Clinical and In Situ Characterization of Hepatitis Delta Virus in Sjogren’s Syndrome

Hepatitis delta virus (HDV) has been detected in the minor salivary gland (MSG) tissue of Sjogren’s Syndrome (SjS) patients in the absence of an HBV co-infection. HDV antigen expression was previously shown to trigger an SjS-like phenotype in vivo, demonstrating a cause-and-effect association. We hypothesize that if HDV regulates SjS development, then HDV profiles may correlate with disease manifestations. This retrospective study characterized HDV in a cohort of 48 SjS MSG between 2014-2021. Analyses of HDV antigen (HDAg) expression, including cell type and subcellular localization, in situ hybridization of HDV RNA, and comparative analyses with associated SjS and viral hepatitis clinical features were conducted. HDAg was detected in MSG acinar, ductal, and adipose cells. HDAg localized with nuclei and mitochondria. HDV genomic RNA localized to the nucleus. A significant negative correlation was noted between HDAg intensity and focal lymphocytic inflammation. No significant associations were detected between MSG-localized HDAg and liver enzymes, or an evident HBV co-infection. This study has identified a non-hepatic reservoir for chronic HDV persistence in SjS-affected MSG and a unique mitochondrial localization for HDV antigen. Detection of non-hepatic HDV-mediated disease in the absence of an evident current or past HBV co-infection warrants further investigation.