Role In Pathogenesis Of pSS Research Articles

B cell receptor repertoire analysis in primary Sjogren’s syndrome salivary glands identifies repertoire features associated with clinical activity

BackgroundPrimary Sjogren’s syndrome (pSS) is a complex autoimmune disease featuring damage to salivary and lacrimal glands, with the possibility of manifestations across multiple organs. Antibody-producing B cells have long been appreciated to play a significant role in pSS pathogenesis, with a number of autoreactive antibody species having been identified to be elevated in pSS patients. While several studies have attempted to characterize the BCR repertoires of peripheral blood B cells in pSS patients, much remains unknown about the repertoire characteristics of gland-infiltrating B cells.MethodsThrough paired scRNAseq and scBCRseq, we profiled the BCR repertoires of both infiltrating and circulating B cells in a small cohort of patients. We further utilize receptor reconstruction analyses to further investigate repertoire characteristics in a wider cohort of pSS patients previously profiled through RNAseq.ResultsVia integrated BCR and transcriptome analysis of B cell clones, we generate a trajectory progression pattern for infiltrated memory B cells in pSS. We observe significant differences in BCR repertoires between the peripheral blood and labial gland B cells of pSS patients in terms of relative expansion, isotype usage, and BCR clustering. We further observe significant decreases in IgA2 isotype usage among pSS patient labial and parotid gland B cells these analyses relative to controls as well as a positive correlation between kappa/lambda light chain usage and clinical disease activity.ConclusionsThrough BCR repertoire analysis of pSS patient salivary glands, we identify a number of novel repertoire characteristics that may serve as useful indicators of clinical disease and disease activity. By collecting these BCR repertoires into an accessible database, we hope to also enable comparative analysis of patient repertoires in pSS and potentially other autoimmune disorders.

Possible role for IL-40 and IL-40-producing cells in the lymphocytic infiltrated salivary glands of patients with primary Sjögren’s syndrome

ObjectivesAim of this study was to investigate the expression of interleukin (IL)-40, a new cytokine associated with B cells homoeostasis and immune response, in primary Sjögren syndrome (pSS) and in...

Sjögren's syndrome: one year in review 2022.

Primary Sjögren's syndrome (pSS) is a complex disabling systemic autoimmune disorder. The hallmark of pSS is the T-cell-mediated hyperactivation of B-cells, evolving from asymptomatic conditions to systemic complications and lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. B-cells show multiple possible roles in disease pathogenesis, from autoantibody production, to antigen presentation, and cytokine production. B-cells hyperactivation is supported by genetic risk factors, T-cell dependent and independent mechanisms, and the presence of different pathogenic B-cell subsets must be reminded.Many aspects have been investigated in the last year regarding genetic and epigenetics, B- and T-cell role in pSS pathogenesis, their interaction with salivary gland epithelial cells (SGECs) and in their direct or indirect use as biomarkers and predictors of disease development, activity, and lymphomagenesis.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Plasmacytoid DCs From Patients With Sjögren's Syndrome Are Transcriptionally Primed for Enhanced Pro-inflammatory Cytokine Production

Primary Sjögren's syndrome (pSS) is a systemic auto-immune disease typified by dryness of the mouth and eyes. A majority of patients with pSS have a type-I interferon (IFN)-signature, which is defined as the increased expression of IFN-induced genes in circulating immune cells and is associated with increased disease activity. As plasmacytoid dendritic cells (pDC) are the premier type-I IFN-producing cells and are present at the site of inflammation, they are thought to play a significant role in pSS pathogenesis. Considering the lack of data on pDC regulation and function in pSS patients, we here provided the first in-depth molecular characterization of pSS pDCs. In addition, a group of patients with non-Sjögren's sicca (nSS) was included; these poorly studied patients suffer from complaints similar to pSS patients, but are not diagnosed with Sjögren's syndrome. We isolated circulating pDCs from two independent cohorts of patients and controls (each n = 31) and performed RNA-sequencing, after which data-driven networks and modular analysis were used to identify robustly reproducible transcriptional “signatures” of differential and co-expressed genes. Four signatures were identified, including an IFN-induced gene signature and a ribosomal protein gene-signature, that indicated pDC activation. Comparison with a dataset of in vitro activated pDCs showed that pSS pDCs have higher expression of many genes also upregulated upon pDC activation. Corroborating this transcriptional profile, pSS pDCs produced higher levels of pro-inflammatory cytokines, including type-I IFN, upon in vitro stimulation with endosomal Toll-like receptor ligands. In this setting, cytokine production was associated with expression of hub-genes from the IFN-induced and ribosomal protein gene-signatures, indicating that the transcriptional profile of pSS pDCs underlies their enhanced cytokine production. In all transcriptional analyses, nSS patients formed an intermediate group in which some patients were molecularly similar to pSS patients. Furthermore, we used the identified transcriptional signatures to develop a discriminative classifier for molecular stratification of patients with sicca. Altogether, our data provide in-depth characterization of the aberrant regulation of pDCs from patients with nSS and pSS and substantiate their perceived role in the immunopathology of pSS, supporting studies that target pDCs, type-I IFNs, or IFN-signaling in pSS.

