases such as rheumatic fever and systemic lupuserythematosus. See also: Antigen–Antibody Binding;Epitopes; Monoclonal Antibodies

Molecular Mimicry to AvoidRecognition

The host–pathogen relationship is dependent on the im-mune defence mechanisms of the host and the virulencefactors of the infectious pathogen. The host recognizes thepathogen as foreign and dangerous and will use the im-mune system to combat the disease caused by the micro-organism. However, the clever pathogen will use virulencefactors to overcome the immune defences of the host. Thevirulence factors of the pathogen may use molecular mim-icry to improve its chances of survival against the immuneresponses of the host. Virulence factors of extracellularpathogens reside on the surface of the microorganism suchas a bacterium which may cover itself with molecules thatare very similar to those in the host in an attempt to survive.An example would be the hyaluronic acid capsule sur-rounding group A streptococci or the streptococcal Mprotein, which contains the a-helical structure conservedthroughout nature in a helical proteins such as myosins,tropomyosins, vimentin and laminin. The a helical coiled-coil streptococcal M proteins inactivate complement orcause the surface of the bacterium to become coated withfibrinogen in an attempt to thrwart the immune system(Fischetti, 1989; Horstmann et al., 1992). Therefore, thestreptococcal M proteins are antiphagocytic and preventthe recognition of Streptococcus pyogenes bacteria byphagocytic polymorphonuclear leukocytes. Other extra-cellular pathogens, such as encapsulated Streptococcuspneumoniae or H. influenzae, use similar mechanisms toevade humoral immune defences of complement andantibody. See also: Bacterial Capsules and Evasion ofImmune Responses; Immune Mechanisms Against Extra-cellular Pathogens; Immune Response: Evasion andSubversion by Pathogens; Phagocytosis

Virulence factors of intracellular pathogens and virusesmay resemble proteins which are highly similar to those inthe host. Heat shock proteins are highly conserved andshared among many microoganisms and man. Hsp 60 hasbeen found to have immunoregulatory properties wherebyacting as a danger signal to interact with innate immunecells (Habich andBurkart, 2007).Heat shock proteins havebeen implicated as a causal antigen in adjuvant arthritisand perhaps other arthritides in man (Cohen and Young,1991). Heat shock proteins of the intracellular pathogenMycobacterium tuberculosis have been implicated in auto-immune diabetes and arthritis (Cohen, 1991) and may beinvolved in adjuvant-induced arthritis in animal models.However, studies have suggested that heat shock proteins

are important in stabilizing T regulatory cell populationsand have been shown to have protective effects inmodels ofarthritis (van Eden et al., 2000). Thus, heat shock proteinsmay affect the immune system to prevent or induce auto-immune responses under certain conditions. See also:Antigens; Chaperones, Chaperonin and Heat-ShockProteinsMolecular mimicry not only occurs between host and

pathogenbutoccurs betweenmicrobes aswell. Bacteria andviruses share structures and conformations between them-selves. Molecular mimicry between microbes is an advan-tage for animals andmansince antigenic redundancy allowsthe host to recognize more than one infectious agent with asingle antibody molecule. For example, cytotoxic anti-streptococcal monoclonal antibodies neutralize certain en-teroviruses such as polio and coxsackievirus (Cunninghamet al., 1992). This finding suggests that antibodies can beefficient and ‘kill two birds with one stone’, or a single an-tibody can recognize two different microbes. Further stud-ies show that antibodies against the heat shock protein,hsp-65, react with certain streptococcal M proteins (Quinnet al., 1996). These studies demonstrate molecular mimicrynot only between host and pathogen but also among differ-ent microbial pathogens themselves. See also: AntibodyFunction; Antigen Recognition by T LymphocytesMolecular mimicry may also play a role in antibody

driven selection of highly mutable viruses. Cytotoxicmonoclonal antibodies that neutralize myocarditic cox-sackieviruses and react with group A streptococcal Mproteins induce escape mutants of myocarditic coxsackie-viruses (Huber et al., 1994). The viral escape mutants werealterated in MHC association of susceptibility to my-ocarditis. Viruses altered by antibodies to microbial andself-crossreactive epitopes may change the genetic suscep-tibility patterns of viral-induced autoimmune diseases.See also: Autoimmune Disease; EnterovirusesThe V region immunoglobulin genes encoding crossre-

