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Special Issue "Mechanisms of Disease in Sjögren Syndrome"

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: closed (31 August 2018).

Special Issue Editors

Dr. Cintia S. De Paiva
E-Mail Website
Guest Editor
Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
Interests: Sjogren syndrome; dry eye; lacrimal gland; aging; microbiome; dendritic cells; CD4+ T cells; goblet cells
Special Issues, Collections and Topics in MDPI journals
Prof. Stephen C. Pflugfelder
E-Mail Website
Guest Editor
Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA
Interests: dry eye; ocular surface; autoimmunity; Sjogren syndrome; conjunctiva; goblet cells; dendritic cells
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Sjögren Syndrome (SS) is an autoimmune disorder that affects exocrine glands, mainly the lacrimal and salivary glands. Clinically, patients often complain of fatigue, dry eye, and dry mouth, although disease manifestations are very heterogeneous. SS is accompanied by elevated tissue and serum cytokines, serum autoantibodies and tissue fibrosis that eventually leads to loss of function. Patients with SS are at increased risk of developing lymphoma. Among dry eye conditions, SS causes severe reduction of lacrimal function and ocular surface disease. Although our understanding of the pathological mechanisms has improved in the past 20 years, there is still much to discover about how inflammation causes glandular and mucosal disease in SS.

In this Special Issue of IJMS, we are seeking articles that provide new insights into the underlying mechanisms of Sjögren Syndrome, including molecular and cellular mechanisms involved in the initiation and perpetuation of autoimmunity, new diagnostic tools/biomarkers, and new therapies and treatment options.

Prof. Stephen C. Pflugfelder
Assist. Prof. Cintia S De Paiva
Guest Editors

Manuscript Submission Information

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Keywords

  • Dry eye
  • Dry mouth
  • Sjögren Syndrome
  • Lacrimal gland
  • Salivary gland
  • Animal models of Sjögren Syndrome
  • Goblet cell
  • Autoantibodies

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Published Papers (18 papers)

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Editorial

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Editorial
Mechanisms of Disease in Sjögren Syndrome—New Developments and Directions
Int. J. Mol. Sci. 2020, 21(2), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21020650 - 19 Jan 2020
Cited by 3 | Viewed by 904
Abstract
Sjögren Syndrome (SS) is an autoimmune disease that affects the exocrine glands, mainly salivary and lacrimal glands [...] Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)

