RGD Reference Report - Impaired Interleukin-27-Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome. - Rat Genome Database

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Impaired Interleukin-27-Mediated Control of CD4+ T Cell Function Impact on Ectopic Lymphoid Structure Formation in Patients With Sjögren's Syndrome.

Authors: Lucchesi, Davide  Coleby, Rachel  Pontarini, Elena  Prediletto, Edoardo  Rivellese, Felice  Hill, David G  Derrac Soria, Alicia  Jones, Simon A  Humphreys, Ian R  Sutcliffe, Nurhan  Tappuni, Anwar R  Pitzalis, Costantino  Jones, Gareth W  Bombardieri, Michele 
Citation: Lucchesi D, etal., Arthritis Rheumatol. 2020 Sep;72(9):1559-1570. doi: 10.1002/art.41289. Epub 2020 Jul 21.
RGD ID: 126790516
Pubmed: PMID:32307922   (View Abstract at PubMed)
DOI: DOI:10.1002/art.41289   (Journal Full-text)

OBJECTIVE: Ectopic lymphoid structures (ELS) develop at sites of infection, autoimmunity, and cancer. In patients with Sjögren's syndrome (SS), ELS support autoreactive B cell activation and lymphomagenesis. Interleukin-27 (IL-27) is a key regulator of adaptive immunity and limits Th17 cell-driven pathology. We undertook this study to elucidate 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 or absence of IL-17A neutralization. In SG biopsy samples, IL-27-producing cells were identified by multicolor immunofluorescence microscopy. Lesional and circulating IL-27 levels were determined by gene expression and enzyme-linked immunosorbent assay. The in vitro effect of IL-27 on T cells was assessed using fluorescence-activated cell sorting and cytokine release.
RESULTS: In experimental sialadenitis, Il27ra-/- mice had larger and more hyperactive ELS (focus score; P < 0.001), increased autoimmunity, and an expanded Th17 response (P < 0.001), compared to wild-type mice. 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 levels (P < 0.01), and in SG biopsy samples, 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 interferon-γ release upon IL-27 stimulation.
CONCLUSION: Our data indicate that the physiologic 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
sialadenitis exacerbatesISOIl27 (Mus musculus)126790516; 126790516mRNA:increased expression:saliva-secreting gland (mouse)RGD 
sialadenitis exacerbatesIEP 126790516mRNA:increased expression:saliva-secreting gland (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Il27  (interleukin 27)

Genes (Mus musculus)
Il27  (interleukin 27)

Genes (Homo sapiens)
IL27  (interleukin 27)

Additional Information