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-γdouble-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.
Original language | English |
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Pages (from-to) | 1588-1599 |
Number of pages | 12 |
Journal | Annals of the Rheumatic Diseases |
Volume | 79 |
Issue number | 12 |
DOIs | |
Publication status | Published - 1 Dec 2020 |
Bibliographical note
Funding Information:Funding This work was supported by project grants from the Medical Research Council (MR/N003063/1 to MB), versus Arthritis UK (grant 20 089 to MB and grant 21 753 to EP) and the William Harvey Research Foundation (to MB). FR is funded by an NIHR Transitional Research Fellowship (TRF-2018–11-ST2-002). BF and SJB have received support from the NIHR Birmingham Biomedical Research Centre and the National Institute for Health Research (NIHR)/Wellcome Trust Birmingham Clinical Research Facility.
Funding Information:
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.
Publisher Copyright:
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Keywords
- autoimmune diseases
- cytokines
- sjogren's syndrome
- t-lymphocyte subsets
ASJC Scopus subject areas
- Rheumatology
- Immunology and Allergy
- Immunology
- General Biochemistry,Genetics and Molecular Biology