the epstein - barr virus ( ebv ) is a member of the herpesviridae virus family .
it is estimated that the incidence of ebv infection among adults is between 90% and 95% .
however , it is evident that ebv may cause infectious mononucleosis ( i m ) in the lytic phase of ebv s life cycle .
past ebv infection is associated with burkitt lymphoma , hodgkin disease , and nasopharyngeal or stomach cancer .
in addition , there is a hypothesis that past ebv infection can also lead to certain allergic and autoimmune diseases .
once a person has been infected with ebv , she or he will carry ebv latent infection of b - lymphocytes .
viral load remains relatively constant over time in circulating b - cells with a non - activated phenotype .
although potential mechanisms of autoimmune diseases have not been clearly elucidated , both genetic and environmental factors , such as infectious agents , are considered to be responsible for their development .
also , five possible mechanisms for the pathogenesis of autoimmune diseases have been distinguished : molecular mimicry  activation of autoreactive t cells by microbial peptides with structural similarity to self - peptides ; viral and bacterial superantigens  activation of autoreactive t cells that express particular v segments ; enhanced processing and presentation of auto - antigens by antigen - presenting cells recruited to an inflammatory site and followed by autoreactive lymphocyte priming ; bystander activation 
enhanced cytokine production that induces the expansion of autoreactive t cells ; activation of lymphocytes by lymphotropic viruses  an infection of b cells resulting in b cell proliferation , excess antibody production , and formation of circulating immune complexes [ 6 , 7 ] .
epstein - barr virus is considered to be an aetiological factor of autoimmune diseases because of the following : the virus is a common pathogen responsible for the worldwide prevalence of autoimmune diseases ; ebv stays in the body throughout life , which explains the chronic course of autoimmune diseases that are often accompanied by exacerbations of symptoms ; the virus modifies the host immune response .
it encodes a homolog of the bcl-2 oncogene that inhibits apoptosis and interferon  ( ifn- ) signaling in b - cells .
it is also responsible for changes in the production of pro - inflammatory cytokines , such as tumor necrosis factor  ( tnf- ) , interleukin ( il)-1 , and il-6 , as well as of viral cytokines that share immunosuppressive properties with il-10 [ 8 , 9 ] .
interleukin 1 , tnf- , and ifn- can induce hla class ii expression and lead to auto - antigen presentation and auto - reactive t - cell activation . the epstein - barr virus can also infect t lymphocytes . in 1971 , evan demonstrated raised antibody titres to ebv in patients with systemic lupus erythematosus ( sle ) .
this was the reason to suspect that the ebv might participate in the development of autoimmune diseases . moreover , there is now evidence that ebv infection can cause autoimmune diseases , for example sle [ 13 , 14 ] , multiple sclerosis ( ms ) , rheumatoid arthritis ( ra ) , sjgren s syndrome [ 17 , 18 ] , or autoimmune hepatitis .
several mechanisms of autoimmunity have been shown to be involved in the pathogenesis of these diseases . as far as lupus erythematosus is concerned , these are : high ebv dna viral loads , elevated ebv antibody concentrations , impaired ebv - specific t - cell responses , and the phenomenon of molecular mimicry [ 5 , 20 ] . for rheumatoid arthritis , they include : high anti - ebv titres , cell - mediated control of ebv , cross - reactivity between ebv and human self - proteins ( molecular mimicry ) , presence of the ebv genome in synovial membrane , and a cell - mediated response to the ebv within the joint . for primary sjgren s syndrome ( pss ) , they are : more frequent presence of ebv dna in saliva and salivary tissue , as well as an elevated level of anti - ebv titres . patients with infectious mononucleosis have been reported with various antibodies in their serum .
this can also suggest that there is a link between the ebv infection and autoimmune diseases .
autoimmune thyroid disorders ( aitds ) are the most common organ - specific autoimmune diseases .
autoimmune thyroid disorders develop upon activation of specific helper t cells directed against the thyroid antigens , the thyroid peroxidase ( tpo ) , and the thyrotropin receptor ( tshr ) .
activated helper t cells induce b cells to secrete thyroid antibodies , such as the thyroid peroxidase antibodies ( tpoabs ) and the thyrotropin receptor antibodies ( trabs ) .
family clustering of these disorders may provide evidence for their genetic and environmental aetiology . according to hansen ,
environmental factors are also said to play a role in aitds , accounting for 20 - 40% of cases with regard to monozygous twins .
other factors that are also considered to be responsible for autoimmune thyroid disorders include : irradiation , treatment with radioiodine , iodine or iodine - rich amiodarone , selenium intake , hormones , oral contraceptives , drugs , antiretrovirals , pregnancy and/or parity , stress , direct trauma , seasonal variation , smoking , campath-1h anti - cd52 , ifn- , il-2 , granulocyte - macrophage colony - stimulating factor ( gm - csf ) , viral and/or bacterial infections , and lack of infections ( the hygiene hypothesis ) [ 27 , 30 ] .
this confirms an infectious aetiology of the disorders . to be specific , thyrocytes express a functional toll - like receptor 3 ( tlr3 ) which , when overexpressed , may cause hashimoto s thyroiditis ( ht ) that can be induced by a virus infection .
penhale and young have demonstrated that rats that have undergone both thymectomy and irradiation are less susceptible to aitds if maintained under specific pathogen - free conditions . in 1983 ,
carter and smith infected chicken embryos with an avian leukosis virus , rav-7 . as a result ,
tozolli , in turn , has suggested that toxoplasma gondii may participate in aitds . in a study by wasserman
, it was shown that prior infection with toxoplasma gondii can be closely associated with elevated thyroid peroxidase antibodies .