active autoantibodies are germline or near-germline in or-igin (Antone et al., 1997). Immunoglobulin germline genesmay conform to different antigens conferring crossreactiv-ity not seen in high affinity, highly mutated immunoglob-ulins (Wedemayer et al., 1997). See also: AntibodiesAntigen presentation may lead to diverse reactions by

the host immune system which range from tolerance, an-ergy or suppression to hyperresponsiveness or autoim-mune disease. Controlling factors in the host reside indendritic cells which on one hand can direct T cells instrong immune responses and on the other hand can affectimmune tolerance by dampening the host responses(Steinman et al., 2003; Brinster and Shevach, 2005; Itoet al., 2007). In addition, regulatory T cells play an impor-tant role in controlling immune responses against host andmicrobial antigens (Shevach, 2000; DiPaolo et al., 2005;Sutmuller et al., 2006; Valencia et al., 2006). Infections of-ten reduce the numbers of T regulatory cells allowing for astrong immune response against the pathogen. T regula-tory cells prevent deleterious autoimmune responses bycrossreactive mimicking T cells which recognize the

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microbial pathogen and host tissue epitopes. Deletion of Tregulatory cells leads to autoimmune disease in animalsmodels (Sakaguchi, 2000; Ono et al., 2006). Immune dys-regulation may also occur in the susceptible host withproduction of crossreactive, polyreactive and cytotoxicantibodies due to a loss of B-cell tolerance (Diamond et al.,1992; Iliev et al., 1994; Ray et al., 1996; Liao et al., 1995).Autoantibodies and complement may deposit in tissueswhere crossreacting antigens act like a sieve for capturingthe autoantibodies and complement and inflammation isthus initiated. Upregulation of cytokines and cell adhesionmoleculesmay lead toT-cell infiltrationof the target organ.To summarize, autoimmunity leading to disease is a resultof host susceptibility, dysregulation of the immune re-sponses in the host and environmental triggers such as in-fectious microbes. See also: Antigen Presentation toLymphocytes; Autoimmune Disease: Aetiology andPathogenesis; Superantigens

Mimicry of T- and B-cell Epitopes

B-cell epitopes

Antibodies which react with microbial and self-antigensrecognize conformational epitopes on the surface of mac-romolecules such as proteins, glycoproteins and complexcarbohydrates. These epitopes may be one of the threetypes reported earlier in the definition of molecular mim-icry. The antibodies may recognize (1) identical structuresshared between the two molecules, (2) similar but non-identical structures sharedbetween the twomolecules or (3)very different chemical structures such as carbohydratesand peptides. Antibodies, produced by B lymphocytes, cancause disease by damaging tissues as they complex withtarget tissue antigens and activate complement. Therefore,antibody deposited in tissues causes activation of the com-plement system and induces inflammation. Studies to iden-tify immunological mimicry and B-cell epitopes are bestperformed usingmonoclonal antibodies from animalmod-els or from humans with disease. Almost all of the pastwork to understand molecular mimicry has been done us-ingmonoclonal antibodies from immunized animalmodelsor from humans with disease. With the advent of mono-clonal antibodies, it became possible to detect molecularmimicry or demonstrate crossreactivity of a single anti-body with two different molecules. The mimicry is identi-fied by immunoreactivity of the antibody with tissues andWestern blotting and screening synthetic peptides of themimicking molecules themselves in immunoassays to de-tect crossreactivity with the monoclonal antibody. Addi-tional evidence of the mimicry is the presence of identicalor similar amino acid sequences in two different molecules(Huber and Cunningham, 1996). The amino acid se-quences of the protein molecules are aligned by computerprograms and sequence similarities are shown structu-rally by amino acid sequence identity and homology.

