Session Title: Sjögren's Syndrome - Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose: The exact cause of exocrine gland dysfunction in primary Sjögren’s syndrome (pSS) has not been fully delineated, but it is thought that both innate and adaptive immunity may contribute significantly. Recent data have unveiled the structure and function of the P2X7 receptor/NLRP3 inflammasome pathway in stimulating caspase-1 activation and the subsequent release of the inflammatory cytokines IL-1β and IL-18. Thus, the growing evidence for the presence of P2X7R in salivary gland has suggested a fascinating scenario for the initiation and amplification of the innate immune response in pSS exocrinopathy.
Aim of the study: 1) to assess the expression of P2X7 receptor in minor salivary gland biopsies (MSGBs) and in peripheral lymphocytes of pSS patients; 2) to explore any correlation among P2X7 receptor, the other components of the inflammasome (i.e.NLRP3, caspase-1) and salivary levels of the released IL-18; 3) to correlate P2X7 receptor to patients clinico-serological and histopathological features
Methods: Consecutive patients with a diagnosis of pSS (AECG criteria) were enrolled in this proof of concept study. The control group consisted of subjects with suspected SS who did not fulfill the AECG criteria for pSS. Analysis of P2X7R, NLRP3 and caspase-1 gene expression was performed by real-time PCR on an ABI PRISM 7900 sequence detector (Applied Biosystems). Levels of IL-18 were assessed in patients unstimulated whole saliva by Western blot. Patients’ clinico-serological and histopathological data were prospectively collected. For statistical comparisons, the t-test, the chi square test and logistic regression analysis were employed. P-values <0.05 were considered significant.
Results: Out of the 36 consecutive patients included in the study, 21/36 met the AECG criteria for pSS while the other 15/36 no-SS represented the control group. The P2X7R-mRNA was represented in MSGBs and in peripheral lymphocytes of both pSS and no-SS but its expression was significantly higher in pSS subjects than in no-SS control group (MSGBs p<0.0001; peripheral lymphocytes p=0.002). Similarly NLRP3 (p=0.0002) and caspase-1 (p=0.0004) gene expression was significantly higher in pSS and this was paralleled by an increased expression of IL-18 in pSS salivary samples. The P2X7R-mRNA was significantly higher in pSS patients with positivity for anti-Ro/SSA (p<0.0001) and correlated with MSGBs focus score (p=0.01).
Conclusion: This study suggests a potential involvement of the P2X7R/inflammasome-caspase-1- IL-18 axis in the pathogenesis of pSS exocrinopathy and opens novel opportunities for studying the complex mechanisms underlying pSS.
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