epstein  barr virus ( ebv ) is a gamma - herpesvirus with a 172-kb dna genome , which infects more than 90% of world population .
ebv is a successful virus that utilizes normal b cell biology to infect , persist , and replicate in b cells ( thorley - lawson , 2001 ; thorley - lawson and gross , 2004 ) .
ebv predominantly infects resting b lymphocytes through complement receptor 2 ( cd21 ) in vitro ( for a review of ebv biology , young and rickinson , 2004 ) .
primary infection of ebv may cause short term proliferation of b cells in human hosts .
the infection is usually self - limited and controlled by the strongly elevated t cell immune response .
if the infection occurs in adolescence or adulthood , up to 50% t cells in the host can be specific to the virus , which may cause the clinical symptom of infectious mononucleosis ( i m ) .
ebv then persists latently in the host within long - life memory b cells . during latency , up to eight ebv encoded proteins and several non - coding rnas are expressed .
these include two ebv encoded small rnas ( eber1 and eber2 ) , nuclear antigens , and membrane proteins .
ebv nuclear antigen 1 ( ebna-1 ) binds to the latent viral dna replication origin and maintains the viral genome in the ebv positive cells after cell division ( yates et al . , 1985 ) .
ebna-2 interacts with a dna binding protein cbf1 through mimicking notch signaling pathway , blocks differentiation , and allows cell proliferation ( ling et al .
two ebv latent membrane proteins ( lmps ) adopt the signaling pathways involved in b cell activation and differentiation to sustain the long - life of ebv positive cells .
both lmp1 and lmp2a are multiple membrane - spanning proteins that function as constitutive active receptors independent of ligand binding ( gires et al . , 1997 ) .
on one hand , the carboxyl terminus of lmp1 contains consensus tumor - necrosis - factor - receptor - associated factor ( traf)-binding domains and interacts with multiple members , in a b cell activation molecule cd40 mimicking pattern that can activate stat , jnk , and nf-b pathways and lead to b cell survival and growth . on the other hand , lmp2a contains immunoreceptor tyrosine - based activation motifs ( itams ) and associates with lyn kinase , and lmp2a can then replace the survival signal provided by b cell receptor ( bcr ; caldwell et al . , 1998 ) .
overall , the ebv - infected nave b cell blasts proliferate in a way that resembles the antigen - activated blasts ( thorley - lawson and mann , 1985 ) .
however , different from terminally differentiated plasma cells that eventually undergo apoptosis , these ebv positive cells follow the path of b cell differentiation into memory b cells through migration into germinal center ( gc ; thorley - lawson , 2001 ) .
four different types of latency programs were defined according to the expression profile of ebv latent genes .
these memory cells do not express ebna-1 or other latent proteins ( referred as latency 0 ) under normal condition , but only express ebna-1 when cells are dividing ( hochberg et al . , 2004 ) . in vitro ,
the ebv transformed lymphoblastoid cell line ( lcl ) with all eight viral latent proteins , ebv encoded small rna ( ebers ) , and bamhi a transcripts can be continuously propagated .
ebna-1 , ebna-2 , ebna-3a , ebna - lp , and lmp1 are required for this transformation process ( kutok and wang , 2006 ) .
because of the strong immunogenicity of ebv latent proteins , the lcl - like viral gene expression pattern ( type iii latency ) , can only be observed in immunocompromised patients in vivo . alternatively ,
ebv positive burkitt 's lymphoma ( bl ) cells express only ebna-1 and ebv encoded rnas ( type i latency ) , whereas cells with type ii latency expressing also lmp1 and lmp2 are observed in hodgkin 's disease ( hd ) .
the above mentioned information indicates that after primary infection , a subset of ebv positive b cells survive and emerge into the memory compartment
. these cells can go for limited expansion or extrafollicular proliferation and sustain in the host for a longtime .
in addition to b cell , ebv also infects epithelial cells and maybe some t cells .
ebv is also highly associated with several neoplastic diseases , such as endemic bl , t cell lymphoma , nasopharyngeal carcinoma ( npc ) , hd , and immunoblastic lymphomas in immunocompromised patients ( young and rickinson , 2004 ) .
viral genomes or subsets of viral gene products can be detected in the tumor tissues , and antibody levels are usually elevated in patients sera . though not fully illustrated , recent knowledge provides some hints to the ebv associated disease mechanisms .
