PT  - JOURNAL ARTICLE
AU  - Elena Pontarini
AU  - William James Murray-Brown
AU  - Cristina Croia
AU  - Davide Lucchesi
AU  - James Conway
AU  - Felice Rivellese
AU  - Liliane Fossati-Jimack
AU  - Elisa Astorri
AU  - Edoardo Prediletto
AU  - Elisa Corsiero
AU  - Francesca Romana Delvecchio
AU  - Rachel Coleby
AU  - Eva Gelbhardt
AU  - Aurora Bono
AU  - Chiara Baldini
AU  - Ilaria Puxeddu
AU  - Piero Ruscitti
AU  - Roberto Giacomelli
AU  - Francesca Barone
AU  - Benjamin Fisher
AU  - Simon J Bowman
AU  - Serena Colafrancesco
AU  - Roberta Priori
AU  - Nurhan Sutcliffe
AU  - Stephen Challacombe
AU  - Gianluca Carlesso
AU  - Anwar Tappuni
AU  - Costantino Pitzalis
AU  - Michele Bombardieri
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.