Lucchesi, Davide, Coleby, Rachel, Pontarini, Elena, Prediletto, Edoardo, Rivellese, Felice, Hill, David G., Derrac Soria, Alicia, Jones, Simon, Humphreys, Ian, Sutcliffe, Nurhan, Tappuni, Anwar R., Pitzalis, Costantino, Jones, Gareth W. and Bombardieri, Michele
2020.
Impaired IL‐27 mediated control of CD4+ T cell function impacts on ectopic lymphoid structure formation in patients with Sjögren's Syndrome.
Arthritis and Rheumatology
72
(9)
, pp. 1559-1570.
10.1002/art.41289
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Abstract
Objectives: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity and cancer. In patients with Sjogren’s syndrome (SS), ELS support autoreactive B-cell activation and support lymphomagenesis. IL-27 is a key regulator of adaptive immunity and limits Th17 cell-driven pathology. Here, we elucidated the role of IL-27 in ELS formation and function in autoimmunity using a murine model of sialadenitis and in patients with SS. Methods: ELS formation was induced in wild-type and IL27ra-/- mice via salivary gland (SG) cannulation of a replication-deficient adenovirus in the presence/absence of IL-17A neutralization. In SG biopsies IL-27-producing cells were identified by multicolour immune-fluorescence microscopy. Lesional and circulating IL-27 levels were determined by gene expression and ELISA. The in-vitro effect of IL-27 on T-cells was determined by FACS and cytokine release. Results: In experimental sialadenitis, Il27ra-/- mice had larger and hyperactive ELS (focus score P<0.001), increased autoimmunity and an expanded Th17 response (P<0.001) compared to wild-type. IL-17 blockade in Il27ra-/- mice suppressed the aberrant ELS response (B and T cell reduction against control P<0.01). SS patients displayed increased circulating IL-27 (P<0.01) and in SG biopsies IL-27 was expressed by DC-LAMP+ dendritic cells in association with CD3+ T-cells. Remarkably, in SS T cells but not in T-cells from patients with rheumatoid arthritis or healthy controls, IL-27-mediated suppression of IL-17 secretion was severely impaired and associated with an aberrant IFN-γ release upon IL-27 stimulation. Conclusions: Our data indicate that the physiological ability of IL-27 to limit the magnitude and function of ELS through control of Th17 cell expansion is severely impaired in SS patients highlighting a defective immunoregulatory checkpoint in this condition.
Item Type: | Article |
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Date Type: | Publication |
Status: | Published |
Schools: | Medicine Systems Immunity Research Institute (SIURI) |
Subjects: | R Medicine > R Medicine (General) R Medicine > RB Pathology |
Publisher: | Wiley |
ISSN: | 2326-5191 |
Funders: | Versus Arthritis, MRC |
Date of First Compliant Deposit: | 22 April 2020 |
Date of Acceptance: | 5 April 2020 |
Last Modified: | 08 Sep 2020 12:10 |
URI: | http://orca.cf.ac.uk/id/eprint/131144 |
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