Very High Frequencies of Epstein Barr Virus Latently Infected B Lymphocytes in the Blood of Patients with Systemic Lupus Erythematosus

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Very High Frequencies of Epstein Barr Virus Latently Infected B Lymphocytes

in the Blood of Patients with Systemic Lupus Erythematosus

Category:  25 SLE‹human etiology and pathogenesis

J Gross1, A Thorley-Lawson2

1New England Medical Center, Boston, MA;2Tufts University School of

Medicine, Boston, MA

Presentation Number: 692

Poster Board Number: 157

Keywords: systemic lupus erythematosus, Epstein Barr virus, B lymphocyte

EBV infection is tightly regulated in the blood of healthy carriers. The

frequency of infected B cells remains remarkably stable over years. Only

memory B cells are infected, and little or no viral gene expression is

observed. We hypothesized that the immune dysfunction present in SLE would

have a significant impact on the regulation of EBV infection. Therefore, we

investigated EBV infection in the blood of patients with SLE and controls.

Methods: The frequency of EBV infected B cells was estimated by DNA-PCR

detection of single infected cells in limiting dilutions of B cells. The

phenotype of infected cells was determined by sorting B cell populations by

flow cytometry. EBV gene expression was determined by RT-PCR.

Results: In the blood of 29 patients with SLE, the frequencies of EBV

infected B cells were significantly higher (median 30 infected cells per 106

B cells) than those of 24 healthy individuals (median 5)(p<0.0001) and

generally were higher than those of 14 patients with other systemic

autoimmune diseases (median 16)(p=0.088). EBV infected cells were found in

memory (CD20+, IgD-) but not naive (CD20+, IgD+) B cell populations, similar

to observations in healthy individuals.

Patients treated with immunosuppressive agents (IS) following organ

transplant have high frequencies of EBV infected cells in the blood.

However, treatment of SLE patients with IS did not significantly alter the

frequency of infected memory cells (no IS median 149 per 106 IgD- B cells,

IS median 132, p=0.68). A group of 7 patients with clinically active SLE,

indicated by a SLE disease activity index (SLEDAI) score of >4, tended to

have higher frequencies of infected memory B cells (median 1659 per 106 IgD-

B cells) than those with inactive disease (SLEDAI ¾4)(median 125 per 106

IgD- B cells, p=0.061). In 8 SLE patients, fluctuations in the frequency of

infected cells were observed over time, which generally correlated with the

state of their disease.

Expression of EBV latency membrane proteins (LMP) 1 and 2 was identified in

B cells from the blood of 4 of 16 (25%) and 2 of 15 (13%) SLE patients,

respectively. This represents a modest increase over the normal population.

There was no expression of the growth promoting latency gene Epstein Barr

nuclear antigen 2 (EBNA-2).

Conclusion: These results suggest: 1) SLE often leads to high frequencies of

EBV infected cells. This effect is independent of treatment with

immunosuppressive agents, and this effect may be intensified by disease

activity; 2) EBV infection in blood of SLE patients remains restricted to

memory B cells. 3) EBV gene expression in the blood of patients with SLE is

limited to two latency genes with no expression of EBNA-2. Further

investigation of the cause of elevated frequency of EBV infected B cells in

patients with SLE may provide unique insight into the B cell deregulation of

this autoimmune disease.