the ebv associated bl ( endemic bl in tropic africa ) demonstrates that the complex interaction of ebv with b cells predisposes the development of bl ( for reviews , brady et al . , 2008 ; thorley - lawson and allday , 2008 ) .
malaria infection in endemic region is considered as another co - factor for the development of bl .
ebv - negative bl also occurred in other area , and myc - translocation to ig locus is the most critical feature observed in both sporadic and endemic bls .
the translocation is highly dependent on the enzyme activity of aid ( activation - induced cytidine deaminase ; muramatsu et al .
aid is highly expressed in gc to provide the class switch and hypermutation of ig variable region .
after translocation , the activated myc on one hand can lead to cell growth and proliferation , but myc also leads to p53 and bim dependent apoptosis .
effects of ebv proteins may prevent b cells from myc induced apoptosis , thus sustain the survival of these memory b cells .
the malaria infection may represent a chronic antigenic stimulation with repeated opportunistic infections that can promote more ebv - infected cells to become memory cells .
it is still not clear whether chronic b cell antigen stimulation can link to the prolonged or atypical expression of aid , and lead to the higher frequency of myc - translocation ( thorley - lawson and allday , 2008 ) .
hodgkin 's lymphoma ( hl ) is characterized by the presence of a minority of malignant hodgkin / reed sternberg ( hrs ) cells among a background of non - neoplastic b and t cells ( for a review , kapatai and murray , 2007 ) . a complex cytokine cross - talk among hrs cells and neighboring cells
may provide proliferative and anti - apoptotic signals for tumor cell growth . according to the who classification
, hl can be divided into two major types : classical and nodular lymphocyte predominant hl ( harris et al . , 1999 ) .
nevertheless , ebv positive and negative hls share similar morphological patterns , while different signaling pathways are involved in the pathogenesis .
ebv positive hrs cells display type ii latency gene expression profile with ebers , ebna-1 , lmp1 and lmp2 , and bamhi a rightward transcripts ( barts ) .
the lack of expression of functional surface immunoglobulin is the hall mark of classical hl . but because of the clonally rearranged immunoglobulin genes identified in hrs cell , the b cell origin of hl
under normal situation , antigen - activated b cells go to gc for somatic hypermutation to generate high affinity bcrs , and those cells with unfavorable mutations will be eliminated through fas - mediated apoptosis .
the current scenario for hl is that the expression of ebv genes may prevent the apoptosis of cells with certain mutations and promote them into hrs cells ( kapatai and murray , 2007 ) .
it has been a longtime question why ebv only causes these malignant diseases within a small portion of infected population .
recent studies further indicated that ebv infection may regulate cd8 nkt development in the host ; and the failure of cd8 nkt conversion may contribute to disease development in some cases ( he et al . , 2010 ) .
nkt cells are unconventional t cells that are cd1d - restricted , lipid antigen - reactive , immune regulatory t lymphocytes .
nkt cells can produce a broad range of cytokines upon antigen stimulation within minutes to hours .
different subsets of nkt are involved in regulating cell - mediated immunity to various infectious organisms , cancer , allergy , and autoimmune diseases .
it is still unclear why such a small subset of t cells [ t cell receptor ( tcr)- v14-j18 ] can have such broad influence .
most notably , nkt cell numbers vary substantially between individuals ( from undetectable to over 3% of blood lymphocytes ) .
this may be either the result of differences in intrathymic development , migration efficiency or the maintenance , or expansion in peripheral blood ( for a review , godfrey et al . , 2010 ) .
generally speaking , type i nkt cells can mediate strong antitumor responses on -galcer - induced ifn- and drive t cells into th1-bias .
type ii nkt cells suppress tumor immunity through il-13 secretion ( berzofsky and terabe , 2008 ) .
it is therefore attractive to study the nkt population variation in different diseases and ask how the nkt population could be manipulated .
a recent study revealed that the frequencies of regulatory cd8 nkt , but not cd4 nkt cells , in ebv associated hl and npc patients are much lower than that in healthy ebv carriers ( yuling et al . , 2009 ) .
in the human - thymus - sever combined immunodeficient ( hu - thy - scid ) chimera mouse model , the authors further demonstrated that ebv promotes the generation of ifn--biased ebv specific cd8 nkt cells , which can suppress tumorigenesis by ebv associated malignancies in vivo ( xiao et al .
