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

Autor:	Pontarini E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Murray-Brown WJ; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Croia C; Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Lucchesi D; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Conway J; Oncology R&D, Astrazeneca, Gaithersburg, Maryland, USA., Rivellese F; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Fossati-Jimack L; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Astorri E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Prediletto E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Corsiero E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Romana Delvecchio F; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Coleby R; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Gelbhardt E; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Bono A; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Baldini C; University of Pisa, Rheumatology Unit, Pisa, PI, Italy., Puxeddu I; Immuno-Allergology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Ruscitti P; Department of Clinical Sciences and Applied Biotechnology, University of L'Aquila, L'Aquila, Abruzzo, Italy., Giacomelli R; Department of Clinical Sciences and Applied Biotechnology, University of L'Aquila, L'Aquila, Abruzzo, Italy., Barone F; RRG, Institute of Inflamation and Ageing, University of Birmingham, Birmingham, UK, UK.; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK., Fisher B; RRG, Institute of Inflamation and Ageing, University of Birmingham, Birmingham, UK, UK.; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK., Bowman SJ; NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK., Colafrancesco S; Dipartimento di Medicina Interna e Specilità Mediche, UOC Reumatologia, Universita degli Studi di Roma La Sapienza Facolta di Medicina e Odontoiatria, Roma, Lazio, Italy., Priori R; Dipartimento di Medicina Interna e Specilità Mediche, UOC Reumatologia, Universita degli Studi di Roma La Sapienza Facolta di Medicina e Odontoiatria, Roma, Lazio, Italy., Sutcliffe N; Rheumatology, Barts Health NHS Trust, London, London, UK., Challacombe S; Oral Medicine, KCL Dental Institute, London, UK., Carlesso G; Early ICA Discovery, Early Oncology R&D, AstraZeneca, Gaithersburg, Maryland, USA., Tappuni A; Institute of Dentistry, Barts and The London School of Medicine and Dentistry, London, London, UK., Pitzalis C; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK., Bombardieri M; Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, London, England, UK m.bombardieri@qmul.ac.uk.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2020 Dec; Vol. 79 (12), pp. 1588-1599. Date of Electronic Publication: 2020 Sep 22.
DOI:	10.1136/annrheumdis-2020-217646
Abstrakt:	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. Competing Interests: Competing interests: BF: Consultancy for Novartis, Roche, and BMS. SJB: Consultancy for Astrazeneca, Biogen, BMS, Celgene, Medimmune, MTPharma, Novartis, Ono, UCB, xtlbio. MB: consultancy and/or unrestricted grant support from Medimmune, GSK, Janssen, UCB. GC and JC are AstraZeneca employees and own company stocks. (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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