Elevation of Serum IL-35 in Patients with Primary Sjögren's Syndrome.

Interleukin-35 (IL-35) is a critical anti-inflammatory cytokine in autoimmune disease. In the current study, we aimed to investigate the serum IL-35 levels and its clinical association in patients with primary Sjögren's syndrome (pSS) and to investigate whether or not IL-35 participates in the pathogenesis of pSS. One hundred seventy-six pSS patients and 60 healthy controls (HCs) were recruited. Disease activity was assessed according to EULAR SS disease activity index. Serum IL-35 levels were quantified by enzyme-linked immunosorbent assay. The correlations between the serum IL-35 levels with the clinical parameters were analyzed by a Spearman's correlation test. The serum IL-35 levels in the patients with pSS were significantly increased compared with the HCs. The serum IL-35 levels were elevated in the patients with pSS. Strikingly, the serum IL-35 levels in pSS patients with short disease duration (<1 year) were significantly lower compared with HCs. However, the serum IL-35 levels in pSS patients with medium (1-2 year) and long disease duration (>2 years) were higher compared with HCs. We also found a positive correlation between expression of IL-35 and erythrocyte sedimentation rate, disease activity, and immunoglobulin G. Furthermore, the pSS patients with RF-positive showed high serum IL-35 levels. These findings suggest that IL-35 could play a key role in pSS pathogenesis. In addition, our results highlight the potential exploitation of IL-35 as a biomarker of disease activity and may represent a novel therapeutic agent for pSS.

CD4 T lymphocyte autophagy is upregulated in the salivary glands of primary Sj\xf6gren\u2019s syndrome patients and correlates with focus score and disease activity

BackgroundPrimary Sjögren’s syndrome (pSS) is a common chronic autoimmune disease characterized by lymphocytic infiltration of exocrine glands and peripheral lymphocyte perturbation. In the current study, we aimed to investigate the possible pathogenic implication of autophagy in T lymphocytes in patients with pSS.MethodsThirty consecutive pSS patients were recruited together with 20 patients affected by sicca syndrome and/or chronic sialoadenitis and 30 healthy controls. Disease activity and damage were evaluated according to SS disease activity index, EULAR SS disease activity index, and SS disease damage index. T lymphocytes were analyzed for the expression of autophagy-specific markers by biochemical, molecular, and histological assays in peripheral blood and labial gland biopsies. Serum interleukin (IL)-23 and IL-21 levels were quantified by enzyme-linked immunosorbent assay.ResultsOur study provides evidence for the first time that autophagy is upregulated in CD4+ T lymphocyte salivary glands from pSS patients. Furthermore, a statistically significant correlation was detected between lymphocyte autophagy levels, disease activity, and damage indexes. We also found a positive correlation between autophagy enhancement and the increased salivary gland expression of IL-21 and IL-23, providing a further link between innate and adaptive immune responses in pSS.ConclusionsThese findings suggest that CD4+ T lymphocyte autophagy could play a key role in pSS pathogenesis. Additionally, our data highlight the potential exploitation of T cell autophagy as a biomarker of disease activity and provide new ground to verify the therapeutic implications of autophagy as an innovative drug target in pSS.

Blockade of critical immune regulators results in different roads to pathogenesis in Primary Sjögren’s syndrome

Abstract Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease that affects exocrine glands resulting in severe dryness of mucosal surfaces, primarily the mouth and eyes. Female, but not male NOD.H-2h4 mice develop pSS-like manifestations in aged mice. Previously, we have shown that pSS disease that arise in these mice is driven by early peripheral dysregulation that manifests as spontaneous germinal centers (sGC) that are dependent on CD40/CD40L interactions (Mahmoud, T et al., Sci Transl Med 2016). We now examined if other key immune pathways also play a role in pathogenesis of pSS. We found that NOD.H-2h4 mice deficient in either CD28/IFNg or PD1/IFNg developed exacerbated pSS manifestations, compared to the NOD.H-2h4 wild type (WT) mice. As in the WT mice, a single treatment with anti-CD40L mAb in CD28/IFNg−/− mice diminished both sGC and salivary gland tertiary lymphoid structures (TLS). Unexpectedly, however, the aggressive disease noted in PD1/IFNg−/− animals was not similarly inhibited by treatment with anti-CD40L mAb. While anti-CD40L dissolved the sGC, it had no effect on the TLS that develop in the salivary glands of these PD1/IFNg−/− mice. The different results following anti-CD40L mAb treatment in CD28/IFNg−/−vs. PD1/IFNg−/− mice is likely not due to lack of functional Tregs in CD28/IFNg−/− mice, as while transient depletion of Tregs in PD1/IFNg−/− mice resulted increased salivary gland TLS, anti-CD40L still had minimal impact on disease.

T Regulatory and T Helper 17 Cells in Primary Sjögren's Syndrome: Facts and Perspectives.

