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Molecular Mechanisms of Sjögren's Syndrome 2.0

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 30249

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Special Issue Editor

Dr. Biji Theyilamannil Kurien

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Guest Editor

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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Special Issue Information

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 skin, nose, throat, vagina; arthralgias and myalgias, peripheral neuropathies, pulmonary, thyroid and renal disorders; and lymphoma. Increased tissue, 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 disease (secondary SS), like 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 are looking for articles that can pave the way to better understanding the molecular mechanisms mediating the pathological conditions of Sjögren’s syndrome. This would include articles that provide insights into molecular aspects of the initiation and progression of disease by glandular vascular endothelial cells, environmental triggers, free radical mediated oxidative damage, 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 (11 papers)

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Research

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13 pages, 6483 KiB

Open AccessArticle

Inhibitory Effects of Extracellular Vesicles from iPS-Cell-Derived Mesenchymal Stem Cells on the Onset of Sialadenitis in Sjögren’s Syndrome Are Mediated by Immunomodulatory Splenocytes and Improved by Inhibiting miR-125b

by Qingguo Zhao, Eun-Hye Bae, Yu Zhang, Arash Shahsavari, Pranayvir Lotey, Ryang Hwa Lee and Fei Liu

Int. J. Mol. Sci. 2023, 24(6), 5258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065258 - 09 Mar 2023

Cited by 2 | Viewed by 1485

Abstract

Extracellular vesicles (EVs) from allogeneic-tissue-derived mesenchymal stem cells (MSCs) are promising to improve Sjögren’s syndrome (SS) treatment, but their application is hindered by high variations in and limited expandability of tissue MSCs. We derived standardized and scalable MSCs from iPS cells (iMSCs) and reported that EVs from young but not aging iMSCs (iEVs) inhibited sialadenitis onset in SS mouse models. Here, we aim to determine cellular mechanisms and optimization approaches of SS-inhibitory effects of iEVs. In NOD.B10.H2^b mice at the pre-disease stage of SS, we examined the biodistribution and recipient cells of iEVs with imaging, flow cytometry, and qRT-PCR. Intravenously infused iEVs accumulated in the spleen but not salivary glands or cervical lymph nodes and were mainly taken up by macrophages. In the spleen, young but not aging iEVs increased M2 macrophages, decreased Th17 cells, and changed expression of related immunomodulatory molecules. Loading miR-125b inhibitors into aging iEVs significantly improved their effects on repressing sialadenitis onset and regulating immunomodulatory splenocytes. These data indicated that young but not aging iEVs suppress SS onset by regulating immunomodulatory splenocytes, and inhibiting miR-125b in aging iEVs restores such effects, which is promising to maximize production of effective iEVs from highly expanded iMSCs for future clinical application. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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10 pages, 2095 KiB

Open AccessArticle

Alternate-Day Fasting Ameliorates Newly Established Sjögren’s Syndrome-like Sialadenitis in Non-Obese Diabetic Mice

by Dongfang Li, Shoko Onodera, Shu Deng, Bashaer Alnujaydi, Qing Yu and Jing Zhou

Int. J. Mol. Sci. 2022, 23(22), 13791; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232213791 - 09 Nov 2022

Viewed by 1655

Abstract

Intermittent fasting confers protections to various diseases including autoimmune disorders, but the specific effects of intermittent fasting on Sjögren’s syndrome (SS) remains inconclusive. The present study was undertaken to determine the specific impact of alternate-day fasting (ADF) on newly established SS-like sialadenitis using non-obese diabetic (NOD) mice. Female NOD mice were deprived of food every other day from 10 to 13 weeks of age, the early stage of established SS, and then analyzed for the disease characteristics. Mice in the ADF group had higher salivary flow rate and attenuated submandibular gland (SMG) inflammation, compared to the control mice fed with standard chow ad libitum. The improvements were accompanied with a decrease in the total leukocytes, T and B lymphocytes and activated CD4 and CD8 T cells, and a down-regulation of pro-inflammatory cytokines IFN-γ and IL-17, chemokine receptor CXCR3 and its ligands CXCL9 and CXCL11 in the SMGs. ADF also led to elevated mRNA levels of water channel protein aquaporin 5 and tight junction protein claudin-1, two factors crucial for normal salivary secretion in the SMGs. In addition, ADF reduced the proportion of IFN-γ- and IL-17- expressing CD4 T cells and diminished mRNA levels of IFN-γ, TNF-α, and IL-17 in the total submandibular draining lymph node cells. Taken together, ADF is effective in ameliorating newly established SS-associated salivary gland exocrinopathy in NOD mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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12 pages, 1406 KiB

