Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma. Issue 12 (22nd September 2020)

• Record Type: Journal Article
• Authors: Pontarini, Elena; Murray-Brown, William James; Croia, Cristina; Lucchesi, Davide; Conway, James; Rivellese, Felice; Fossati-Jimack, Liliane; Astorri, Elisa; Prediletto, Edoardo; Corsiero, Elisa; Romana Delvecchio, Francesca; Coleby, Rachel; Gelbhardt, Eva; Bono, Aurora; Baldini, Chiara; Puxeddu, Ilaria; Ruscitti, Piero; Giacomelli, Roberto; Barone, Francesca; Fisher, Benjamin; Bowman, Simon J; Colafrancesco, Serena; Priori, Roberta; Sutcliffe, Nurhan; Challacombe, Stephen; Carlesso, Gianluca; Tappuni, Anwar; Pitzalis, Costantino; Bombardieri, Michele
• Is Part Of: Annals of the rheumatic diseases. Volume 79:Issue 12(2020)
• Page Start: 1588
• Page End: 1599
• Publication Date: 2020-09-22
• Subjects: sjogren's syndrome -- t-lymphocyte subsets -- cytokines -- autoimmune diseases; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/annrheumdis-2020-217646
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Objectives: To explore the relevance of T-follicular-helper (Tfh) and pathogenic peripheral-helper T-cells (Tph) in promoting ectopic lymphoid structures (ELS) and B-cell mucosa-associated lymphoid tissue (MALT) lymphomas (MALT-L) in Sjögren's syndrome (SS) patients. Methods: Salivary gland (SG) biopsies with matched peripheral blood were collected from four centres across the European Union. Transcriptomic (microarray and quantitative PCR) analysis, FACS T-cell immunophenotyping with intracellular cytokine detection, multicolor immune-fluorescence microscopy and in situ hybridisation were performed to characterise lesional and circulating Tfh and Tph-cells. SG-organ cultures were used to investigate functionally the blockade of T-cell costimulatory pathways on key proinflammatory cytokine production. Results: Transcriptomic analysis in SG identified Tfh-signature, interleukin-21 (IL-21) and the inducible T-cell co-stimulator (ICOS) costimulatory pathway as the most upregulated genes in ELS+SS patients, with parotid MALT-L displaying a 400-folds increase in IL-21 mRNA. Peripheral CD4 + CXC-motif chemokine receptor 5 (CXCR5) + programmed cell death protein 1 (PD1) + ICOS + Tfh-like cells were significantly expanded in ELS+SS patients, were the main producers of IL-21, and closely correlated with circulating IgG and reduced complement C4. In the SG, lesional CD4 + CD45RO + ICOS + PD1 + cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5 + CD4 + PD1 + ICOS + Foxp3 - Tfh-cells and a uniquely expanded population of CXCR5 - CD4 + PD1 hi ICOS + Foxp3 - Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in ex vivo SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α). Conclusions: Overall, these findings highlight Tfh and Tph-cells, IL-21 and the ICOS costimulatory pathway as key pathogenic players in SS immunopathology and exploitable therapeutic targets in SS.