Research

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Article
Molecular Evidence for Precursors of Sjögren’s Foci in Histologically Normal Lacrimal Glands
Int. J. Mol. Sci. 2019, 20(1), 223; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20010223 - 08 Jan 2019
Cited by 1 | Viewed by 1768
Abstract
Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs [...] Read more.
Understanding the formation of Sjogren’s lymphocytic infiltrates could permit earlier diagnosis and better outcomes. We submitted gene transcript abundances in histologically normal rabbit lacrimal glands to principal component analysis. The analysis identified a cluster of transcripts associated with Sjögren’s foci, including messenger RNAs (mRNAs) for C–X–C motif chemokine ligand 13 (CXCL13) and B-cell activating factor (BAFF), which dominated the major principal component. We interpreted the transcript cluster as the signature of a cluster of integrally functioning cells. Pregnancy and dryness increased the likelihood that the cluster would develop to high levels, but responses were subject to high levels of stochasticity. Analyzing microdissected samples from high- and low-cluster-level glands, we found that certain transcripts, including mRNAs for C–C motif chemokine ligand 21 (CCL21), CXCL13, cluster of differentiation 4 (CD4), CD28, CD25, BAFF, and interleukin 18 (IL-18) were significantly more abundant in immune cell clusters (ICs) from the high-cluster-level gland; mRNAs for CCL2, CD25, and IL-1RA were significantly more abundant in acinus-duct axis samples; mRNAs for CCL4, BAFF, IL-6, and IL-10 were more abundant in some acinus-duct samples; cells with high prolactin immunoreactivity were more frequent in interacinar spaces. In conclusion, integrated functional networks comprising Sjögren’s infiltrates, such as ICs, acinar cells, ductal cells, and interacinar cells, can form in histologically normal glands, and it is feasible to detect their molecular signatures. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Reduced Corneal Innervation in the CD25 Null Model of Sjögren Syndrome
Int. J. Mol. Sci. 2018, 19(12), 3821; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123821 - 30 Nov 2018
Cited by 15 | Viewed by 1748
Abstract
Decreased corneal innervation is frequent in patients with Sjögren Syndrome (SS). To investigate the density and morphology of the intraepithelial corneal nerves (ICNs), corneal sensitivity, epithelial cell proliferation, and changes in mRNA expression of genes that are involved in autophagy and axon targeting [...] Read more.
Decreased corneal innervation is frequent in patients with Sjögren Syndrome (SS). To investigate the density and morphology of the intraepithelial corneal nerves (ICNs), corneal sensitivity, epithelial cell proliferation, and changes in mRNA expression of genes that are involved in autophagy and axon targeting and extension were assessed using the IL-2 receptor alpha chain (CD25 null) model of SS. ICN density and thickness in male and female wt and CD25 null corneas were assessed at 4, 6, 8, and 10/11 wk of age. Cell proliferation was assessed using ki67. Mechanical corneal sensitivity was measured. Quantitative PCR was performed to quantify expression of beclin 1, LC3, Lamp-1, Lamp-2, CXCL-1, BDNF, NTN1, DCC, Unc5b1, Efna4, Efna5, Rgma, and p21 in corneal epithelial mRNA. A significant reduction in corneal axon density and mechanical sensitivity were observed, which negatively correlate with epithelial cell proliferation. CD25 null mice have increased expression of genes regulating autophagy (beclin-1, LC3, LAMP-1, LAMP-2, CXCL1, and BDNF) and no change was observed in genes that were related to axonal targeting and extension. Decreased anatomic corneal innervation in the CD25 null SS model is accompanied by reduced corneal sensitivity, increased corneal epithelial cell proliferation, and increased expression of genes regulating phagocytosis and autophagy. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Deciphering Molecular and Phenotypic Changes Associated with Early Autoimmune Disease in the Aire-Deficient Mouse Model of Sjögren’s Syndrome
Int. J. Mol. Sci. 2018, 19(11), 3628; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113628 - 17 Nov 2018
Cited by 7 | Viewed by 1661
Abstract
Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify [...] Read more.