Open AccessArticle

Clinical Study of the Relationship between Sjögren Syndrome and T-Cell Large Granular Lymphocytic Leukemia: Single-Center Experience

by Vadim Gorodetskiy, Vladimir Vasilyev, Yulia Sidorova, Bella Biderman, Natalia Kupryshina, Murad Vagida, Natalya Ryzhikova and Andrey Sudarikov

Int. J. Mol. Sci. 2022, 23(21), 13345; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113345 - 01 Nov 2022

Cited by 2 | Viewed by 1248

Abstract

The relationship between Sjögren syndrome (SS) and T-cell large granular lymphocytic (T-LGL) leukemia remains unclear. In this paper, we report for the first time a large case series of 21 patients with primary and secondary SS associated with T-LGL leukemia. Our results suggest the importance of considering T-LGL leukemia in the diagnostic evaluation of SS patients, particularly when neutropenia occurs. We also postulate that elevated antinuclear antibody titers in patients with T-LGL leukemia indicate the need for the clinical assessment of SS. To assess whether SS affects the frequency of the signal transducer and activator of transcription 3 (STAT3) gene mutations in T-LGL leukemia, we examined STAT3 mutations by next-generation sequencing in two cohorts of patients: with SS-associated T-LGL leukemia and T-LGL leukemia in the setting of rheumatic diseases but without SS. While our results suggest that SS, per se, is not associated with an increased frequency of STAT3 mutations in T-LGL leukemia, further studies are needed to better assess the role of the STAT pathway in the development of concomitant SS and T-LGL leukemia. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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13 pages, 3485 KiB

Open AccessArticle

Interleukin-22 Exerts Detrimental Effects on Salivary Gland Integrity and Function

by Jing Zhou, Shoko Onodera, Yang Hu and Qing Yu

Int. J. Mol. Sci. 2022, 23(21), 12997; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112997 - 27 Oct 2022

Cited by 2 | Viewed by 1365

Abstract

Interleukin-22 (IL-22) affects epithelial tissue function and integrity in a context-dependent manner. IL-22 levels are elevated in salivary glands of Sjögren’s syndrome (SS) patients, but its role in the pathogenesis of this disease remains unclear. The objective of this study is to elucidate the impact of IL-22 on salivary gland tissue integrity and function in murine models. We showed that IL-22 levels in sera and salivary glands increased progressively in female non-obese diabetic (NOD) mice, accompanying the development of SS. Administration of IL-22 to the submandibular glands of NOD mice prior to the disease onset reduced salivary secretion and induced caspase-3 activation in salivary gland tissues, which were accompanied by alterations in multiple genes controlling tissue integrity and inflammation. Similarly, IL-22 administration to submandibular glands of C57BL/6 mice also induced hyposalivation and caspase-3 activation, whereas blockade of endogenous IL-22 in C57BL/6 mice treated with anti-CD3 antibody mitigated hyposalivation and caspase-3 activation. Finally, IL-22 treatment reduced the number of viable C57BL/6 mouse submandibular gland epithelial cells cultured in vitro, indicating a direct impact of this cytokine on these cells. We conclude that IL-22 exerts a detrimental impact on salivary gland tissues. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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14 pages, 2184 KiB

Open AccessArticle

A Small Step, a Giant Leap: Somatic Hypermutation of a Single Amino Acid Leads to Anti-La Autoreactivity

by Tabea Bartsch, Claudia Arndt, Liliana R. Loureiro, Alexandra Kegler, Edinson Puentes-Cala, Javier Andrés Soto, Biji T. Kurien, Anja Feldmann, Nicole Berndt and Michael P. Bachmann

