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Molecular Mechanisms of Sjögren's Syndrome 3.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 15 May 2024 | Viewed by 6515

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Dr. Biji Theyilamannil Kurien

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The Arthritis and Clinical Immunology Program, Oklahoma Medical Research Foundation, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
Interests: systemic lupus erythematosus; Sjögren’s syndrome; prolidase deficiency; free radical biology; experimental urolithiasis; curcumin and other curcuminoids; dietary supplements; microgravity
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Dear Colleagues,

Sjögren’s syndrome (SS), a systemic autoimmune rheumatic disorder, is characterized by the B-cell infiltration of exocrine glands and the production of autoantibodies to self-antigens, such as Ro60 (SS-A), La (SS-B), and muscarinic 3 receptors. The most common symptoms of SS are dry eyes (keratoconjunctivitis sicca), dry mouth (xerostomia), and extreme tiredness. Additional symptoms include dryness of the skin, nose, throat, and vagina; arthralgias and myalgias; peripheral neuropathies; pulmonary, thyroid, and renal disorders; and lymphoma. Increased levels of tissue and serum cytokines and tissue fibrosis are also seen in SS subjects. Females account for 90% of all SS cases. Two age peaks have been identified for primary SS: the first after menarche (twenties to thirties), and the second following menopause (mid-fifties). SS can occur alone (primary SS) or along with another autoimmune diseases (secondary SS), such as systemic lupus erythematosus, rheumatoid arthritis, autoimmune hypothyroidism, and systemic sclerosis. The molecular mechanisms mediating pathological dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of Sjögren’s syndrome. There is no cure for Sjögren's syndrome currently, and treatment is mainly palliative.

In this Special Issue of IJMS, we seek articles that can pave the way to better understanding the molecular mechanisms mediating the pathological conditions of Sjögren’s syndrome. This includes articles that provide insights into the molecular aspects of the initiation and progression of disease by glandular vascular endothelial cells, environmental triggers, free-radical-mediated oxidative damage, the cytokine activation of lymphocytes, glandular lymphocyte and dendritic cell homing, the structure and function of autoantigens and autoantibody induction, germinal center-like structure formation, and the apoptosis of glandular cells. We also welcome review papers in these areas, as well as articles describing novel therapeutic targets and treatment options, new diagnostic tools, and biomarkers.

Dr. Biji Theyilamannil Kurien
Guest Editor

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Keywords

autoimmunity
Sjögren’s syndrome
autoantibodies
salivary gland
lacrimal gland
dry eyes/mouth

Published Papers (5 papers)

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Research

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15 pages, 1220 KiB

Open AccessArticle

B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren’s Disease: A Pilot Monocentric Exploratory Study

by Dario Bruno, Barbara Tolusso, Gianmarco Lugli, Clara Di Mario, Luca Petricca, Simone Perniola, Laura Bui, Roberta Benvenuto, Gianfranco Ferraccioli, Stefano Alivernini and Elisa Gremese

Int. J. Mol. Sci. 2024, 25(6), 3259; https://doi.org/10.3390/ijms25063259 - 13 Mar 2024

Cited by 1 | Viewed by 734

Abstract

Primary Sjögren’s disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin’s lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren’s disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren’s disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren’s disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren’s disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren’s disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren’s disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren’s disease, profoundly impacting the risk of NHL development. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 3.0)

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25 pages, 4273 KiB

Open AccessArticle

Pervasive Sharing of Causal Genetic Risk Factors Contributes to Clinical and Molecular Overlap between Sjögren’s Disease and Systemic Lupus Erythematosus

by Karen Chau, Yanint Raksadawan, Kristen Allison, John A. Ice, Robert Hal Scofield, Iouri Chepelev and Isaac T. W. Harley

Int. J. Mol. Sci. 2023, 24(19), 14449; https://doi.org/10.3390/ijms241914449 - 22 Sep 2023

