THU0001\u2005CIRCULATING INNATE LYMPHOID CELLS IN IGG4-RELATED DISEASE

Abstract

Background: IgG4-related disease (IgG4-RD) is characterized by lymphoplasmacytic infiltrates, IgG4+ plasma cells, fibrosis and frequent ectopic lymphoid structures (ELS). Excessive Th2 cytokines production and role of T follicular helper (Tfh) cells have been reported. Innate cells (ILCs), a heterogeneous population of non-B non-T lymphocytes lacking antigen-specific receptors, are able to produce type 2 cytokines (ILC2s) or to participate to ELS formation (ILC3s) and could contribute to IgG4-RD lesions. Objectives: To analyze circulating blood ILCs in IgG4-RD. Methods: IgG4-RD patients were identified according to the Comprehensive Diagnostic Criteria. Patients treated with steroids or DMARDs within 3 months or rituximab within 6 months prior inclusion were excluded. Peripheral blood mononuclear cells were isolated and analyzed by flow cytometry. ILCs were defined as lymphoid CD45+Lineage(Lin)-CD127+ cells. Among ILCs, 3 subsets were defined according to CRTH2 and CD117 expression. In some patients, transcription factor expression (T-bet, GATA3, RORγt) as well as cytokine production (IFNγ, IL-4/IL-13, IL-17/IL-22) after different stimulations were analyzed in ILC subsets. Results were compared to healthy controls (HC), correlated to clinical and biological characteristics, and compared before and after treatment. Results: Twenty patients with active untreated IgG4-RD and 30 HC were included. In IgG4-RD group, mean age was 64 years and sex ratio 4:1. Serum IgG4 levels were >1.35 g/l for 85% of patients and median eosinophil count 410/mm3. Most patients (65%) were analyzed at diagnosis. Main organs involved were lymph nodes (n=15), pancreas (n=9), salivary glands (n=8), biliary tree and kidney (n=5), lung and retroperitoneum (n=4), with ≥3 organs involved in 65%. Number of blood ILCs was not modified in IgG4-RD patients (1.2 ± 2.6 x103/ml vs 1.5 ± 1.3 x103/ml in HC, p= 0.29; 0.07 ± 0.06% of CD45+ lymphocytes vs 0.09 ± 0.05% in HC, p= 0.35). ILC1s, ILC2s, and ILC3s represented respectively 30%, 29% and 32% of total ILCs in HC. IgG4-RD patients presented a decrease in ILC2s (23.8% [12.4-29.3], p= 0.04) and ILC3s (21.2% [8.8-28.1], p= 0.002) and an increase in ILC1s (54.1% [33.8-68.7], p= 0.0009) proportions. ILC2s (274/ml [152-594] vs 554/ml [62-1000], p= 0.045) and ILC3s (214/ml [120-620] vs 509/ml [336-908], p= 0.04) numbers were decreased in IgG4-RD patients. No correlation was found between number or proportion of total ILCs or any ILCs subsets and clinical or biological characteristics such as age, number of organ involved, IgG4-RD Responder Index or serum IgG4. No correlation was found between Tfh and ILC3s, or between eosinophils and ILC2s numbers. As human ILC3s and ILC2s can convert in vitro into IFNγ producing cells, we explore if ILC plasticity could contribute to ILCs subset distribution observed. GATA3 or RORγT expression by ILC1s was not modified (p= 0.29, respectively) in IgG4-RD patients compared to HC. As previously reported, no cytokine production (IFNγ, IL-4/IL-13, IL-17/IL-22) was observed after different stimulations of blood ILCs. Analyzes before and after treatment found no difference in proportion or absolute number of total or subsets of circulating ILCs. Conclusion: Circulating ILC2s and ILC3s are decreased in IgG4-RD. Recruitment of ILC2s or ILC3s in tissues, where they could participate to Th2 cytokine production, ELS formation and fibrosis, needs further investigations. Disclosure of Interests: None declared