Journal Article

Aberrant signaling of immune cells in Sjögren’s syndrome patient subgroups upon interferon stimulation

Petrovic, Aleksandra, Jonsson, Roland, Davies, Richard, Brun, Johan G., Hammenfors, Daniel, Solberg, Silje M., Bergum, Brith, Aarebrot, Anders K., Sarkar, Irene, Joshi, Anagha M., Appel, Silke

2022

Overview

BackgroundPrimary Sjögren’s syndrome (pSS) is a systemic autoimmune disease, characterized by mononuclear cell infiltrates in the salivary and lacrimal glands, leading to glandular atrophy and dryness. Patient heterogeneity and lack of knowledge regarding its pathogenesis makes pSS a difficult disease to manage.MethodsAn exploratory analysis using mass cytometry was conducted of MAPK/ERK and JAK/STAT signaling pathways in peripheral blood mononuclear cells (PBMC) from 16 female medication free pSS patients (8 anti-Sjögren’s syndrome-related antigen A negative/SSA- and 8 SSA+) and 8 female age-matched healthy donors after stimulation with interferons (IFNs).ResultsWe found significant differences in the frequencies of memory B cells, CD8+ T central and effector memory cells and terminally differentiated CD4+ T cells among the healthy donors and patient subgroups. In addition, we observed an upregulation of HLA-DR and CD38 in many cell subsets in the patients. Upon IFNα2b stimulation, slightly increased signaling through pSTAT1 Y701 was observed in most cell types in pSS patients compared to controls, while phosphorylation of STAT3 Y705 and STAT5 Y694 were slightly reduced. IFNγ stimulation resulted in significantly increased pSTAT1 Y701 induction in conventional dendritic cells (cDCs) and classical and non-classical monocytes in the patients. Most of the observed differences were more prominent in the SSA+ subgroup, indicating greater disease severity in them.ConclusionsAugmented activation status of certain cell types along with potentiated pSTAT1 Y701 signaling and reduced pSTAT3 Y705 and pSTAT5 Y694 induction may predispose pSS patients, especially the SSA+ subgroup, to upregulated expression of IFN-induced genes and production of autoantibodies. These patients may benefit from therapies targeting these pathways.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Atrophy / Autoantibodies / Autoimmune diseases / CD38 antigen / CD4 antigen / CD8 antigen / Cell activation / Cell differentiation / Cells / Dendritic cells / Effector cells / Immunological memory / Immunology / Lacrimal gland and Nasolacrimal duct / Leukocytes (mononuclear) / Lymphocytes B / Lymphocytes T / MAP kinase / mass cytometry (CyTOF) / Memory cells / Monocytes / Pathogenesis / patient stratification / Patients / Peripheral blood mononuclear cells / phospho-signaling / Phosphorylation / Signal transduction / Sjogren's syndrome / Sjögren’s syndrome / Stat3 protein / Stat5 protein / type I and type II interferons / γ-Interferon