THU0045 IL-25/IL-17RB AXIS IS ACTIVATED AND ASSOCIATED WITH ILC2 EXPANSION IN GRANULOMATOSIS WITH POLYANGIITIS (GPA)
Authors: Daniele Mauro, Giuliana Guggino, Angelo Ferrante, Cristiano Alessandri, Serena Fasano, Daniela Iacono, Marianna Lo Pizzo, Riccardo Alessandro, Aroldo Rizzo, Francesco Ciccia
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Pathogenesis of Granulomatosis with polyangiitis (GPA) is still unknown. However, it has been observed a skewing of circulating CD4+ T cells toward the Th17 and Th2 phenotype. The pro-inflammatory cytokine interleukin 25 (IL-25) is a member of IL-17 cytokine family associated to the Th2 immune phenotype. Through the receptor IL17RB, IL-25 further sustains the Th2-type immune response and elicits the expansion of the type 2 innate lymphoid cells (ILC2) and M2 macrophages. A pathogenic role of the innate lymphoid cells in GPA has been recently demonstrated; however, the relevance of IL-25 in this condition remains unexplored. <h3>Objectives:</h3> Aim of the study was to evaluate the expression of IL-25/IL-25R axis and its functional relevance in patients with granulomatosis with polyangiitis (GPA). <h3>Methods:</h3> Thirty patients with a diagnosis of GPA fulfilling the Chapel Hill Consensus Conference and ACR classification criteria, and 20 age-matched healthy controls (HC) were included in this study: age range 30-66 years, 40% female in GPA group and 32-63 years, 20% female in HC. IL-25 and IL-33 serum levels were measured by ELISA at the diagnosis and after Rituximab (RTX) therapy (n=15). Immunohistochemical staining for IL-25, IL-33, IL-17B was performed on sections of renal biopsies obtained from GPA patients (n=10). Kidney ILC2 infiltration was assessed by confocal microscopy. Frequencies ILC1, ILC2 and ILC3 were evaluated by flow cytometry analysis by CD45, Lyn, CRTH2, GATA3, Tbet, CD56, NKp44, IL-22, IL-23R, RORc. Expression levels of IL-5 and IL-13 in kidney were quantified by quantitative real-time PCR (qRT-PCR). <h3>Results:</h3> Increased pre-RTX serum levels of IL-25 and IL-33 at baseline were observed in GPA compared to HC (p&lt;0.0001). Both serum IL-25 and IL-33 correlated with the Birmingham Vasculitis Activity Score (BVAS) (r<sup>2</sup>0.51 p&lt;0.0001 and r<sup>2</sup>0.14 p&lt;0.05 respectively). IL-25, IL-17RB and IL-33 expressing cells were increased in GPA renal biopsies vs HC (p&lt;0.0001). Frequencies of circulating ILC1 and ILC3 were not significantly increased in GPA. Conversely, the frequency of ILC2 was expanded in GPA vs HC (p&lt;0.0001) and correlated with BVAS (r<sup>2</sup>0.60 p&lt;0.0001). The number of ILC2 and the levels of expression of IL-5 and IL-13 in GPA kidney were increased (p&lt;0.0001). RTX therapy led to a reduction in IL-25 and IL-33 serum levels and in the frequency of circulating ILC2. <h3>Conclusion:</h3> Our data confirm the increases in IL-33 levels previously reported by other authors. The increased circulating and tissue levels of IL-25 and IL-25 receptor-expressing cells, including ILC2, suggests a role for the IL-25/IL-17RB axis in GPA pathogenesis. Treatment with anti-CD20 Rituximab may lead to modulation of IL-25/IL-17RB axis and reduction in ILC2.&nbsp; <h3>Disclosure of Interests:</h3> Daniele Mauro: None declared, Giuliana Guggino Grant/research support from: Laborest, Pfizer, Consultant for: Novartis, Abbvie, Speakers bureau: Sandoz, Angelo Ferrante: None declared, cristiano alessandri: None declared, SERENA FASANO: None declared, Daniela Iacono Speakers bureau: PFIZER, Marianna Lo Pizzo: None declared, Riccardo Alessandro: None declared, Aroldo Rizzo: None declared, Francesco Ciccia Grant/research support from: CELGENE, PFIZER, Consultant for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, Paid instructor for: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, Speakers bureau: UCB, NOVARTIS, CELGENE, PFIZER, LILLY, JANSSEN, ROCHE, AMGEN&nbsp;