Sjögren’s syndrome (SS) is characterized by extensive lymphocytic infiltration of the salivary and lacrimal gland (LG), resulting in acinar cell destruction and organ dysfunction. The underlying pathogenesis of SS remains largely unknown, and studies historically focus on defining late-stage disease. Here, we identify tissue programs associated with disease onset using transcriptomic and immunohistological analysis of LGs from 5- and 7-week-old mice deficient in autoimmune response element (Aire). At 5 weeks of age (wk), Aire-/- mice show minimal tissue dysfunction and destruction compared to 7 wk Aire-/-, which exhibit severe dry eye, poor tear secretion, extensive lymphocytic infiltration, reduced functional innervation, and increased vascularization. Despite this mild phenotype, 5 wk Aire-/- LGs were highly enriched for signaling pathways previously associated with SS, including interferon gamma (IFNγ), interleukin 1 beta (IL1β), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), toll-like receptor (TLR) signaling, and interleukin-6/signal transducer and activator of transcription 3 (IL6/STAT3) signaling. Novel signaling pathways such as the semaphorin–plexin pathway were also noted. Intriguingly, we found an expansion of the ductal network with increasing disease. Activated STAT3, a blocker of apoptosis, was restricted to the ductal system and also increased with damage, highlighting its potential as a promoter of ductal cell survival. These data demonstrate the early activation of signaling pathways regulating inflammation, innervation, and cell survival before the onset of clinical disease indicators, suggesting their potential value as diagnostic biomarkers. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease—Activated Receptor-2, in Human Corneal Epithelial Cells
Int. J. Mol. Sci. 2018, 19(11), 3530; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113530 - 09 Nov 2018
Cited by 14 | Viewed by 2230
Abstract
Cathepsin S (CTSS) activity is increased in tears of Sjögren’s syndrome (SS) patients. This elevated CTSS may contribute to ocular surface inflammation. Human corneal epithelial cells (HCE-T cells) were treated with recombinant human CTSS at activity comparable to that in SS patient tears [...] Read more.
Cathepsin S (CTSS) activity is increased in tears of Sjögren’s syndrome (SS) patients. This elevated CTSS may contribute to ocular surface inflammation. Human corneal epithelial cells (HCE-T cells) were treated with recombinant human CTSS at activity comparable to that in SS patient tears for 2, 4, 8, and 24 h. Acute CTSS significantly increased HCE-T cell gene and protein expression of interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) from 2 to 4 h, while matrix metalloproteinase 9 (MMP-9), CTSS, and protease-activated receptor-2 (PAR-2) were increased by chronic CTSS (24 h). To investigate whether the increased pro-inflammatory cytokines and proteases were induced by CTSS activation of PAR-2, HCE-T cells were transfected with PAR-2 siRNA, reducing cellular PAR-2 by 45%. Cells with reduced PAR-2 expression showed significantly reduced release of IL-6, TNF-α, IL-1β, and MMP-9 into culture medium in response to acute CTSS, while IL-6, TNF-α, and MMP-9 were reduced in culture medium, and IL-6 and MMP-9 in cell lysates, after chronic CTSS. Moreover, cells with reduced PAR-2 expression showed reduced ability of chronic CTSS to induce gene expression of pro-inflammatory cytokines and proteases. CTSS activation of PAR-2 may represent a potential therapeutic target for amelioration of ocular surface inflammation in SS patients. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Epidermal Fatty Acid-Binding Protein: A Novel Marker in the Diagnosis of Dry Eye Disease in Sjögren Syndrome
Int. J. Mol. Sci. 2018, 19(11), 3463; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113463 - 04 Nov 2018
Cited by 9 | Viewed by 1962
Abstract
Purpose: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of the lacrimal and salivary glands. This study compared the concentrations of epidermal fatty-acid binding protein (E-FABP) in the saliva, serum, and tears of SS patients with dry eye and dry mouth, with [...] Read more.
Purpose: Sjögren syndrome (SS) is a chronic inflammatory autoimmune disease of the lacrimal and salivary glands. This study compared the concentrations of epidermal fatty-acid binding protein (E-FABP) in the saliva, serum, and tears of SS patients with dry eye and dry mouth, with those of healthy adults to investigate the usefulness of E-FABP as a diagnostic marker for SS. Design: Prospective, observational case series. Participants: The subjects were 11 new patients with untreated Sjogren syndrome and 12 healthy control individuals. Methods: The diagnosis of SS was in accordance with the Ministry of Health, Labour and Welfare (Japan) Diagnostic Criteria (1999). Saliva, serum, and tear