SAT0377 Interferon Gamma-Inducible Protein 16 (IFI16) in Primary SjÖgren's Syndrome: A Novel Player in Disease Pathogenesis?

Abstract

BackgroundAlthough the pathogenesis of primary Sjögren's syndrome (pSS) is not fully elucidated, several studies suggest that the interferon (IFN) signature is involved in both induction and perpetuation of the disease (1). The interferon gamma-inducible protein 16 (IFI16), normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders, including systemic lupus erythematosus and systemic sclerosis. This leads to tolerance breaking to this self-protein with consequent development of anti-IFI16 autoantibodies (2-4).ObjectivesAim of the present study was to investigate the possible pathogenic and/or clinical significance of IFI16 and anti-IFI16 antibodies in pSS.MethodsSixty-seven female patients with pSS were evaluated and 182 healthy donors (HD) acted as controls. IFI16 and anti-IFI16 concentrations were assessed in serum samples with ELISA. IFI16 was also evaluated in 10 pSS minor salivary glands (MSGs). MSGs of sicca-non pSS subjects displaying either normal architecture or non-specific chronic sialadenitis (NSCS) acted as controls. Hematoxilin and eosin staining and CD3/CD20 double immunofluorescence were performed in serial sections to grade all MSGs and to assess B/T cell compartmentalization respectively.ResultsIFI16 was not constitutively expressed in normal MSGs. In NSCS-MSGs, IFI16 was expressed by glandular epithelium, endothelial cells and some of infiltrating lymphocytes, but not by plasma cells. pSS-MSGs displayed marked expression and cytoplasmic mislocalization of IFI16 by acinar and ductal epithelial cells as well as infiltrating lymphocytes and peri/intra-lesional endothelium compared to MSGs with normal architecture or NSCS. Within the mononuclear cell infiltrate, IFI16 distribution in mononuclear cell infiltrates overlapped that of T lymphocytes appearing nicely compartmentalized in those pSS-MSGs displaying B/T cell segregation.pSS patients displayed higher concentration of IFI16 protein and higher titer of anti-IFI16 antibodies in the serum compared to HD. Serum IFI16 concentration was directly correlated with disease duration and focus score and inversely correlated with the age at diagnosis. IFI16 protein positivity in the serum was associated with concurrent positivity for rheumatoid factor. Of interest, the direct correlation between IFI16 positivity and the focus score was independent of disease duration and age at diagnosis. No correlations between anti-IFI16 antibodies and any clinical and/or serological parameters were identifiedConclusionsThe overexpression and cytoplasmic mislocalization of IFI16 protein at glandular level, the occurrence of free IFI16 protein in the serum and the detection of specific circulating autoantibodies in pSS, may suggest a link between this autoantigen and pSS pathogenesis. Larger and prospective studies are required to shed additional light on the pathogenic mechanisms mediated by IFI16 as well as on a possible application of serum IFI16 protein detection in cl...

Distinct Anti-IFI16 and Anti-GP2 Antibodies in Inflammatory Bowel Disease and Their Variation with Infliximab Therapy

“…[30][31][32]34 In some of these previous studies, increased aberrant IFI16 expression has been demonstrated in target tissues, including the skin in SLE and the salivary glands in SjS. 33,35 Consistent with these findings and a previous report by Vanhove et al, we were able to demonstrate aberrant epithelial IFI16 expression in inflamed colon mucosa from both CD and UC patients by immunohistochemistry. 12 Considering that: i) gut epithelial cells do not express IFI16 in the normal setting; ii) IFI16 is a nuclear DNA sensor for pathogen exogenous DNA; and iii) IBD likely results from an aberrant immune response against micro-organisms, bacteria or viruses that are able to invade cells of the gut mucosa and release or produce exogenous dsDNA, it is not surprising that pattern recognition receptors, such as IFI16, are aberrantly upregulated in these patients and may trigger the production of specific autoantibodies.…”

“…In the same cohort, we also evaluated anti-GP2 antibody levels and confirmed the findings previously reported. [35][36][37][38][39][40][41] Anti-GP2 IgG subtype titres were significantly increased in CD as was the IgA subtype although to a lesser extent compared with UC and HC, with a statistically significant correlation between IgG and IgA subtype expression levels.…”

“…In addition to anti-IFI16 antibodies, IFI16 protein was also recently found to be present in sera from patients with various autoimmune diseases. 29,31,35 The highest serum levels of IFI16 protein were found in patients with rheumatoid arthritis. 29,31 Despite this evidence, we failed to detect any circulating IFI16 protein in IBD patients using the same ELISA sandwich used in our previous reports (data not shown).…”

“…[32][33][34] Aberrant IFI16 expression has also been demonstrated in minor salivary glands from patients with primary SjS. 35 A recent report by Wiebe Vanhove highlighted the importance of PYHIN inflammasome signalling in IBD and linked the responsiveness of anti-tumour necrosis factor (anti-TNF) therapy to signalling mediated by these inflammasomes. 12 They demonstrated a significant upregulation of AIM2 and IFI16 proteins in colonic mucosal biopsies from active UC patients versus controls.…”