to further illustrate the interplay between ebv and nkt development , the same group demonstrated that the average frequency of total and cd8 nkt cells in peripheral blood mononuclear cells ( pbmcs ) of healthy ebv latent individuals is significantly higher than that in patients with acute ebv i m or hl , and in ebv - negative normal control subjects .
ebv challenge induced a population of nkt precursors develops and differentiates into mature cd8 nkt cells in the thymus and liver of human - thymus / liver - scid chimera mouse model .
these cd8 nkt cells produce more perforin and are cd8 positive , similar to that detected on cd8 nkt cells in pbmcs from healthy latent ebv - infected subjects and i m patients at 1 year post - onset .
the authors proposed that thymic ebv - infected dendritic cells and il-7 may regulate the cd8 nkt development process .
it clearly demonstrated that ebv can induce differential cd4 versus cd8 lineage commitment , in addition to known classical endogenous elements ( he et al . , 2010 ) .
thus the distinctive subsets of cd4 and cd8 nkt cells in ebv - infected individuals may differentially modify the pathogenesis of ebv .
alternatively , it may be possible that the biased nkt will affect the specific individual 's response to later infections or malignant diseases .
keeping the above observation in mind , we may check possible mechanisms involved in ebv associated autoimmune diseases , such as systemic lupus erythematosus ( sle ) and rheumatoid arthritis ( ra ; for a review , toussirot and roudier , 2008 ) .
both sle and ra are complex disorders with a genetic background , as suggested by familial cases .
patients of both diseases have higher titers of anti - ebv antibodies , impaired t cell responses to ebv antigens and higher viral load in pbmcs ( james et al . , 2001 ;
alanine rich sequences and cellular nuclear antigens were identified ( vaughan et al . , 1995 ) .
a proposed disease mechanism is the interplay between genetic predisposition and ebv infection leads to the development of cross reacting autoantibodies , and later the non - cross - reactive antibodies against autoepitopes ( toussirot and roudier , 2008 ) .
in addition to sle and ra , multiple sclerosis ( ms ) is another ebv associated chronic inflammatory disease with repetitive damages of myelin sheet in the central nervous system ( cns ) .
ms is a disease that also has been linked to genetic and environmental factors ( for a review , compston and coles , 2008 ) .
based on the geographic distribution , ms was proposed to be a rare disease that caused by a common infection . the most promising data suggesting ebv as the viral factor is that the risk of ms is 20 times higher among people who have contracted i m , as compared with seronegative individuals ( ascherio and munger , 2007 ) . in a large scale follow - up study for ms development in us military , the risk of ms increased with elevated levels of serum antibodies to ebna complex and less strongly to vca igg .
some of the serum antibody levels were elevated even 5 years before disease development ( levin et al . , 2005 ; compston and coles , 2008 ) .
detection of ebv specific antibodies in ms patients also showed a highly correlation in other studies . however
because ebv is highly prevalent in healthy population , it has been a long - term debate on the role of ebv as the etiology agent of ms .
the detection of ebv dna or viral proteins by different groups then gave controversial results , which may be due to different samples included or the sensitivities of assays employed ( lunemann and munz , 2009 ) .
recent detection of ebv markers in the postmortem brain tissue from patients with secondary progressive phase of ms thus provide a clue for the pathogenic contribution of ebv to ms patients .
( 2007 ) demonstrated that almost 100% of the early onset ms cases with the secondary progressive phase contain dysregulated ebv infected plasma cells in ms brains .
lmps were regularly detected in ms brains , whereas viral lytic proteins were only detected in ectopic b cell follicles and acute lesions .
notably , activated cd8 t cells with membrane associated perforin staining were observed at sites of major accumulation of ebv - infected cells , suggesting t cell cytotoxicity toward ebv positive plasma cells ( serafini et al . , 2007 ) .
further study of the intrathecal b cells indicated that these cells are cd27 antigen - experienced cells and with the co - expression of lmp1 and 2a . moreover
, lmp2a positive cells also express b cell - activating factor of the tumor - necrosis factor family ( baff ) , suggesting these cells are responsible for persistent intrathecal synthesis of oligoclonal antibodies .
the ebv positive cell pattern is very similar to the ectopic follicles observed in the tonsil of healthy ebv carriers .