See also: Antigen–Antibody Binding; Epitopes; Inflam-mation: Acute; Monoclonal AntibodiesRecognition of conformational epitopes by antibodies

may produce conflicting results in immunoassays such asthe enzyme-linked immunosorbent assay (ELISA) andWestern blot (Cunningham et al., 1997). TheWestern blotprocedure may cause the loss of conformational determi-nants and loss of immunoreactivity, whereas the sameepitopes may be retained and react in the ELISA. Theconformation which an antigen acquires on differentimmunoassay matrices may also present different results.However, these methods when combined with ELISA in-hibition and immunofluorescence cell or tissue assays to-gether can be powerful tools to demonstrate monoclonalantibody crossreactivity with antigens in the microbe andhost tissues. In studies of human serum, only affinitypu-rified antibodies eluted from antigen bound to matricesmay be used to demonstrate antibody crossreactivity.See also: Enzyme-linked Immunosorbent Assay; WesternBlotting: ImmunoblottingRecently, mimicry has been shown to lead to the induc-

tion of autoantibodies which alter signalling in cells bybinding to cell surface receptors (Kirvan et al., 2003;Li et al.,2006). Mimicry between microbial pathogens and host tis-sues may lead to the induction of antibodies which signalcells in an autoantibody-mediated cell signalling mecha-nism. Themost recent studies have shown that crossreactiveantibodies against cardiac myosin and the b adrenergic re-ceptor in the heart can lead to induction and activationof protein kinase A signaling (Li, Heuser et al., 2006;Mascaro-Blanco et al., 2008). The passive transfer of auto-antibodies which signal myocardial cells led to sites ofapoptosis in the heart (Li et al., 2006). Such pathogenicsignalling autoantibodies may lead to dilated cardiomyopa-thy in humans (Mascaro-Blanco et al., 2008).Autoantibody-mediated cell signalling andmimicrymay

lead to imbalance in dopamine release and signalling in thebrain (Kirvan et al., 2003, 2007). Antibodies against groupA streptococcal epitopes were found to bind to neuronalcells and to signal Ca++ calmodulin-dependent proteinkinase II (CaMkinase II) in neuronal cells and lead to do-pamine release (Kirvan et al., 2003). The crossreactiveantibodies that produced the neuronal cell signalling wereassociated with Sydenham chorea, a central nervous sys-tem movement disorder in streptococcal-associated rheu-matic fever (Swedo, 1994; Kirvan et al., 2003).

T-cell epitopes

Studies of crossreactive T-cell epitopes using T-cell clonesfrom animal models or human autoimmune diseases hasnot been as easy to demonstrate as mimicking B-cellepitopes. However, a few studies have shown that T-cellclones respond to different peptide epitopes from differentmolecules of the host and infectious pathogen. These stud-ies include (1) T-cell clones from multiple sclerosis respon-sive to myelin basic protein which also recognize viral andmicrobial peptides (Wucherpfennig and Strominger, 1995)

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and (2) T-cell clones from rheumatic carditis recognizingcardiac myosin and M protein peptides (Ellis et al., 2005;Fae et al., 2006). The microbial peptides identified in thestudy of T-cell clones from multiple sclerosis patientsshowed no amino acid sequence homology with the auto-antigen sequence except for T-cell receptor (TCR) aminoacid contact residues. The large number of peptides whichmay be required to identify the crossreactive peptides hasled investigators to use random combinatorial peptide li-braries to identify crossreactive peptide ligands for auto-reactive T cells (Barnaba and Sinigaglia, 1997; Hemmeret al., 1997). T-cell clones crossreactivewith cardiacmyosinand streptococcal M protein were shown to be highly spe-cific for homologous sequences from both human cardiacmyosin and streptococcalMprotein (Ellis et al., 2005). Theavidity of the crossreactive T-cell clones were higher forstreptococcal M protein than for human cardiac myosinbut this would be expected since clones recognizing cardiacmyosin epitopes too strongly would be deleted in the thy-mus during selection. Importantly, studies fromGuilhermeet al. have shown that T cells from hearts of patients withstreptococcal-induced acute rheumatic heart disease haveT-cell clones which recognize human cardiac myosin andstreptococcalM protein epitopes. These T-cell clones stud-ied in rheumatic fever are some of the most well-definedcrossreactive T-cell clones investigated (Ellis et al., 2005;Fae et al., 2006). See also: T-cell Receptors; T LymphocyteResponses: Development

