Hepatitis Delta Virus Detected in Salivary Glands of Sjögren’s Syndrome Patients and Recapitulates a Sjögren’s Syndrome-Like Phenotype in Vivo

Abstract

Background Low-level, chronic viral infections have been suspect in the development of select autoimmune diseases, including primary Sjögren’s syndrome (pSS). Multiple studies have shown stimulation of antiviral response pathways in pSS tissues suggestive of a viral infection. Yet, with this data in hand, a causal link between a viral infection and development of pSS had not been identified. Therefore, a study was designed to further define the viral landscape within pSS-affected salivary gland tissue to identify potential viral-mediated triggers in the pathogenesis of this autoimmune disease. Methods A viral microarray was utilized to measure viral transcripts present in salivary gland tissue from patients diagnosed with pSS compared to healthy controls. Murine models of salivary gland localized HDV antigen expression were developed to evaluate the capacity of a chronic HDV signature to trigger the development of a pSS-like phenotype. Results Through this analysis, two distinct viral profiles were identified, including the increased presence of hepatitis delta virus (HDV) in 50% of pSS patients evaluated. Presence of HDV antigen and sequence were confirmed in minor salivary gland tissue. Patients with elevated HDV levels in salivary gland tissue were negative for detectible hepatitis B virus (HBV) surface antigen and antibodies to HBV or HDV. Expression of HDV antigens in vivo resulted in reduced stimulated saliva flow, increase in focal lymphocytic infiltrates, and development of autoantibodies. Conclusion Identification of HDV in pSS patients and induction of a complete pSS-like phenotype in vivo provides further support of a viral-mediated etiopathology in the development of pSS.

Antiviral treatment and liver‐related complications in hepatitis delta

“…The findings need also to be confirmed for other patients infected with other HBV and HDV genotypes than HBV genotype D and HDV genotype 1. Moreover, HDV RNA has recently been detected also in salivary glands in HBsAg‐negative patients with Sjogren's syndrome . To what extent antiviral therapies may have an effect on HDV RNA in extrahepatic tissues required further investigation.…”

Myd88 is required for disease development in a primary Sjögren's syndrome mouse model

“…Historically, adaptive immune dysfunction was thought to be the prime driver of SS, although more recent studies show that the innate immune system is equally crucial in mediating disease [34]. Accordingly, work in many different SS mouse models demonstrates an important role for innate immune activation in disease pathogenesis [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. For example, the IL-14a-transgenic pSS model has increased lymphotoxin a in the salivary tissue, even before the arrival of lymphocytes in the gland [43].…”

Innate immunity in Sjögren's syndrome

“…Corroborating work shows that some SS patients display an IFN gene signature ( vide supra ), and IFNα is secreted by plasmacytoid dendritic cells (pDCs) in response to viral agonists in salivary tissue in SS [19, 39, 46, 47]. In addition, studies in mouse models provide evidence for a virally-mediated disease etiology, as mice infected with murine CMV (mCMV) or HCVδ virus develop a SS-like disease [48, 49]. Moreover, an elegant genetic study in mice shows salivary hypofunction is induced by type I IFN signaling [50].…”