Discrepancy of Serological and Molecular Patterns of Circulating Epstein-Barr Virus Reactivation in Primary Sjögren's Syndrome

Abstract

Primary Sjögren's syndrome (pSS) is characterized by B cell hyperactivation, production of autoantibodies and increased risk of B cell lymphomas. Serological profile of Epstein-Barr virus (EBV) reactivation and increase EBV DNA levels in exocrine glands are observed in pSS, but whether these abnormalities are accompanied with disturbed systemic EBV control or have any association with pSS activity remains to be investigated. In this observational study, we initially explored anti-EBV antibodies and cell-free DNA in 395 samples from a cross-sectional plasma collection of pSS patients included in ASSESS French national cohort. Results were assessed in relation with disease activity. Further, to assess cell-associated EBV DNA we organized a case-control study including 20 blood samples from pSS patients followed in University Hospital Center of Montpellier. Results were compared with matched controls. Robust response against EBV early antigen (EA) was observed in pSS patients with anti-SSA/B (Sjögren's syndrome A and B) and anti-SSA autoantibodies compared to anti-SSA/B negatives ( P < 0.01 and P = 0.01, respectively). Increased beta-2 microglobulin, kappa and lambda light chains, and immunoglobulin G levels were more frequently observed in anti-EA seropositive pSS subjects compared to anti-EA negative subjects ( P < 0.001; P = 0.001; P = 0.003, respectively). Beta-2 microglobulin was independently associated with anti-EA positivity in multivariate analysis ( P < 0.001). Plasma cell-free EBV DNA and EBV cellular reservoir was not different between pSS patients and controls. We conclude that serological evidence of EBV reactivation was more frequently observed and more strongly associated with anti-SSA/B status and B cell activation markers in pSS. However, serological profile of EBV reactivation was not accompanied by molecular evidence of systemic EBV reactivation. Our data indicated that EBV infection remains efficiently controlled in the blood of pSS patients.

Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis

“…The ESSDAI score in both groups of patients with positive EBV serology (G1 and G2) was higher than in EBV-negative patients (G3). G1 patients had a non-significantly higher ESSDAI compared to G2 patients, in line with a recent report by Sanosian 44 , who didn't find distinct ESSDAI scores in anti-EBV EA-positive compared to anti-EBV EA-negative patients. No differences were found in specific clinical ESSDAI domains between G1 and G2 groups, contrasting to the report of Pasoto 41 , who found higher articular activity in anti-EBV EA-positive patients.…”

Epithelial–immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis

“…EBV DNA has been detected at increased levels in the salivary glands of patients with pSS compared with healthy individuals, with Ro52-reactive perifollicular plasma cells being frequently infected 92 , 93 . Furthermore, patients who were also positive for anti-SSA and/or anti-SSB antibodies had higher titres of IgG antibodies against the EBV early antigen than those patients without anti-SSA and anti-SSB antibodies 91 .…”

<p>Infections as Risk Factor of Sjögren’s Syndrome</p>

“… 31 , 32 Other research also shows EBV infection rates are higher among SS patients with the presence of both anti-SSA and anti-SSB autoantibodies compared to SS patients with only anti-SSA or without the presence of both the autoantibodies. 33 Therefore it is highly speculated that EBV reactivity increases due to the presence of both anti-SSA and anti-SSB.…”