Constitutive activation of natural killer cells in Primary Biliary Cholangitis
Constitutive activation of natural killer cells in Primary Biliary Cholangitis
Natural killer (NK) cells are innate immune cells that interface with the adaptive immune system to generate a pro-inflammatory immune environment. Primary Biliary Cholangitis (PBC) is a hepatic autoimmune disorder with extrahepatic associations including systemic sclerosis, Sjogren's syndrome and thyroiditis. Immunogenetic studies have identified polymorphisms of the IL-12/STAT4 pathway as being associated with PBC. As this pathway is important for NK cell function we investigated NK cells in PBC. Circulating NK cells from individuals with PBC were constitutively activated, with higher levels of CD49a and the liver-homing marker, CXCR6, compared to participants with non-autoimmune chronic liver disease and healthy controls. Stimulation with minimal amounts of IL-12 (0.005 ng/ml) led to significant upregulation of CXCR6 (p < 0.005), and enhanced IFNγ production (p < 0.02) on NK cells from PBC patients compared to individuals with non-autoimmune chronic liver disease, indicating dysregulation of the IL-12/STAT4 axis. In RNAseq studies, resting NK cells from PBC patients had a constitutively activated transcriptional profile and upregulation of genes associated with IL-12/STAT4 signaling and metabolic reprogramming. Consistent with these findings, resting NK cells from PBC patients expressed higher levels of pSTAT4 compared to control groups (p < 0.001 vs. healthy controls and p < 0.05 vs. liver disease controls). In conclusion NK cells in PBC are sensitive to minute quantities of IL-12 and have a "primed" phenotype. We therefore propose that peripheral priming of NK cells to express tissue-homing markers may contribute to the pathophysiology of PBC.
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Hydes, Theresa J.
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Blunt, Matthew D.
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Naftel, Jennifer
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Vallejo, Andres F.
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Seumois, Grégory
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Wang, Alice
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Vijayanand, Pandurangan
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Polak, Marta E.
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Khakoo, Salim I.
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15 November 2019
Hydes, Theresa J.
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Blunt, Matthew D.
b1109de3-6045-4bc3-bd77-6cf26504697d
Naftel, Jennifer
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Vallejo, Andres F.
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Seumois, Grégory
0be7d3d6-5526-458c-aa5c-cce52410a2ed
Wang, Alice
25480e34-b2e8-4646-9dc3-14086684c23d
Vijayanand, Pandurangan
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Polak, Marta E.
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Khakoo, Salim I.
6c16d2f5-ae80-4d9b-9100-6bfb34ad0273
Hydes, Theresa J., Blunt, Matthew D., Naftel, Jennifer, Vallejo, Andres F., Seumois, Grégory, Wang, Alice, Vijayanand, Pandurangan, Polak, Marta E. and Khakoo, Salim I.
(2019)
Constitutive activation of natural killer cells in Primary Biliary Cholangitis.
Frontiers in Immunology, 10, , [2633].
(doi:10.3389/fimmu.2019.02633).
Abstract
Natural killer (NK) cells are innate immune cells that interface with the adaptive immune system to generate a pro-inflammatory immune environment. Primary Biliary Cholangitis (PBC) is a hepatic autoimmune disorder with extrahepatic associations including systemic sclerosis, Sjogren's syndrome and thyroiditis. Immunogenetic studies have identified polymorphisms of the IL-12/STAT4 pathway as being associated with PBC. As this pathway is important for NK cell function we investigated NK cells in PBC. Circulating NK cells from individuals with PBC were constitutively activated, with higher levels of CD49a and the liver-homing marker, CXCR6, compared to participants with non-autoimmune chronic liver disease and healthy controls. Stimulation with minimal amounts of IL-12 (0.005 ng/ml) led to significant upregulation of CXCR6 (p < 0.005), and enhanced IFNγ production (p < 0.02) on NK cells from PBC patients compared to individuals with non-autoimmune chronic liver disease, indicating dysregulation of the IL-12/STAT4 axis. In RNAseq studies, resting NK cells from PBC patients had a constitutively activated transcriptional profile and upregulation of genes associated with IL-12/STAT4 signaling and metabolic reprogramming. Consistent with these findings, resting NK cells from PBC patients expressed higher levels of pSTAT4 compared to control groups (p < 0.001 vs. healthy controls and p < 0.05 vs. liver disease controls). In conclusion NK cells in PBC are sensitive to minute quantities of IL-12 and have a "primed" phenotype. We therefore propose that peripheral priming of NK cells to express tissue-homing markers may contribute to the pathophysiology of PBC.
Text
fimmu-10-02633
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Accepted/In Press date: 24 October 2019
Published date: 15 November 2019
Identifiers
Local EPrints ID: 436394
URI: http://eprints.soton.ac.uk/id/eprint/436394
ISSN: 1664-3224
PURE UUID: 968f05a3-e1e8-497f-80a3-cbec18158f6a
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Date deposited: 10 Dec 2019 17:30
Last modified: 17 Mar 2024 03:46
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Contributors
Author:
Theresa J. Hydes
Author:
Jennifer Naftel
Author:
Andres F. Vallejo
Author:
Grégory Seumois
Author:
Alice Wang
Author:
Pandurangan Vijayanand
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