Background: Interleukin (IL)-22 is a potent mediator of cellular inflammatory responses that has been recently reportedto play a role in the pathogenesis of primary Sjogren's Syndrome (p-SS) (1, 2) and of T and B lymphomas. IL-22biological activity is initiated by binding to a cell-surface complex composed of two subunits, IL-22R1 and IL-10R2receptor chains, and further regulated by interactions with a soluble binding protein, IL-22BP. Unlike the IL-10R2, which is constitutively expressed in many human tissues, IL-22R1 is not detectable in immune cells.Objectives: Aim of this study was to better characterize the role of IL-22 axis in the pathogenesis of p-SS and p-SSassociated lymphomas.Methods: Minor salivary gland biopsies were obtained from 30 patients with p-SS and 20 with non-specific chronic sialoadenitis(n-SS) and evaluated by RT-PCR for IL-22, IL-22R1 and IL-22BP expression. The protein expression of IL-22, IL-22R1 and p-STAT3 was evaluated by immunohistochemistry and IL-22R1-expressing cells were caharcterized byconfocal microscopy. Flow cytometry analysis of IL-22R1 expression was also conducted on peripheral bloodmononuclear cells (PBMCs) from p-SS (n=30), n-SS (n=20), SLE (n=20) and rheumatoid arthritis (n=20) patients andnormal controls (n=30). PBMCs isolated from 10 p-SS and 10 controls were also cultured with (or without) recombinant IL-22 and the modulation of the transcripts for pro-inflammatory cytokines was assessed by RT-PCR. Paraffin embeddedsections of non-Hodgkin lymphomas from 5 p-SS patients were finally evaluated for the expression of IL-22R1.Results: IL-22, STAT3 and IL-22BP but not IL-22R1 transcript levels were significantly up-regulated in the inflamedsalivary glands of p-SS but not in n-SS. Immunohistochemistry confirmed the increased salivary expression of IL-22 andp-STAT3 also demonstrating a significant increased protein levels of IL-22R1 in p-SS. Confocal microscopy analysisshowed that IL-22R1 was aberrantly and strongly expressed in monocytes/macrophages infiltrating the p-SS salivaryglands and these cells also co-expressed p-STAT3, suggesting the occurrence of autocrine activation of p-STAT3.CD68+ cells obtained from the peripheral blood also aberrantly expressed IL-22R1 in p-SS patients. IL-22R1 expressionon cells of hematopoietic origin was never observed in control disease patients, n-SS and healthy controls. Thestimulation with recombinant IL-22 of PBMCs from p-SS but not controls significantly up-regulated the expression of IL-17and IL-22. Non-Hodgkin lymphoma tissues from p-SS patients were also characterized by the aberrant expression of IL-22R1 on macrophages and neoplastic B cells.Conclusions: The aberrant expression of IL-22RA1 on cells of hematopoietic origin seems to be a specificimmunological signature of patients with p-SS and p-SS associated lymphomas and suggests a fundamental role of IL-22signaling in the pathogenesis of p-SS and its neoplastic evolution. Targeting of IL-22 pathway may represent a successfultherapeutic strategy in p-SS patients.References: 1. Ciccia F, et al. Ann RheumDis 2012. 2. Ciccia F, et al. Ann Rheum Dis 2012.
|Number of pages||1|
|Publication status||Published - 2013|