Viewed by 1278

Abstract

SjD (Sjögren’s Disease) and SLE (Systemic Lupus Erythematosus) are similar diseases. There is extensive overlap between the two in terms of both clinical features and pathobiologic mechanisms. Shared genetic risk is a potential explanation of this overlap. In this study, we evaluated whether these diseases share causal genetic risk factors. We compared the causal genetic risk for SLE and SjD using three complementary approaches. First, we examined the published GWAS results for these two diseases by analyzing the predicted causal gene protein–protein interaction networks of both diseases. Since this method does not account for overlapping risk intervals, we examined whether such intervals also overlap. Third, we used two-sample Mendelian randomization (two sample MR) using GWAS summary statistics to determine whether risk variants for SLE are causal for SjD and vice versa. We found that both the putative causal genes and the genomic risk intervals for SLE and SjD overlap 28- and 130-times more than expected by chance (p < 1.1 × 10⁻²⁴ and p < 1.1 × 10⁻⁴¹, respectively). Further, two sample MR analysis confirmed that alone or in aggregate, SLE is likely causal for SjD and vice versa. [SjD variants predicting SLE: OR = 2.56; 95% CI (1.98–3.30); p < 1.4 × 10⁻¹³, inverse-variance weighted; SLE variants predicting SjD: OR = 1.36; 95% CI (1.26–1.47); p < 1.6 × 10⁻¹¹, inverse-variance weighted]. Notably, some variants have disparate impact in terms of effect size across disease states. Overlapping causal genetic risk factors were found for both diseases using complementary approaches. These observations support the hypothesis that shared genetic factors drive the clinical and pathobiologic overlap between these diseases. Our study has implications for both differential diagnosis and future genetic studies of these two conditions. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 3.0)

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10 pages, 278 KiB

Open AccessCommunication

Endothelial Dysfunction in Primary Sjögren’s Syndrome: Correlation with Serum Biomarkers of Disease Activity

by Alexandru Caraba, Stela Iurciuc, Mihaela Nicolin and Mircea Iurciuc

Int. J. Mol. Sci. 2023, 24(18), 13918; https://doi.org/10.3390/ijms241813918 - 10 Sep 2023

Viewed by 873

Abstract

To assess the relationship between endothelial dysfunction and serum cytokines, anti-SSA and anti-SSB antibodies, beta-2 microglobulin levels, focus score and EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) in primary Sjögren’s syndrome (pSS) patients. The study included 90 patients with pSS and 45 healthy subjects, matched for age and gender, as controls. Serum beta-2 microglobulin, total cholesterol, HDL-cholesterol, triglycerides, TNF-α, and IL-6 were analyzed in both the groups. Patients with pSS were also tested for antinuclear antibodies, anti-SAA (anti-Sjögren’s syndrome-related antigen A) antibodies, anti-SSB (anti-Sjögren syndrome related antigen B) antibodies, and focus score (the histopathologic one, based on minor salivary gland biopsy). Endothelial dysfunction was assessed by means of flow-mediated dilation (FMD) in the brachial artery. Data are presented as mean ± standard deviation. Statistical analysis was performed using the t-test and the Pearson’s correlation. Differences were considered to be statistically significant if the value of p < 0.05. Endothelial dysfunction was identified in pSS patients (p < 0.00001). The serum levels of cytokines (TNF-α, respective IL-6) and beta-2 microglobulin were increased in pSS patients compared with controls (p < 0.00001). Endothelial dysfunction (expressed as FMD%) was correlated with focus score, ESSDAI, levels of anti-SSA and anti-SSB antibodies, beta-2 microglobulin, IL-6, and TNF-α, with statistical significance. Endothelial dysfunction is present in pSS patients and is associated with a high focus score and activity as well as increased concentrations of antibodies, pro-inflammatory cytokines, and beta 2-microglobulin. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 3.0)