Int. J. Mol. Sci. 2021, 22(21), 12046; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222112046 - 07 Nov 2021

Cited by 1 | Viewed by 1890

Abstract

The anti-La mab 312B, which was established by hybridoma technology from human-La transgenic mice after adoptive transfer of anti-human La T cells, immunoprecipitates both native eukaryotic human and murine La protein. Therefore, it represents a true anti-La autoantibody. During maturation, the anti-La mab 312B acquired somatic hypermutations (SHMs) which resulted in the replacement of four aa in the complementarity determining regions (CDR) and seven aa in the framework regions. The recombinant derivative of the anti-La mab 312B in which all the SHMs were corrected to the germline sequence failed to recognize the La antigen. We therefore wanted to learn which SHM(s) is (are) responsible for anti-La autoreactivity. Humanization of the 312B ab by grafting its CDR regions to a human Ig backbone confirms that the CDR sequences are mainly responsible for anti-La autoreactivity. Finally, we identified that a single amino acid replacement (D > Y) in the germline sequence of the CDR3 region of the heavy chain of the anti-La mab 312B is sufficient for anti-La autoreactivity. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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20 pages, 3438 KiB

Open AccessArticle

Defective Efferocytosis in a Murine Model of Sjögren’s Syndrome Is Mediated by Dysfunctional Mer Tyrosine Kinase Receptor

by Richard Witas, Astrid Rasmussen, Robert H. Scofield, Lida Radfar, Donald U. Stone, Kiely Grundahl, David Lewis, Kathy L. Sivils, Christopher J. Lessard, A. Darise Farris and Cuong Q. Nguyen

Int. J. Mol. Sci. 2021, 22(18), 9711; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189711 - 08 Sep 2021

Cited by 8 | Viewed by 3077

Abstract

Sjögren’s syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjS^S) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjS^S mice, as evidenced by reduced Rac1 activation in SjS^S mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjS^S mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjS^S mice. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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21 pages, 5036 KiB

Open AccessArticle

And Yet It Moves: Oxidation of the Nuclear Autoantigen La/SS-B Is the Driving Force for Nucleo-Cytoplasmic Shuttling

by Nicole Berndt, Claudia C. Bippes, Irene Michalk, Tabea Bartsch, Claudia Arndt, Edinson Puentes-Cala, Javier Andrés Soto, Liliana R. Loureiro, Alexandra Kegler, Dominik Bachmann, Joanne K. Gross, Tim Gross, Biji T. Kurien, R. Hal Scofield, A. Darise Farris, Judith A. James, Ralf Bergmann, Marc Schmitz, Anja Feldmann and Michael P. Bachmann

Int. J. Mol. Sci. 2021, 22(18), 9699; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189699 - 08 Sep 2021

Cited by 7 | Viewed by 3029

Abstract

Decades ago, we and many other groups showed a nucleo-cytoplasmic translocation of La protein in cultured cells. This shuttling of La protein was seen after UV irradiation, virus infections, hydrogen peroxide exposure and the Fenton reaction based on iron or copper ions. All of these conditions are somehow related to oxidative stress. Unfortunately, these harsh conditions could also cause an artificial release of La protein. Even until today, the shuttling and the cytoplasmic function of La/SS-B is controversially discussed. Moreover, the driving mechanism for the shuttling of La protein remains unclear. Recently, we showed that La protein undergoes redox-dependent conformational changes. Moreover, we developed anti-La monoclonal antibodies (anti-La mAbs), which are specific for either the reduced form of La protein or the oxidized form. Using these tools, here we show that redox-dependent conformational changes are the driving force for the shuttling of La protein. Moreover, we show that translocation of La protein to the cytoplasm can be triggered in a ligand/receptor-dependent manner under physiological conditions. We show that ligands of toll-like receptors lead to a redox-dependent shuttling of La protein. The shuttling of La protein depends on the redox status of the respective cell type. Endothelial cells are usually resistant to the shuttling of La protein, while dendritic cells are highly sensitive. However, the deprivation of intracellular reducing agents in endothelial cells makes endothelial cells sensitive to a redox-dependent shuttling of La protein. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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Review