the disease model of ms was proposed by the authors that through the proliferative , anti - apoptotic , and b cell activation signals provided by ebv latent proteins , ebv may promote the intracerebral expansion and maturation of b cells and form ectopic lymphoid follicles
. it also explains that the oligoclonal igg in the csf and brain tissue is synthesized persistently by ebv positive b cells ( serafini et al . , 2010 ) .
there are still remaining questions . why are the ebv positive b cells homing to brain ?
other possibilities for the contribution of ebv in ms are also proposed by other groups .
the idea is that virus positive cells may be few , but these cells may induce enough pro - inflammatory cytokine production and lead to the development of disease .
for example , ebv was demonstrated to infect primary human brain microvessel endothelial cells in vitro ( casiraghi et al . , 2011 ) .
the infection also leads to increased production of several pro - inflammatory mediators , such as ccl-5 and icam-1 , which may promote adhesion of leukocytes to the endothelium .
it is likely that the entry of autoreactive t cells may follow a breach of the blood  brain barrier ( bbb ) and lead to cns lesions in ms .
it explains why viral and myelin - specific lymphocytes and macrophages infiltrate into ms brains , and interferon - beta treatment may prevent ms relapse through blocking virus replication and subsequent production of cytokines ( casiraghi et al . , 2011 ) .
alternatively , another recent study focused on the development of cd8 cytotoxic t cells observed in ms patients ( ji et al .
the authors used a major histocompatibility complex ( mhc ) class i - restricted tcr transgenic model that generates cd8 myelin basic protein ( mbp ) specific t cells to study the break of cd8 t cell tolerance and induction of cns autoimmunity .
the results indicate that viral infection triggers the activation of cd8 t cells bearing dual tcrs in the experimental animals , suggesting these t cells may contribute to cns autoimmune diseases ( ji et al . , 2010 ; ransohoff , 2010 ) .
indeed , dual - receptor tcrs are present in humans and proposed to enhance antiviral defense .
the second receptor could be against myelin in a small subset of individuals , which may be associated with specific mhc ii subtypes .
it is possible that reinfection or reactivation of the specific virus may activate the t cell antiviral memory and also the anti - myelin activity ( ransohoff , 2010 ) .
the question then is why infection of ebv , but not other viruses , links to the development of ms .
we may then think again the stimulatory effect of ebv on nkt development , regarding the viral modulation on immune system ( he et al .
it was previously known that the infection of hiv or htlv-1 may result in a decrease in nkt cells ( lin et al . , 2005 ; azakami et al . , 2009
it thus indicates that various viral infections may have different impacts on the development of host immune response , and ebv may be a very unique virus . from an evolution point of view
, it is plausible that ebv may serve certain roles to help immune system development in most population .
the ebv associated diseases may be rare events resulting from host genetic variations , which let the host immune system be modified by ebv in a bias manner .
the disease statuses may develop upon the stimulation of combinatory environmental factors such as other infectious agents , which may activate ebv replication at the same time . in other words , these ebv associated diseases may be due to the differential immune modulation ability of ebv in people with different genetic background , rather than a direct pathogenic effect of ebv gene products . taken together , multi - factorial study designs including genetic factors , individual variations of subsets of regulatory immune cells , and environmental factors such as different infections are required for understanding the pathogenic mechanism of ebv associated diseases in the future .
the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .
 host immune system is designed ( or evolved ) to fight against different pathogens . 
 many viruses infect the immune cells for the propagation of new progenies , thus the infection may modulate the host immune homeostasis . 
 it has been more than 45 years since the discovery of epstein  barr virus ( ebv ) from a burkitt 's lymphoma derived cell line . 
 the ability of ebv to transform primary b cells in vitro leads to the suggestion for its oncogenic potential . 
 however , except the clear understanding of the role of ebv in post - transplantation lymphoproliferative disease , it remains ambiguous why such a ubiquitous virus causes malignant diseases only in a very small subset of individuals . 
 possible explanation is that ebv may cooperate with other environmental and host genetic factors and lead to the development of ebv associated neoplastic diseases . 
 in addition to infecting b cells , recent studies revealed that ebv may impact host immune system more broadly than previously thought , for example the development of regulatory nkt subsets . instead of an intensive review 
 , this article aims to provide a linkage to recent advances on the interplay between ebv and host immune system and to inspire further studies on ebv related diseases , especially autoimmune diseases . 
EpsteinBarr Virus
EBV and its Associated Malignant Diseases
EBV and NKT Cell Development
EBV and Autoimmune Diseases
Conflict of Interest Statement