Historically, primary Sjögren's syndrome (pSS) was thought to be a T helper (h) 1 driven disease due to the predominance of CD4+T lymphocytes and their products in target organs and peripheral blood of patients. In the last decades, the identification of a number of T cell subsets, including Th17, T regulatory (Treg), and follicular helper T cells, challenged this long-standing paradigm and prompted to identify their role in pSS pathogenesis. In addition the impact of abnormal proinflammatory cytokine production, such as IL-6, IL-17, IL-22, and IL-23, has also attracted considerable attention. However, although several studies have been carried out in experimental models and patients with pSS, many aspects concerning the role of Treg cells and IL-17/Th17 cell system in pSS pathogenesis are not fully elucidated. In particular, the role played by different IL-17-producing T cell subsets as well as the effects of pharmacological therapies on Treg/Th17 cell balance represents an intriguing issue. The aim of this review article is to provide an overview of current knowledge on Treg cells and IL-17-producing T cells in pSS pathogenesis. We believe that these insights into pSS pathogenesis may provide the basis for successful therapeutic intervention in this disease.

AB0174 Increased Proportion of CD38+Igd+ B Cells Contributes to Pathogenesis of Primary SjÖGren's Syndrome

BackgroundPrimary Sjögren's syndrome (pSS) is characterized by overproduction of autoantibodies against nuclei etc. and clinical manifestations caused by immune complexes, such as peripheral neuropathy, vasculitic lesions and hypocomplementemia. These denote...

Distribution of peripheral blood lymphocyte populations in patients with primary Sj�gren�s syndrome

Event Abstract Back to Event Distribution of peripheral blood lymphocyte populations in patients with primary Sjögren’s syndrome Gintaras Sudzius1*, Dainius Characiejus1, Diana Mieliauskaite2, Almantas Siaurys1, Irena Butrimiene2 and Irena Dumalakiene1 1 State Research Institute Center for Innovative Medicine, Department of Immunology, Lithuania 2 State Research Institute Center for Innovative Medicine, Department of Innovative diagnostic treatment and health monitoring technology, Lithuania Distribution of lymphocyte populations’ in peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) without (1pSS) or with (2pSS) extraglandular manifestations were investigated. 30 1pSS, 23 2pSS and 35 healthy controls were enrolled in the study. PBMCs were stimulated in whole blood with PMA and ionomycin, PBMCs labelled for CD3, CD4, CD8, CD19, CD16+56, CD25, CD27, CD57, Foxp3 and IL-17A and analyzed by flow cytometry. Decline in CD3+ T cells in PBMCs of patients with pSS was detected. The reason for this was significantly decreased absolute counts of CD4+, CD8+ and CD3+CD16+56 cells in patients with pSS. Significant decrease in absolute counts of CD4+IL17A+ and CD8brightCD57-CD27+ cells in patients with pSS were observed as compared to control group. Absolute counts of CD4+25brightFoxp3 and CD19+ cells were similar in all three groups and CD3-CD16+56 cells was significantly decreased only in 1pSS group. All results between 1pSS and 2pSS groups were comparable. However, different correlations between lymphocyte populations in 1pSS and 2pSS groups were found. Only in 1pSS the correlation between CD3-CD16+56 and CD3+CD16+56, CD3-CD16+56 and CD4+25brightFoxp3, CD4+ and CD19+, CD4+ and CD8brightCD57-CD27+ cells was registered. Whereas, in 2pSS the correlation between CD4+ and CD4+IL-17A+, CD8+ and CD3+CD16+56, CD4+IL-17A+ and CD8brightCD57-CD27+ cells was revealed. Declining and variations of T-lymphocyte subsets in pSS patients` could be the result of increased apoptosis and/or migration to inflamed tissues of CD4+IL-17A+, CD8brightCD57-CD27+, CD3+CD16+56 and CD3-CD16+56 (only in 1pSS group) cells. We suppose that these cell populations play an important role in pSS pathogenesis. Acknowledgements This research was funded by a grant No. LIG-23/2010 from the Research Council of Lithuania. Keywords: primary Sjögren's syndrome, extraglandular manifestations, distribution of lymphocyte populations, PBMCs, lymphocitopenia Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Immune-mediated disease pathogenesis Citation: Sudzius G, Characiejus D, Mieliauskaite D, Siaurys A, Butrimiene I and Dumalakiene I (2013). Distribution of peripheral blood lymphocyte populations in patients with primary Sjögren’s syndrome. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.00226 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 14 Mar 2013; Published Online: 22 Aug 2013. * Correspondence: Mr. Gintaras Sudzius, State Research Institute Center for Innovative Medicine, Department of Immunology, Vilnius, Lithuania, gintaras.sudzius@gmail.com Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Gintaras Sudzius Dainius Characiejus Diana Mieliauskaite Almantas Siaurys Irena Butrimiene Irena Dumalakiene Google Gintaras Sudzius Dainius Characiejus Diana Mieliauskaite Almantas Siaurys Irena Butrimiene Irena Dumalakiene Google Scholar Gintaras Sudzius Dainius Characiejus Diana Mieliauskaite Almantas Siaurys Irena Butrimiene Irena Dumalakiene PubMed Gintaras Sudzius Dainius Characiejus Diana Mieliauskaite Almantas Siaurys Irena Butrimiene Irena Dumalakiene Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.