specimens were collected during internal medicine, dental, and ophthalmological examinations. The ophthalmological tests included the Dry Eye-related Quality of life Score (DEQS), tear break-up time (BUT), vital staining with fluorescein (FS) and lissamine green (LG), and the Schirmer test-1. The E-FABP concentration in the tears, saliva, and serum was measured by enzyme-linked immunosorbent assay (ELISA). Main outcome measure: The E-FABP concentrations were compared between patients and controls. Results: There were significant differences between the patient and healthy control groups in all ophthalmological test results. There were no significant differences between the groups in the E-FABP concentrations in the saliva (p = 0.1513) or the serum (p = 0.4799), but the E-FABP concentration in the tears significantly differed between groups. The E-FABP concentration in tears tended to be significantly lower in patients with SS (mean, 323.5 ± 325.6 pg/mL) than healthy control subjects (mean, 4076 pg/mL; p = 0.0136). The E-FABP concentration in tears significantly correlated with the results of dry eye parameters. Conclusion: The E-FABP concentration in tears appears to be related to ocular surface epithelial damage and tear stability and may be a promising novel biomarker in the diagnosis of SS. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Type I Interferon Signaling Is Required for Dacryoadenitis in the Nonobese Diabetic Mouse Model of Sjögren Syndrome
Int. J. Mol. Sci. 2018, 19(10), 3259; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103259 - 20 Oct 2018
Cited by 6 | Viewed by 2034
Abstract
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland [...] Read more.
Nonobese diabetic (NOD) mice spontaneously develop lacrimal and salivary gland autoimmunity similar to human Sjögren syndrome. In both humans and NOD mice, the early immune response that drives T-cell infiltration into lacrimal and salivary glands is poorly understood. In NOD mice, lacrimal gland autoimmunity spontaneously occurs only in males with testosterone playing a role in promoting lacrimal gland inflammation, while female lacrimal glands are protected by regulatory T cells (Tregs). The mechanisms of this male-specific lacrimal gland autoimmunity are not known. Here, we studied the effects of Treg depletion in hormone-manipulated NOD mice and lacrimal gland gene expression to determine early signals required for lacrimal gland inflammation. While Treg-depletion was not sufficient to drive dacryoadenitis in castrated male NOD mice, chemokines (Cxcl9, Ccl19) and other potentially disease-relevant genes (Epsti1, Ubd) were upregulated in male lacrimal glands. Expression of Cxcl9 and Ccl19, in particular, remained significantly upregulated in the lacrimal glands of lymphocyte-deficient NOD-severe combined immunodeficiency (SCID) mice and their expression was modulated by type I interferon signaling. Notably, Ifnar1-deficient NOD mice did not develop dacryoadenitis. Together these data identify disease-relevant genes upregulated in the context of male-specific dacryoadenitis and demonstrate a requisite role for type I interferon signaling in lacrimal gland autoimmunity in NOD mice. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Outer Membrane Protein of Gut Commensal Microorganism Induces Autoantibody Production and Extra-Intestinal Gland Inflammation in Mice
Int. J. Mol. Sci. 2018, 19(10), 3241; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103241 - 19 Oct 2018
Cited by 4 | Viewed by 1780
Abstract
Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was [...] Read more.
Gut commensal microorganisms have been linked with chronic inflammation at the extra-intestinal niche of the body. The object of the study was to investigate on the chronic effects of a gut commensal Escherichia coli on extra-intestinal glands. The presence of autoimmune response was diagnosed by autoantibody levels and histological methods. Repeated injection of E. coli induced mononuclear cell inflammation in the Harderian and submandibular salivary glands of female C57BL/6 mice. Inflammation was reproduced by adoptive transfer of splenocytes to immune-deficient Rag2 knockout mice and CD4+ T cells to mature T cell-deficient TCRβ-TCRδ knockout mice. MALDI TOF mass spectrometry of the protein to which sera of E. coli-treated mice reacted was determined as the outer membrane protein A (OmpA) of E. coli. Multiple genera of the Enterobacteriaceae possessed OmpA with high amino-acid sequence similarities. Repeated injection of recombinant OmpA reproduced mononuclear cell inflammation of the Harderian and salivary glands in mice and elevation of autoantibodies against Sjögren’s-syndrome-related antigens SSA/Ro and SSB/La. The results indicated the possibility of chronic stimuli from commensal bacteria-originated components as a pathogenic factor to elicit extra-intestinal autoimmunity. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Thrombospondin-1 Is Necessary for the Development and Repair of Corneal Nerves
