PT  - JOURNAL ARTICLE
AU  - Pontarini, Elena
AU  - Murray-Brown, William James
AU  - Croia, Cristina
AU  - Lucchesi, Davide
AU  - Conway, James
AU  - Rivellese, Felice
AU  - Fossati-Jimack, Liliane
AU  - Astorri, Elisa
AU  - Prediletto, Edoardo
AU  - Corsiero, Elisa
AU  - Romana Delvecchio, Francesca
AU  - Coleby, Rachel
AU  - Gelbhardt, Eva
AU  - Bono, Aurora
AU  - Baldini, Chiara
AU  - Puxeddu, Ilaria
AU  - Ruscitti, Piero
AU  - Giacomelli, Roberto
AU  - Barone, Francesca
AU  - Fisher, Benjamin
AU  - Bowman, Simon J
AU  - Colafrancesco, Serena
AU  - Priori, Roberta
AU  - Sutcliffe, Nurhan
AU  - Challacombe, Stephen
AU  - Carlesso, Gianluca
AU  - Tappuni, Anwar
AU  - Pitzalis, Costantino
AU  - Bombardieri, Michele
TI  - Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren’s syndrome with ectopic germinal centres and MALT lymphoma
AID  - 10.1136/annrheumdis-2020-217646
DP  - 2020 Dec 01
TA  - Annals of the Rheumatic Diseases
PG  - 1588--1599
VI  - 79
IP  - 12
4099  - http://ard.bmj.com/content/79/12/1588.short
4100  - http://ard.bmj.com/content/79/12/1588.full
SO  - Ann Rheum Dis2020 Dec 01; 79
AB  - 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+PD1hiICOS+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.