It is important to consider the influence of peptide lig-ands with different affinities for an individual T-cell recep-tor. The strength of the TCR–peptide interaction willdetermine the outcome of the T-cell selection and responseto the mimicking peptide. Current evidence supports thehypothesis that molecular mimicry activates and expandspotentially autoreactive T cells (Barnaba and Sinigaglia,1997) which participate in disease. See also: AntigenRecognition by T Lymphocytes

Synthetic peptides of microbial antigens mimicking au-toantigens are used to determine if themimicrywill actuallyproduce disease in animal models. This has been shown tobe the case in animal models of myocarditis and experi-mental allergic encephalomyelitis. Immunization withmimicking peptides leads to infiltration of T cells into theorgan or tissue site. Theoretically, the microbial peptideantigen mimicks a cryptic epitope present in the autoan-tigen and breaks immune tolerance in the susceptible hostand produces autoimmune disease. Studies are underwayto identify the epitopes recognized by T cells recoveredfrom lesions in humans and animal models. See also:Autoimmune Disease: Animal Models

In herpes stromal keratitis, CD4+T cells target cornealtissues and produce blindness due to this autoimmune dis-order. T-cell clones that react with host tissues and produceautoimmune keratitis in animalmodels were found to reactwith a herpesvirus coat protein (Zhao et al., 1998). Mutantherpesviruses lacking these epitopes do not produce theautoimmune disease. See also: Autoimmune Disease;Herpesviruses (Human)

The presentation of the processed antigenic peptide tothe T-cell receptor may influence the outcome of the im-mune response. The rigour of the message to the T cell bythe antigen-presenting cell may be determined by the pep-tide presented and by the type of antigen- presenting cell. Ifthe T cell develops into a T helper 1 (Th1) cell, it infiltratesinto tissues and produces inflammatory cytokines inter-leukin 2 and g interferon. A change in antigen presentationmay affect the T-cell phenotype or lead to immune devi-ation or a switch from the Th1 to the Th2 T-cell phenotypeor vice versa. In animal models of autoimmune disease, aswitch from Th2 to Th1 cells produces disease and thepresence of the Th2 response prevents autoimmune disease(Mosman andCoffman, 1989; Fitch et al., 1993; Samoilovaet al., 1997). The Th2 phenotype is associated with theproductionof interleukins 4, 5 and10and is associatedwithdownregulation of autoimmune disease in animal models.See also:Antigen-presentingCells;AntigenPresentation toLymphocytes; Cytokines; T Lymphocytes: HelpersThe discovery of Th17 cells and their importance in in-

fection and inflammation provides another subset ofstrongly reactive T cells which are important in the re-sponses against pathogens (Bettelli et al., 2006;Annunziatoet al., 2007; Weaver et al., 2007; Harrington et al., 2006).T helper (Th) 17 cells represent a novel subset of CD4+T cells that are protective against extracellular microbes,but are responsible for autoimmune disorders in mice(Annunziato et al., 2007). Mimicry could potentially be animportant factor in activating the Th17 T-cell subset.Cytokines are important in generating and maintaining

the T-cell phenotype associated with autoimmune disease,such as the Th1 or Th17 phenotype (Annunziato et al.,2007). The local environment is critical in the developmentor abrogation of autoimmune disease. Either Th1, Th17 orTh2 cell phenotypes potentially may be activated by mim-icking peptides from the microbe and/or host. Further-more, a disease-producing peptide may result in toleranceagainst disease if given to animal models by methods re-sulting in tolerance. The mechanisms of tolerance are im-portant to understand for prevention or downregulation ofthe disease. Mimicking host or microbial peptides whichproduce disease might be used in the future as vaccines forprevention of specific autoimmune diseases. The peptidescould function in several ways to regulate or turn off theautoimmune response, including suppression, immune de-viation or deletion of autoreactive T cells. A possible dis-advantage of tolerization against autoimmune disease withmicrobial peptides may be downregulation of immunity tothe infectious pathogen.