Int. J. Mol. Sci. 2018, 19(10), 3191; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103191 - 16 Oct 2018
Cited by 7 | Viewed by 1648
Abstract
Thrombospondin-1-deficient (TSP-1−/−) mice are used as an animal model of Sjögren’s Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren’s Syndrome. This type of dry eye is linked to the [...] Read more.
Thrombospondin-1-deficient (TSP-1−/−) mice are used as an animal model of Sjögren’s Syndrome because they exhibit many of the symptoms associated with the autoimmune type of dry eye found in primary Sjögren’s Syndrome. This type of dry eye is linked to the inflammation of the lacrimal gland, conjunctiva, and cornea, and is thought to involve dysfunction of the complex neuronal reflex arc that mediates tear production in response to noxious stimuli on the ocular surface. This study characterizes the structural and functional changes to the corneal nerves that are the afferent arm of this arc in young and older TSP-1−/− and wild type (WT) mice. The structure and subtype of nerves were characterized by immunohistochemistry, in vivo confocal microscopy, and confocal microscopy. Cytokine expression analysis was determined by Q-PCR and the number of monocytes was measured by immunohistochemistry. We found that only the pro-inflammatory cytokine MIP-2 increased in young corneas of TSP-1−/− compared to WT mice, but tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-2 (MIP-2) all increased in older TSP-1−/− mouse corneas. In contrast, CD11b+ pro-inflammatory monocytes did not increase even in older mouse corneas. Calcitonin gene-related peptide (CGRP)-, but not Substance P (SubP)-containing corneal nerves decreased in older, but not younger TSP-1−/− compared to WT mouse corneas. We conclude that CGRP-containing corneal sensory nerves exhibit distinct structural deficiencies as disease progresses in TSP-1−/− mice, suggesting that: (1) TSP-1 is needed for the development or repair of these nerves and (2) impaired afferent corneal nerve structure and hence function may contribute to ocular surface dysfunction that develops as TSP-1−/− mice age. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Dysregulated Marginal Zone B Cell Compartment in a Mouse Model of Sjögren’s Syndrome with Ocular Inflammation
Int. J. Mol. Sci. 2018, 19(10), 3117; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103117 - 11 Oct 2018
Cited by 5 | Viewed by 2023
Abstract
The risk of developing lymphoma in patients with Sjögren’s syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is [...] Read more.
The risk of developing lymphoma in patients with Sjögren’s syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1−/−)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1−/− mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1−/− mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1−/− MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1−/− mice and highlight their role in the context of SS-related chronic ocular surface disease. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Immune Response Targeting Sjögren’s Syndrome Antigen Ro52 Suppresses Tear Production in Female Mice
Int. J. Mol. Sci. 2018, 19(10), 2935; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19102935 - 27 Sep 2018
Cited by 6 | Viewed by 1328
Abstract
Autoantibodies reactive against Ro52 are present in 70% of Sjögren’s syndrome patients and are associated with higher disease severity. However, their role in causing aqueous deficient dry eye, a major cause for morbidity in Sjögren’s syndrome, is unclear. To investigate whether immune responses [...] Read more.
