Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma.

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 and Bombardieri, Michele (2020) Unique expansion of IL-21+ Tfh and Tph cells under control of ICOS identifies Sjögren's syndrome with ectopic germinal centres and MALT lymphoma. Annals of the rheumatic diseases. ISSN 1468-2060.

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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.


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 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.


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 CD4CXC-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 CD4CD45ROICOSPD1 cells selectively infiltrated ELS+ tissues and were aberrantly expanded in parotid MALT-L. In ELS+SG and MALT-L parotids, conventional CXCR5CD4PD1ICOSFoxp3 Tfh-cells and a uniquely expanded population of CXCR5CD4PD1ICOSFoxp3 Tph-cells displayed frequent IL-21/interferon-γ double-production but poor IL-17 expression. Finally, ICOS blockade in SG-organ cultures significantly reduced the production of IL-21 and inflammatory cytokines IL-6, IL-8 and tumour necrosis factor-α (TNF-α).


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.

Item Type: Article
Subjects: WD Diseases and disorders of systemic, metabolic or environmental origin
Divisions: Ambulatory Care > Rheumatology
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Depositing User: Mrs Yolande Brookes
Date Deposited: 23 Oct 2020 14:52
Last Modified: 23 Oct 2020 14:52
URI: http://www.repository.uhblibrary.co.uk/id/eprint/3576

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