in addition , researchers have shown that htlv-1 may have an impact on the development of both hashimoto s thyroiditis [ 37 , 38 ] and graves disease .
other studies have found that there is a possible link between hiv infection and autoimmune thyroid disorders [ 40 , 41 ] .
also , human foamy virus ( hfv ) proteins have been detected in the thyroid tissue of patients with graves disease .
serological data indicates that the influenza virus , hepatitis c virus , enterobacteriaceae , streptococci , staphylococci , yersinia , and helicobacter can have an influence on aitds as well [ 26 , 42 ] .
nevertheless , conflicting data has also been published with regard to the rubella virus , the parvovirus , as well as hepatitis b and c viruses .
in one study , thyroid tissue specimens obtained from aitd patients and patients with multinodular goitre have been investigated to detect herpesviridae dna .
the group of aitd patients have been reported with herpesviridae dna more frequently than the other group .
however , there was no statistical significance observed in aitd patients , nor in patients with any other viruses .
there is a hypothesis that in genetically susceptible patients , ebv - infected autoreactive b - cells seed the thyroid gland , produce autoantibodies , and send co - stimulatory signals to autoreactive t - cells .
normally , the ebv infection is kept under control , especially by cytotoxic cd8 + t - cells that eliminate proliferating and lytically infected b - cells .
impaired ebv control may result from a decreased number of ebv - specific cd8 + t - cells .
an increased cd4/cd8 ratio is characteristic of autoimmune diseases . in their study , akahori et al .
presented three cases of patients suffering from graves disease comorbid with infectious mononucleosis due to primary ebv infection .
they suggested that inflammation from viral infection might be associated with the development of graves disease .
nagata has shown that in vitro reactivation of the ebv infection causes the production of thyrotropin receptor antibodies ( trabs ) in ebv - infected b - cells with trabs on their surface . moreover , nagata has also reported increased trab titres in children with infectious mononucleosis due to ebv primary infection . in a study by janegova ,
subjects with hashimoto s thyroiditis were reported with latent membrane protein 1 ( lmp1 ) , which was not revealed in the case of graves disease patients .
epstein - barr virus - encoded small rnas ( ebers ) were detected in both hashimoto s thyroiditis and graves disease patients , exclusive of negative control samples .
in addition , an elevated serum level of epstein - barr nuclear antigen ( ebna ) was observed in patients with hashimoto s thyroiditis .
also , it was found that antibodies against ebv viral capsid antigen ( igg - vca ) and against early antigen ( igg - ea - d / dr ) were more common for patients with thyroiditis versus the controls .
the seroprevalence of ebv infection was reported to be higher in children with autoimmune thyroid disorders when compared to the controls . however , tozzoli failed to observe elevated ebv - igg levels in aitd patients when compared to the healthy controls .
it is said that thyroid autoantibodies occur more frequently in subjects with autoimmune diseases versus the general population .
experts suggest that thyroid function screening should be conducted in patients with primary sjgren s syndrome , rheumatoid arthritis , and lupus erythematosus   because these diseases may be connected with ebv infection .
the ebv can lead to in vitro transformation of normal resting b lymphocytes to proliferating lymphoblasts .
moreover , the virus can be found in many lymphomas   therefore , researchers suggest that ebv may participate in the malignant transformation of hashimoto s disease into malignant lymphoma of the thyroid   ( table 1 ) . over 90% of all primary thyroid lymphomas
are diagnosed in individuals with a history of hashimoto s disease , and the majority of them are of b - cell origin . a possible link between the epstein - barr virus ( ebv ) infection and autoimmune thyroid disorders ( aitd ) according to literature
based on the study results , ebv is not the only agent responsible for the development of autoimmune thyroid diseases .
further investigations still need to be undertaken to explain the link between the ebv infection and autoimmune thyroid disorders .
 the epstein - barr virus ( ebv ) , also known as human herpesvirus 4 , is a member of the herpesviridae virus family . 
 ebv infection can cause infectious mononucleosis ( i m ) in the lytic phase of ebv s life cycle . 
 past ebv infection is associated with lymphomas , and may also result in certain allergic and autoimmune diseases . 
 although potential mechanisms of autoimmune diseases have not been clearly elucidated , both genetic and environmental factors , such as infectious agents , are considered to be responsible for their development . 
 in addition , ebv modifies the host immune response . 
 the worldwide prevalence of autoimmune diseases shows how common this pathogen is . 
 normally , the virus stays in the body and remains dormant throughout life . 
 however , this is not always the case , and a serious ebv - related illness may develop later in life . 
 this explains the chronic course of autoimmune diseases that is often accompanied by exacerbations of symptoms . 
 based on the present studies , ebv infection can cause autoimmune diseases , such as systemic lupus erythematosus ( sle ) , multiple sclerosis ( ms ) , rheumatoid arthritis ( ra ) , sjgren s syndrome , and autoimmune hepatitis . 
 the ebv has also been reported in patients with autoimmune thyroid disorders . 
 although ebv is not the only agent responsible for the development of autoimmune thyroid diseases , it can be considered a contributory factor . 
Epstein-Barr virus: biology and disease
Infectious agents and autoimmunity
The role of the Epstein-Barr virus in autoimmunisation
Aetiology of autoimmune thyroid disorders
Epstein-Barr virus as an aetiological factor in autoimmune thyroid disorders
Conclusions