Autoantibodies reactive against Ro52 are present in 70% of Sjögren’s syndrome patients and are associated with higher disease severity. However, their role in causing aqueous deficient dry eye, a major cause for morbidity in Sjögren’s syndrome, is unclear. To investigate whether immune responses targeting Ro52 contribute towards the dry eye, male and female NZM2758 mice were immunized with recombinant Ro52. Tear production was measured by the phenol red thread test. Sera were analyzed for anti-Ro52 levels by immunoprecipitation. Lacrimal glands were evaluated for inflammatory foci and IgG deposits. Our results showed that, although all mice generated anti-Ro52 antibodies, only females developed a significant drop in tear production. None of the mice developed severe lacrimal gland inflammation, and female mice with anti-Ro52 showed higher levels of IgG deposits within their glands. Passive transfer of anti-Ro52 sera caused reduced tear production in female mice, but not in males. This study demonstrates for the first time that immune responses initiated by Ro52 induce aqueous dry eye, and this may be driven by anti-Ro52 antibodies. Furthermore, the sexual dimorphism in glandular dysfunction suggests that the lacrimal glands in females are more susceptible to autoantibody-mediated injury. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Severity of Sjögren’s Syndrome Keratoconjunctivitis Sicca Increases with Increased Percentage of Conjunctival Antigen-Presenting Cells
Int. J. Mol. Sci. 2018, 19(9), 2760; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19092760 - 14 Sep 2018
Cited by 23 | Viewed by 1782
Abstract
This study investigated the relationship between clinical severity and percentage of conjunctival antigen-presenting cells (APCs) in Sjögren’s syndrome (SS)-associated keratoconjunctivitis sicca (KCS). KCS clinical severity was based on symptom severity, tear volume, tear break-up time, and ocular surface dye staining. Conjunctival goblet cell [...] Read more.
This study investigated the relationship between clinical severity and percentage of conjunctival antigen-presenting cells (APCs) in Sjögren’s syndrome (SS)-associated keratoconjunctivitis sicca (KCS). KCS clinical severity was based on symptom severity, tear volume, tear break-up time, and ocular surface dye staining. Conjunctival goblet cell density (GCD) was measured in periodic acid Schiff (PAS)-stained membranes. Conjunctival cells obtained by impression cytology were used for flow cytometry to measure percentages of CD45+HLA-DR+ APCs and mature CD11c+CD86+ dendritic cells (DCs). Compared to normal conjunctiva, the percentages of HLA-DR+ and CD11c+CD86+ cells were higher in the conjunctiva of the KCS group (p < 0.05). The percentage of CD45+HLA-DR+ cells positively correlated with clinical severity (r = 0.71, p < 0.05) and negatively correlated with GCD (r = −0.61, p < 0.05). Clinical severity also negatively correlated with GCD (r = −0.54, p < 0.05). These findings indicate that a higher percentage of APCs and mature DCs in the conjunctiva is associated with more severe KCS in SS. These APCs may contribute to the generation of the pathogenic Th1 cells that cause goblet cell loss in KCS. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Article
Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice
Int. J. Mol. Sci. 2018, 19(2), 565; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19020565 - 13 Feb 2018
Cited by 32 | Viewed by 2629
Abstract
Commensal bacteria play an important role in the formation of the immune system but their role in the maintenance of immune homeostasis at the ocular surface and lacrimal gland remains poorly understood. This study investigated the eye and lacrimal gland phenotype in germ-free [...] Read more.
Commensal bacteria play an important role in the formation of the immune system but their role in the maintenance of immune homeostasis at the ocular surface and lacrimal gland remains poorly understood. This study investigated the eye and lacrimal gland phenotype in germ-free and conventional C57BL/6J mice. Our results showed that germ-free mice had significantly greater corneal barrier disruption, greater goblet cell loss, and greater total inflammatory cell and CD4+ T cell infiltration within the lacrimal gland compared to the conventionally housed group. A greater frequency of CD4+IFN-γ+ cells was observed in germ-free lacrimal glands. Females exhibited a more severe phenotype compared to males. Adoptive transfer of CD4+ T cells isolated from female germ-free mice into RAG1KO mice transferred Sjögren-like lacrimal keratoconjunctivitis. Fecal microbiota transplant from conventional mice reverted dry eye phenotype in germ-free mice and decreased CD4+IFN-γ+ cells to levels similar to conventional C57BL/6J mice. These findings indicate that germ-free mice have a spontaneous lacrimal keratoconjunctivitis similar to that observed in Sjögren syndrome patients and demonstrate that commensal bacteria function in maintaining immune homeostasis on the ocular surface. Thus, manipulation of intestinal commensal bacteria has the potential to become a novel therapeutic approach to treat Sjögren Syndrome. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Review

