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NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment

Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like...

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Autores principales: Pontarini, Elena, Sciacca, Elisabetta, Grigoriadou, Sofia, Rivellese, Felice, Lucchesi, Davide, Fossati-Jimack, Liliane, Coleby, Rachel, Chowdhury, Farzana, Calcaterra, Francesca, Tappuni, Anwar, Lewis, Myles J., Fabris, Martina, Quartuccio, Luca, Bella, Silvia Della, Bowman, Simon, Pitzalis, Costantino, Mavilio, Domenico, De Vita, Salvatore, Bombardieri, Michele
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477027/
https://www.ncbi.nlm.nih.gov/pubmed/34594326
http://dx.doi.org/10.3389/fimmu.2021.706737
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author Pontarini, Elena
Sciacca, Elisabetta
Grigoriadou, Sofia
Rivellese, Felice
Lucchesi, Davide
Fossati-Jimack, Liliane
Coleby, Rachel
Chowdhury, Farzana
Calcaterra, Francesca
Tappuni, Anwar
Lewis, Myles J.
Fabris, Martina
Quartuccio, Luca
Bella, Silvia Della
Bowman, Simon
Pitzalis, Costantino
Mavilio, Domenico
De Vita, Salvatore
Bombardieri, Michele
author_facet Pontarini, Elena
Sciacca, Elisabetta
Grigoriadou, Sofia
Rivellese, Felice
Lucchesi, Davide
Fossati-Jimack, Liliane
Coleby, Rachel
Chowdhury, Farzana
Calcaterra, Francesca
Tappuni, Anwar
Lewis, Myles J.
Fabris, Martina
Quartuccio, Luca
Bella, Silvia Della
Bowman, Simon
Pitzalis, Costantino
Mavilio, Domenico
De Vita, Salvatore
Bombardieri, Michele
author_sort Pontarini, Elena
collection PubMed
description Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands.
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spelling pubmed-84770272021-09-29 NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment Pontarini, Elena Sciacca, Elisabetta Grigoriadou, Sofia Rivellese, Felice Lucchesi, Davide Fossati-Jimack, Liliane Coleby, Rachel Chowdhury, Farzana Calcaterra, Francesca Tappuni, Anwar Lewis, Myles J. Fabris, Martina Quartuccio, Luca Bella, Silvia Della Bowman, Simon Pitzalis, Costantino Mavilio, Domenico De Vita, Salvatore Bombardieri, Michele Front Immunol Immunology Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease resulting from the inflammatory infiltration of exocrine glands, mainly salivary and lacrimal glands, leading to secretory dysfunction and serious complications including debilitating fatigue, systemic autoimmunity, and lymphoma. Like other autoimmune disorders, a strong interferon (IFN) signature is present among subsets of pSS patients, suggesting the involvement of innate immunity in pSS pathogenesis. NCR3/NKp30 is a natural killer (NK) cell-specific activating receptor regulating the cross talk between NK and dendritic cells including type II IFN secretion upon NK-cell activation. A genetic association between single-nucleotide polymorphisms (SNPs) in the NCR3/NKp30 promoter gene and a higher susceptibility for pSS has been previously described, with pSS patients most frequently carrying the major allele variant associated with a higher NKp30 transcript and IFN-γ release as a consequence of the receptor engagement. In the present study, we combined RNA-sequencing and histology from pSS salivary gland biopsies to better characterize NKp30 (NCR3) and its ligand B7/H6 (NCR3LG1) in pSS salivary gland tissues. Levels of NCR3/NKp30 were significantly increased both in salivary glands and in circulating NK cells of pSS patients compared with sicca controls, especially in salivary glands with organized ectopic lymphoid structures. In line with this observation, a strong correlation between NCR3/NKp30 levels and salivary gland infiltrating immune cells (CD3, CD20) was found. Furthermore, NCR3/NKp30 levels also correlated with higher IFN-γ, Perforin, and Granzyme-B expression in pSS SGs with organized ectopic lymphoid structures, suggesting an activation state of NK cells infiltrating SG tissue. Of note, NKp30+ NK cells accumulated at the border of the inflammatory foci, while the NKp30 ligand, B7/H6, is shown to be expressed mainly by ductal epithelial cells in pSS salivary glands. Finally, immunomodulatory treatment, such as the B-cell depleting agent rituximab, known to reduce the infiltration of immune cells in pSS SGs, prevented the upregulation of NCR3/NKp30 within the glands. Frontiers Media S.A. 2021-09-14 /pmc/articles/PMC8477027/ /pubmed/34594326 http://dx.doi.org/10.3389/fimmu.2021.706737 Text en Copyright © 2021 Pontarini, Sciacca, Grigoriadou, Rivellese, Lucchesi, Fossati-Jimack, Coleby, Chowdhury, Calcaterra, Tappuni, Lewis, Fabris, Quartuccio, Bella, Bowman, Pitzalis, Mavilio, De Vita and Bombardieri https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Pontarini, Elena
Sciacca, Elisabetta
Grigoriadou, Sofia
Rivellese, Felice
Lucchesi, Davide
Fossati-Jimack, Liliane
Coleby, Rachel
Chowdhury, Farzana
Calcaterra, Francesca
Tappuni, Anwar
Lewis, Myles J.
Fabris, Martina
Quartuccio, Luca
Bella, Silvia Della
Bowman, Simon
Pitzalis, Costantino
Mavilio, Domenico
De Vita, Salvatore
Bombardieri, Michele
NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title_full NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title_fullStr NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title_full_unstemmed NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title_short NKp30 Receptor Upregulation in Salivary Glands of Sjögren’s Syndrome Characterizes Ectopic Lymphoid Structures and Is Restricted by Rituximab Treatment
title_sort nkp30 receptor upregulation in salivary glands of sjögren’s syndrome characterizes ectopic lymphoid structures and is restricted by rituximab treatment
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477027/
https://www.ncbi.nlm.nih.gov/pubmed/34594326
http://dx.doi.org/10.3389/fimmu.2021.706737
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