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13 pages, 1557 KiB

Open AccessReview

Molecular Mechanisms Linking Inflammation to Autoimmunity in Sjögren’s Syndrome: Identification of New Targets

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

Int. J. Mol. Sci. 2022, 23(21), 13229; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232113229 - 30 Oct 2022

Cited by 9 | Viewed by 2556

Abstract

Sjögren’s syndrome (SS) is a systemic autoimmune rheumatic disorder characterized by the lymphocytic infiltration of exocrine glands and the production of autoantibodies to self-antigens. The involvement of the exocrine glands drives the pathognomonic manifestations of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) that define sicca syndrome. To date, the molecular mechanisms mediating pathological salivary gland dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of this disease, hampering the development of novel therapeutic strategies. Many researchers have identified a multifactorial pathogenesis of SS, including environmental, genetic, neuroendocrine, and immune factors. In this review, we explore the latest developments in understanding the molecular mechanisms involved in the pathogenesis of SS, which have attracted increasing interest in recent years. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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17 pages, 1146 KiB

Open AccessReview

Defining the Role of Monocytes in Sjögren’s Syndrome

by Jose Miguel Sequí-Sabater and Lorenzo Beretta

Int. J. Mol. Sci. 2022, 23(21), 12765; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112765 - 23 Oct 2022

Cited by 7 | Viewed by 3970

Abstract

Sjögren’s syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin’s lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren’s syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren’s syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren’s syndrome pathophysiology and redefine the involvement of monocytes in this disease. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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8 pages, 453 KiB

Open AccessReview

Sensorineural Hearing Loss in Sjögren’s Syndrome

by Yuko Okawa and Kenji Ihara

Int. J. Mol. Sci. 2022, 23(19), 11181; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911181 - 23 Sep 2022

Cited by 2 | Viewed by 3377

Abstract

Sjögren’s syndrome is a chronic autoimmune disease characterized by systemic dysfunction of exocrine glands, mainly the salivary and lachrymal glands. Sjögren’s syndrome consists of two forms: primary Sjögren’s syndrome, which is characterized by dry eyes and dry mouth without autoimmune diseases; and secondary Sjögren’s syndrome, which is characterized by symptoms associated with other autoimmune diseases, such as systemic lupus erythematosus. Disease severities vary considerably from mild glandular dryness to severe glandular involvement with numerous extraglandular and systemic features. Sensorineural hearing loss is sometimes observed in both primary and secondary Sjögren’s syndrome. This review article consists of (1) Pathology of Sjögren’s syndrome, (2) Clinical manifestation of Sjögren’s syndrome, (3) Autoimmune inner ear disease, (4) Histoanatomical features of the inner ear, (5) Immunological characteristics of the inner ear, (6) Pathophysiology of autoimmune inner ear disease, (7) Treatment for sensorineural hearing loss in Sjögren’s syndrome, and (8) Future direction. Finally, we introduce a recently developed disease model of salivary gland inflammation and discuss future expectations for the treatment of sensorineural hearing loss in Sjögren’s syndrome. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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21 pages, 1281 KiB

Open AccessReview

Cadherin Signaling in Cancer and Autoimmune Diseases

by Margherita Sisto, Domenico Ribatti and Sabrina Lisi

Int. J. Mol. Sci. 2021, 22(24), 13358; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222413358 - 12 Dec 2021

Cited by 17 | Viewed by 4908

Abstract

Cadherins mediate cell–cell adhesion through a dynamic process that is strongly dependent on the cellular context and signaling. Cadherin regulation reflects the interplay between fundamental cellular processes, including morphogenesis, proliferation, programmed cell death, surface organization of receptors, cytoskeletal organization, and cell trafficking. The variety of molecular mechanisms and cellular functions regulated by cadherins suggests that we have only scratched the surface in terms of clarifying the functions mediated by these versatile proteins. Altered cadherins expression is closely connected with tumorigenesis, epithelial–mesenchymal transition (EMT)-dependent fibrosis, and autoimmunity. We review the current understanding of how cadherins contribute to human health and disease, considering the mechanisms of cadherin involvement in diseases progression, as well as the clinical significance of cadherins as therapeutic targets. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Sjögren's Syndrome 2.0)

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