THU0001 CIRCULATING INNATE LYMPHOID CELLS IN IGG4-RELATED DISEASE
Authors: Mikael Ebbo, Benjamin De Sainte Marie, Christelle Piperoglou, Nathalie Banzet, Aurélie Grados, Catherine Farnarier, Matthieu Groh, Benjamin Terrier, Jean-Robert Harlé, Nathalie Costedoat-Chalumeau, Frédéric Vély, Nicolas Schleinitz
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> IgG4-related disease (IgG4-RD) is characterized by lymphoplasmacytic infiltrates, IgG4<sup>+</sup> 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. <h3>Objectives:</h3> To analyze circulating blood ILCs in IgG4-RD. <h3>Methods:</h3> 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<sup>+</sup>Lineage(Lin)<sup>-</sup>CD127<sup>+</sup> 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. <h3>Results:</h3> 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 &gt;1.35 g/l for 85% of patients and median eosinophil count 410/mm<sup>3</sup>. 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 x10<sup>3</sup>/ml <i>vs</i> 1.5 ± 1.3 x10<sup>3</sup>/ml in HC, <i>p=</i><i>0.29</i>; 0.07 ± 0.06% of CD45<sup>+</sup> lymphocytes <i>vs</i> 0.09 ± 0.05% in HC, <i>p=</i><i>0.35</i>). 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], <i>p=</i><i>0.04</i>) and ILC3s (21.2% [8.8-28.1], <i>p=</i><i>0.002</i>) and an increase in ILC1s (54.1% [33.8-68.7], <i>p=</i><i>0.0009</i>) proportions. ILC2s (274/ml [152-594] <i>vs</i> 554/ml [62-1000], <i>p=</i><i>0.045</i>) and ILC3s (214/ml [120-620] <i>vs</i> 509/ml [336-908], <i>p=</i><i>0.04</i>) 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 <i>in vitro</i> 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 (<i>p=</i><i>0.29</i>, 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. <h3>Conclusion:</h3> 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. <h3>Disclosure of Interests:</h3> None declared