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 Abnormally

Elevated Epstein-Barr Virus Load

Patients

With Systemic Lupus Erythematosus Have Abnormally Elevated Epstein-Barr Virus

Load in Blood Posted 05/17/2004  Abstract Various genetic and environmental

factors appear to be involved in systemic lupus erythematosus (SLE).

Epstein–Barr virus (EBV) is among the environmental factors that are

suspected of predisposing to SLE, based on the characteristics of EBV itself

and on sequence homologies between autoantigens and EBV antigens. In addition,

higher titers of anti-EBV antibodies and increased EBV seroconversion rates

have been observed in SLE patients as compared with healthy control

individuals. Serologic responses do not directly reflect EBV status within the

body. Clarification of the precise status of EBV infection in SLE patients

would help to improve our understanding of the role played by EBV in this

disease. In the present study we determined EBV types in SLE patients (n = 66)

and normal control individual (n = 63) by direct PCR analysis of mouthwash

samples. We also compared EBV load in blood between SLE patients (n = 24) and

healthy control individuals (n = 29) using semiquantitative PCR assay. The

number of infections and EBV type distribution were similar between adult SLE

patients and healthy control individuals (98.5% versus 94%). Interestingly, the

EBV burden in peripheral blood mononuclear cells (PBMCs) was over 15-fold

greater in SLE patients than in healthy control individuals (mean ± standard

deviation: 463 ± 570 EBV genome copies/3 µg PBMC DNA versus 30 ± 29 EBV genome

copies/3 µg PBMC DNA; P = 0.001), suggesting that EBV infection is abnormally

regulated in SLE. The abnormally increased proportion of EBV-infected B cells

in the SLE patients may contribute to enhanced autoantibody production in this

disease.

Introduction

Systemic lupus erythematosus

(SLE) is an idiopathic disease characterized by variable inflammatory

destruction. A variety of autoantibodies are found in the serum of SLE

patients, indicating that SLE is an autoimmune disease.[1] However, the

mechanisms that lead to the aberrant autoimmune responses are not clearly

understood, and various genetic and environmental factors are thought to be

involved.[2] Epstein–Barr virus (EBV) is suspected to play a role in

predisposing to SLE for several reasons. First, EBV promotes proliferation of B

cells after infection, and thus it poses a prolonged antigenic challenge. This

prolonged EBV antigen expression may trigger SLE in genetically prone

individuals. Second, EBV-infected B cells can become a continuous source of

autoantibodies. Third, sequence homologies exist between SLE autoantigens and

some EBV proteins, such as EBV nuclear antigen (EBNA)-1 and EBNA-2. The

antibodies elicited by these viral antigens may cross-react with autoantigens

and trigger SLE.[3-5]

If EBV is indeed involved in

the pathogenesis of SLE, then there must be some association between EBV

infection and SLE.[6-9] Elevated titers of anti-EBV antibodies have been

detected in SLE patients compared with control individuals.[10-12] It is

difficult to prove that there is any association between EBV and SLE by

comparing seroconversion rates between patients and healthy control individuals

because the majority of adults are seropositive for EBV.[13] Recently,

and coworkers[14,15] examined more than 100 SLE patients and found that the EBV

seroconversion rate was significantly greater in SLE patients than in normal

control individuals, both in young and adult populations. However, these

studies do not prove the existence of a temporal relationship between EBV

infection and development of SLE. In addition, measuring antibodies to EBV

antigen does not directly indicate the status of EBV within the body. This is

because the serologic response can be affected not only by the nature of an

antigen but also by immune dysregulation induced by a patient's underlying

disease or treatment. Recent reports[16,17] indicated that some individuals

developed SLE immediately after an EBV-induced infectious mononucleosis, which

supports the hypothesis that EBV infection could trigger at least some SLE

cases. Hence, clarifying the precise status of an EBV infection in patients

would be valuable in improving our understanding of the role played by EBV in

the pathogenesis of SLE.

There have been few reports

of EBV loads or EBV types in SLE patients. Individual EBV isolates are

classified into type 1 and type 2, based on polymorphisms in their EBNA-2,

EBNA-3A, EBNA-3B, and EBNA-3C genes.[18] All virus isolates can be typed at the

DNA level by PCR amplification across these polymorphic regions.[18] Different

types of EBV produce antigens with different immunogenicity,[19] and T-cell

immunity may be affected by EBV type. Because an EBV-specific cytotoxic T-cell

function appears to be impaired in SLE patients,[20] it is possible that SLE

patients are infected with a specific type of EBV. In the present study we

determined EBV types in SLE patients and normal control individuals by direct

PCR analysis of mouthwash samples. We also compared EBV loads in blood between

SLE patients and healthy control individuals using a semiquantitative PCR

assay.

Conclusion

The type of EBV infecting

adult SLE patients is not different from that in healthy control individuals.

However, many patients with SLE have elevated EBV load in their blood,

suggesting that EBV infection is abnormally regulated in SLE. The increased

numbers of EBV-infected B cells in SLE patients may contribute to an enhanced

autoantibody production in this disease.

Abbreviation Notes

bp, base pair; EBNA,

Epstein–Barr virus nuclear antigen; EBV, Epstein–Barr virus; PBMC,

peripheral blood mononuclear cell; PCR, polymerase chain reaction; SLE,

systemic lupus erythematosus

This work was supported by a

grant (R11-26-0) from the Korea Science & Engineering

Foundation through the RRC (Rheumatism

Research Center)

at the Catholic University.

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