POS0328 MUCOSAL-ASSOCIATED INVARIANT T CELLS ACTIVATION AND IL-17 EXPRESSION CHARACTERIZE THE SYNOVIAL FLUID AND PERIPHERAL BLOOD OF PATIENTS WITH PSORIATIC ARTHRITIS AND ARE MODULATED BY TOFACITINIB
Authors: M. De Santis, A. Tonutti, F. Motta, N. Isailovic, A. Ceribelli, G. M. Guidelli, D. Renna, N. Luciano, C. Selmi
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> The pathogenesis of psoriatic arthritis (PsA) is characterized by a predominant IL-17 signature. Innate-like lymphocytes, such as mucosal-associated invariant T cells (MAIT), are recognized sources of IL-17 in PsA. <h3>Objectives:</h3> 1.To investigate the relevance of MAIT cells, their subsets, and IL-17 production in the synovial fluid (SF) and peripheral blood (PB) of patients with PsA compared to healthy controls (HC), both at baseline and after lymphocyte stimulation. 2.To evaluate the <i>in vitro</i> effect of tofacitinib and dexamethasone in modulating MAIT cells. <h3>Methods:</h3> A case-control study was conducted and PB samples were collected from 10 treatment-naïve patients with PsA, with paired SF in 7 cases. PsA patients had the following characteristics: 5 females (50%), median age 55 years (interquartile range -IQR- 48-58), disease duration 14 months (IQR 6-24), DAPSA 25.5 (IQR 16.3-29.5), serum C-reactive protein 0.21 mg/dL (IQR 0.02-1.93). Two patients had dactylitis, two had enthesitis, none had axial involvement, eight had skin psoriasis, and four had nail psoriasis. PB samples from 6 HC (2 females, 33%; median age 49, IQR 43-54) were used as controls. Mononuclear cells from SF and PB were isolated and analyzed for cell phenotype and IL-17 expression under various conditions, including basal <i>ex vivo</i> conditions and after culture with T cell stimulators [phorbol 12-myristate 13-acetate (PMA) 50 ng/mL and ionomycin (iono) 1 μg/mL], PMA/iono with tofacitinib 300 nM, or PMA/iono with dexamethasone 1000 μM. Levels of IL-17 in the supernatant of SF and PB cultures of PsA patients and HC were also determined with ELISA. <h3>Results:</h3> At baseline, the SF of PsA patients was enriched in MAIT cells; moreover, PB T lymphocytes and MAIT cells were more activated in PsA compared to HC, as mirrored by a higher CD69 expression. However, MAIT cells were significantly more activated compared to T cells in both PB and SF (Figure 1A) and in the majority of cases showed a CD8 effector memory phenotype; moreover, activated SF MAIT cells showed the highest percentage of IL17+ cells, compared to PB (Figure 1B). The stimulation with PMA/iono significantly increased CD69 and IL-17 expression, especially in SF-derived PsA cells due to their higher pro-inflammatory prone state. Tofacitinib reduced the expression of CD69 only in PB-derived T lymphocytes and MAIT cells, with a similar magnitude compared to dexamethasone (Figure 2A and B) and significantly reduced PB-derived IL-17+ T lymphocytes and SF-derived IL-17+ MAIT CD8 cells, while dexamethasone had a stronger effect on PB-derived IL-17+ MAIT CD8 (Figure 2, panels C-D). Considering IL-17 levels in culture supernatants, baseline concentrations were higher in PsA SF compared to PB, while PsA PB levels were comparable to controls. Tofacitinib did not significantly reduce the overall IL-17 production compared to dexamethasone. <h3>Conclusion:</h3> MAIT cells are enriched in the SF of patients with PsA and display a more activated phenotype with enhanced expression of IL-17. Tofacitinib reduces MAIT cell activation, as well as IL-17 production, in both PsA SF and PB, akin to glucocorticoids but with a more potent effect on MAIT cells. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> Maria De Santis: None declared, Antonio Tonutti: None declared, Francesca Motta: None declared, Natasa Isailovic: None declared, Angela Ceribelli: None declared, Giacomo Maria Guidelli AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, Daniela Renna AbbVie, Eli-Lilly, Janssen, Novartis, AbbVie, Eli-Lilly, Janssen, Novartis, Nicoletta Luciano AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, Carlo Selmi AbbVie, Amgen, Alfa-Sigma, Biogen, Eli-Lilly, EUSA Pharma - Recordati, Galapagos, Janssen, Novartis, Octapharma, Pfizer, Recordati Rare Disease, SOBI, AbbVie, Amgen, Alfa-Sigma, Biogen, Eli-Lilly, EUSA Pharma - Recordati, Galapagos, Janssen, Novartis, Octapharma, Pfizer, Recordati Rare Disease, SOBI, AbbVie, Amgen, Janssen, Novartis, Pfizer.