Evidence for coxsackievirus infection in primary Sjögren's syndrome

Abstract

Objective. Primary Sjögren's syndrome (SS) is an autoimmune disease characterized by activation of minor salivary gland (MSG) epithelial cells and B and T lymphocytic infiltrates. These findings have long encouraged the hypothesis that a persistent viral infection of the MSG epithelial cells may drive the autoimmune response; however, the identity of that virus has remained elusive. The aim of this study was to test this hypothesis.Methods. We applied the differential display protocol to MSG RNA samples from patients with primary SS and healthy controls. We then used seminested reverse transcriptase-polymerase chain reaction to amplify the 5 -noncoding region (5 -NCR) of the enteroviral genome in 8 patients with primary SS, 9 patients with secondary SS, and 8 control subjects. Immunohistochemistry was performed to study the expression of the VP1 enteroviral capsid protein in MSG biopsy samples from 12 patients with primary SS, 8 patients with secondary SS, and 16 controls.Results. Differential display analysis yielded a 94-bp fragment of coxsackievirus B4 (CVB4) P2A gene in the primary SS samples. The 5 -NCR was amplified in 7 samples from patients with primary SS and in no samples from patients with secondary SS or controls. The 7 amplified products were sequenced; 4 of the sequences were found to be 98-99% identical to the 5 -NCR of CVB4, and 3 were found to be 97-98% identical to the 5 -NCR of CVA13. Immunohistochemistry for the enteroviral capsid protein VP1 revealed positive staining in epithelial cells and lymphocytic infiltrates in 11 primary SS samples, 1 secondary SS sample, and no control samples.Conclusion. We provide evidence that primary SS may be associated with coxsackievirus infection of the MSG epithelial cells and focal lymphocytic infiltrates. Our findings are formulated in a hypothesis concerning the possible role of coxsackieviruses in the induction and maintenance of autoimmunity in primary SS.

The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes

“…Additionally, RT-PCR for enterovirus was positive in salivary gland biopsies in seven of eight patients with primary Sjogren's syndrome but not in 16 normal salivary glands. Ductal, acinar and infiltrating inflammatory cells stained positively with Dako anti-vp1 in the Sjogren's syndrome cases but not in the controls [22]. Fig.…”

“…Since most of the previous studies [13,21,22] were conducted using fresh biopsy tissues, or tissues removed at the time of organ donation, the authors were able to employ electron microscopy, RT-PCR or in situ hybridisation techniques to confirm the validity of the vp1 staining. These options were not open to us since the pancreatic material from patients with diabetes in the present study was collected almost entirely retrospectively from autopsies performed hours after the death of patients.…”

Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/SSB in salivary gland epithelial cells

“…Epithelial cell viral infection can be one of the best candidates for this process. Epstein-Barr virus (EBV) [21] and Coxsackie viruses [22] have been described as possible inducers of salivary gland epithelial cell activation and apoptosis in SS patients.…”

Primary Sjögren’s Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances

“…(Pflugfelder et al, 1993;Green et al, 1989, Haddad et al, 1992Iwakiri et al, 2009). Coxsackie virus was found to be increased in SS salivary glands, but these findings have been the subject of some controversies (Triantafyllopoulou et al, 2004, Gottenberg et al, 2006a. Innate immunity is classically stimulated by infectious agents, which results in type I interferon production.…”