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Review
Neurological and Inflammatory Manifestations in Sjögren’s Syndrome: The Role of the Kynurenine Metabolic Pathway
Int. J. Mol. Sci. 2018, 19(12), 3953; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19123953 - 08 Dec 2018
Cited by 13 | Viewed by 5293
Abstract
For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren’s syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular [...] Read more.
For decades, neurological, psychological, and cognitive alterations, as well as other glandular manifestations (EGM), have been described and are being considered to be part of Sjögren’s syndrome (SS). Dry eye and dry mouth are major findings in SS. The lacrimal glands (LG), ocular surface (OS), and salivary glands (SG) are linked to the central nervous system (CNS) at the brainstem and hippocampus. Once compromised, these CNS sites may be responsible for autonomic and functional disturbances that are related to major and EGM in SS. Recent studies have confirmed that the kynurenine metabolic pathway (KP) can be stimulated by interferon-γ (IFN-γ) and other cytokines, activating indoleamine 2,3-dioxygenase (IDO) in SS. This pathway interferes with serotonergic and glutamatergic neurotransmission, mostly in the hippocampus and other structures of the CNS. Therefore, it is plausible that KP induces neurological manifestations and contributes to the discrepancy between symptoms and signs, including manifestations of hyperalgesia and depression in SS patients with weaker signs of sicca, for example. Observations from clinical studies in acquired immune deficiency syndrome (AIDS), graft-versus-host disease, and lupus, as well as from experimental studies, support this hypothesis. However, the obtained results for SS are controversial, as discussed in this study. Therapeutic strategies have been reexamined and new options designed and tested to regulate the KP. In the future, the confirmation and application of this concept may help to elucidate the mosaic of SS manifestations. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Review
Interferons and Dry Eye in Sjögren’s Syndrome
Int. J. Mol. Sci. 2018, 19(11), 3548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113548 - 10 Nov 2018
Cited by 14 | Viewed by 2674
Abstract
Various cytokines, including interferon (IFN)-γ and IL-17, are augmented, and autoreactive T cells and B cells are activated in the immune pathogenesis of Sjögren’s syndrome (SS). In particular, IFNs are involved in both the early stages of innate immunity by high level of [...] Read more.
Various cytokines, including interferon (IFN)-γ and IL-17, are augmented, and autoreactive T cells and B cells are activated in the immune pathogenesis of Sjögren’s syndrome (SS). In particular, IFNs are involved in both the early stages of innate immunity by high level of type I IFN in glandular tissue and sera and the later stages of disease progression by type I and type II IFN producing T cells and B cells through B cell activating factor in SS. Genetically modified mouse models for some of these molecules have been reported and will be discussed in this review. New findings from human SS and animal models of SS have elucidated some of the mechanisms underlying SS-related dry eye. We will discuss IFN-γ and several other molecules that represent candidate targets for treating inflammation in SS-related dry eye. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Review
Involvement of Aquaporins in the Pathogenesis, Diagnosis and Treatment of Sjögren’s Syndrome
Int. J. Mol. Sci. 2018, 19(11), 3392; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19113392 - 30 Oct 2018
Cited by 18 | Viewed by 2175
Abstract
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophysiology of SS has not yet been fully deciphered. Classically it has been postulated that sicca symptoms [...] Read more.
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands resulting in diminished production of saliva and tears. The pathophysiology of SS has not yet been fully deciphered. Classically it has been postulated that sicca symptoms in SS patients are a double step process whereby lymphocytic infiltration of lacrimal and salivary glands (SG) is followed by epithelial cell destruction resulting in keratoconjunctivitis sicca and xerostomia. Recent advances in the field of the pathophysiology of SS have brought in new players, such as aquaporins (AQPs) and anti AQPs autoantibodies that could explain underlying mechanistic processes and unveil new pathophysiological pathways offering a deeper understanding of the disease. In this review, we delineate the link between the AQP and SS, focusing on salivary glands, and discuss the role of AQPs in the treatment of SS-induced xerostomia. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Review
Molecular Regulatory Mechanism of Exocytosis in the Salivary Glands
Int. J. Mol. Sci. 2018, 19(10), 3208; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19103208 - 17 Oct 2018
Cited by 6 | Viewed by 2646
Abstract
Every day, salivary glands produce about 0.5 to 1.5 L of saliva, which contains salivary proteins that are essential for oral health. The contents of saliva, 0.3% proteins (1.5 to 4.5 g) in fluid, help prevent oral infections, provide lubrication, aid digestion, and [...] Read more.
Every day, salivary glands produce about 0.5 to 1.5 L of saliva, which contains salivary proteins that are essential for oral health. The contents of saliva, 0.3% proteins (1.5 to 4.5 g) in fluid, help prevent oral infections, provide lubrication, aid digestion, and maintain oral health. Acinar cells in the lobular salivary glands secrete prepackaged secretory granules that contain salivary components such as amylase, mucins, and immunoglobulins. Despite the important physiological functions of salivary proteins, we know very little about the regulatory mechanisms of their secretion via exocytosis, which is a process essential for the secretion of functional proteins, not only in salivary glands, but also in other secretory organs, including lacrimal and mammary glands, the pancreas, and prostate. In this review, we discuss recent findings that elucidate exocytosis by exocrine glands, especially focusing on the salivary glands, in physiological and pathological conditions. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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Review
Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren’s Syndrome
Int. J. Mol. Sci. 2018, 19(8), 2369; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms19082369 - 11 Aug 2018
Cited by 12 | Viewed by 2255
Abstract
The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas [...] Read more.
The pathogenesis of Sjögren’s syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients’ SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor. Full article
(This article belongs to the Special Issue Mechanisms of Disease in Sjögren Syndrome)
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