Internal Image Anti-idiotypes

Idiotypic networks are important in development of anautoimmune response (Dwyer, 1986; Kearney et al., 1989).It is possible that autoimmune responses are driven by ananti-idiotypic antibody in the absence of the infectiouspathogen. Infectious agents such as bacteria may trigger

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production of the initial crossreactive antibody which rec-ognizes both autoantigen and microbial antigen (antibody1). Once generated, antibody 1 becomes an antigen andstimulates a response against itself (antibody 2). See Figure 1

for diagram.Antibody 1 containsmany antigenic sites, oneof which is the combining site. Antibody 2 recognition ofthe unique combining site in antibody 1 will inhibit recog-nition of the crossreactive antigens by antibody 1. Anti-bodies with this characteristic are called an anti-idiotypicantibody and may possess an internal image of the cross-reacting antigens. If the anti-idiotypic antibody (antibody2) contains the internal image of the crossreacting antigens,it will be capable of generating an immune response againstthe original antigens, the microbial and autoantigen. It ispossible for an anti-idiotypic antibody to contain an inter-nal image of a bacterial or viral adhesion which binds to aspecific receptor in host tissues (Paque, 1990). In such acase, the antibody adhesion instead of the bacteriumwouldbind and cause antibody and complement deposition intissues. See also: Idiotype Network; Idiotypes

Anti-idiotypes which may reflect reactivity with host andmicrobial epitopes include studies of systemic lupus erythe-matosus (Datta andGavalchin, 1986; Shoenfeld et al., 1986;Chen et al., 1988), acute rheumatic fever (McCormack et al.,1993), immunoglobulin V gene families(Monestier et al.,1987), pneumococcal anti-idiotype (Diamond and Scharff,1984; Vakil et al., 1991) and rheumatoid factors (Williams,1988).

Peptide Mimic Vaccines

In the development of vaccines, the use of peptides forimmunization may circumvent the T-cell independence ofcarbohydrate antigens. Carbohydrate antigens do not usethe MHC class II molecule to present antigen to helper Tcells, and they are not capable of induction of an efficientsecondary immune response. Antibodies produced againstcarbohydrate antigens have a significantly lower affinitythan those induced by peptide or protein antigens. There-fore, carbohydrate-mimicking peptides may be importanttargets for vaccine development. Infectious pathogens,

including viruses, bacteria, fungi and parasites, are coveredwith carbohydrate molecules that elicit protective host im-mune responses. Anticarbohydrate antibodies bind to bac-teria and promote opsonization and phagocytosis. In thefuture, peptide mimics of carbohydrate antigens may beconstructed to mimic complex carbohydrates. See also:Antigens:Carbohydrates;Antigens: Thymus Independent;Vaccines: SubunitPeptide mimics of carbohydrate moieties on the human

immunodeficiency virus glycoprotein (gp) 120 have beenreported (Agadjanyan et al., 1997). In addition, peptideepitopes are present in myosins and keratins which mimictheN-acetyl-glucosamine epitope of groupA streptococcalcarbohydrate. The cytokeratin peptide which is a mimic ofN-acetyl-glucosamine reacted with lectins such as wheatgerm agglutinin and induced an anti-N-acetyl-glucosamineantibody response in mice. A panel of synthetic peptidescontaining a single amino acid substitution was used toidentify the contact residues important in crossreactivitywith the antibodymolecule. Themimicry of carbohydratesby peptidemolecules may have far reaching applications invaccine development and autoimmunity (Shikhman andCunningham, 1997).

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Bacterium orinfectious agent

Antibacterialantihost

Antibody 3

Infectshost

Antibacterialantihost

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Anti-idiotypecontains bacterial

crossreactiveepitope

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Bacteria/host epitope

Antibody molecules

Figure 1 Anti-idiotype (antibody 2) mimicks the bacterial and host antigen

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adult B cell repertoire. European Journal of Immunology 16:

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(2005) Protection against experimental autoimmune my-

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Molecular Mimicry

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Molecular Mimicry

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