Impaired IL‐27 mediated control of CD4+ T cell function impacts on ectopic lymphoid structure formation in patients with Sjögren's Syndrome

Lucchesi, Davide, Coleby, Rachel, Pontarini, Elena, Prediletto, Edoardo, Rivellese, Felice, Hill, David G., Derrac Soria, Alicia, Jones, Simon ORCID: https://orcid.org/0000-0001-7297-9711, Humphreys, Ian ORCID: https://orcid.org/0000-0002-9512-5337, Sutcliffe, Nurhan, Tappuni, Anwar R., Pitzalis, Costantino, Jones, Gareth W. ORCID: https://orcid.org/0000-0001-7297-9711 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
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:	05 May 2023 23:16
URI:	https://orca.cardiff.ac.uk/id/eprint/131144

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