11 pages, 1603 KiB

Open AccessArticle

CCR9/CXCR5 Co-Expressing CD4 T Cells Are Increased in Primary Sjögren’s Syndrome and Are Enriched in PD-1/ICOS-Expressing Effector T Cells

by Anneline C. Hinrichs, Aike A. Kruize, Floris P. J. G. Lafeber, Helen L. Leavis and Joel A. G. van Roon

Int. J. Mol. Sci. 2023, 24(15), 11952; https://doi.org/10.3390/ijms241511952 - 26 Jul 2023

Cited by 1 | Viewed by 1279

Abstract

Primary Sjögren’s syndrome (pSS) is an autoimmune disease characterised by B cell hyperactivity. CXCR5+ follicular helper T cells (Tfh), CXCR5-PD-1hi peripheral helper T cells (Tph) and CCR9+ Tfh-like cells have been implicated in driving B cell hyperactivity in pSS; however, their potential overlap has not been evaluated. Our aim was to study the overlap between the two CXCR5- cell subsets and to study their PD-1/ICOS expression compared to “true” CXCR5/PD-1/ICOS-expressing Tfh cells. CXCR5- Tph and CCR9+ Tfh-like cell populations from peripheral blood mononuclear cells of pSS patients and healthy controls (HC) were compared using flow cytometry. PD-1/ICOS expression from these cell subsets was compared to each other and to CXCR5+ Tfh cells, taking into account their differentiation status. CXCR5- Tph cells and CCR9+ Tfh-like cells, both in pSS patients and HC, showed limited overlap. PD-1/ICOS expression was higher in memory cells expressing CXCR5 or CCR9. However, the highest expression was found in CXCR5/CCR9 co-expressing T cells, which are enriched in the circulation of pSS patients. CXCR5- Tph and CCR9+ Tfh-like cells are two distinct cell populations that both are enriched in pSS patients and can drive B cell hyperactivity in pSS. The known upregulated expression of CCL25 and CXCL13, ligands of CCR9 and CXCR5, at pSS inflammatory sites suggests concerted action to facilitate the migration of CXCR5+CCR9+ T cells, which are characterised by the highest frequencies of PD-1/ICOS-positive cells. Hence, these co-expressing effector T cells may significantly contribute to the ongoing immune responses in pSS. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 3.0)

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Review

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14 pages, 303 KiB

Open AccessReview

The Potential Utility of Salivary and Tear Proteomics to Discriminate Sjögren’s Disease from Non-Sjögren’s Sicca

by Christopher T. George, Biji T. Kurien and R. Hal Scofield

Int. J. Mol. Sci. 2023, 24(24), 17497; https://doi.org/10.3390/ijms242417497 - 15 Dec 2023

Viewed by 1060

Abstract

Sjögren’s Disease (SjD) is an autoimmune disorder associated with decreased saliva and/or tear secretions, resulting in patients reporting dryness in the mouth and eyes. Serum autoantibodies directed against the Ro60/SS-A and La/SS-B autoantigens are a distinctive feature of the disease. Analysis of the saliva and tear proteomes represents one promising alternative method of both classifying and monitoring the condition, and research into salivary and tear proteomics in patients with SjD, with and without sicca, has shown its efficacy and practicality in both clinical and research settings. Studies analyzing the saliva proteomics of SjD patients have generally shown an overexpression of proteins involved in T-cell activation, the immune response, β-2 microglobulin, and the recruitment of pro-inflammatory agents. These studies also show a decrease in or downregulation of proteins involved in salivary secretion. Studies analyzing the tear proteomics of patients with SjD have generally indicated an upregulation of proteins involved with TNF-α signaling, B-cell survival, and the recruitment of pro-inflammatory agents. Studies also note the differential expression of tear protein folding as a hallmark of ocular involvement in this condition. These findings help to elucidate the biochemical relationship between the proteomes of saliva/tear fluids and the general pathophysiology of the gland involved with the pathogenesis of this condition, giving further credence to the potential role of salivary and tear proteomics in the future of diagnosis and treatment for patients with SjD. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 3.0)

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