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1.
Zhongguo Dang Dai Er Ke Za Zhi ; 26(7): 695-700, 2024 Jul 15.
Artigo em Chinês | MEDLINE | ID: mdl-39014945

RESUMO

OBJECTIVES: To study the clinical manifestations, laboratory features, and labial gland pathological features in children with systemic lupus erythematosus (SLE) complicated by Sjögren's syndrome (SS). METHODS: A retrospective analysis was conducted on 102 children with SLE who underwent labial gland biopsies at Renji Hospital, Shanghai Jiao Tong University School of Medicine from January 2013 to December 2022. The children were divided into two groups based on the presence of SS: the SLE with SS group (SLE-SS; 60 children) and the SLE-only group (42 children). According to the focus score (FS) of the labial glands, children in the SLE-SS group were further subdivided into FS≥4 subgroup (26 children) and FS<4 subgroup (34 children). The clinical data of the groups were compared. RESULTS: Compared to the SLE-only group, children in the SLE-SS group had less skin and mucosal involvement, were more likely to have positive anti-SSA and anti-SSB antibodies, and had higher levels of rheumatoid factor (P<0.05). There was no significant difference in treatment protocols between the two groups (P>0.05). Compared to the FS<4 subgroup, the FS≥4 subgroup had more frequent musculoskeletal involvement (P<0.05), but there was no significant difference in SLE disease activity or other major organ involvement between the subgroups (P>0.05). CONCLUSIONS: Children with SLE complicated by SS are less likely to have skin and mucous membrane involvement and exhibit specific serological characteristics. The SLE-SS children with an FS≥4 are more likely to experience musculoskeletal involvement. However, FS is not associated with disease activity or other significant organ damage.


Assuntos
Lúpus Eritematoso Sistêmico , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/patologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Feminino , Masculino , Criança , Estudos Retrospectivos , Adolescente , Anticorpos Antinucleares/sangue , Pré-Escolar , Fator Reumatoide/sangue , Lábio/patologia
2.
Front Immunol ; 15: 1405126, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39050857

RESUMO

Sjögren's Syndrome (SS) is an autoimmune disorder characterized by dysfunction of exocrine glands. Primarily affected are the salivary glands, which exhibit the most frequent pathological changes. The pathogenesis involves susceptibility genes, non-genetic factors such as infections, immune cells-including T and B cells, macrophage, dendritic cells, and salivary gland epithelial cells. Inflammatory mediators such as autoantibodies, cytokines, and chemokines also play a critical role. Key signaling pathways activated include IFN, TLR, BAFF/BAFF-R, PI3K/Akt/mTOR, among others. Comprehensive understanding of these mechanisms is crucial for developing targeted therapeutic interventions. Thus, this study explores the cellular and molecular mechanisms underlying SS-related salivary gland damage, aiming to propose novel targeted therapeutic approaches.


Assuntos
Glândulas Salivares , Transdução de Sinais , Síndrome de Sjogren , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/genética , Síndrome de Sjogren/etiologia , Humanos , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Glândulas Salivares/imunologia , Animais , Citocinas/metabolismo
3.
Clin Exp Med ; 24(1): 163, 2024 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-39039306

RESUMO

Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disorder wherein CD4+ T cells play a pivotal role in its pathogenesis. However, the underlying mechanisms driving the hyperactivity of CD4+ T cells in pSS remain poorly understood. This study aimed to investigate the potential role of immunometabolic alterations in driving the hyperactivity of CD4+ T cells in pSS. We employed Seahorse XF assay to evaluate the metabolic phenotype of CD4+ T cells, conducted flow cytometry to assess the effector function and differentiation of CD4+ T cells and measured the level of intracellular reactive oxygen species (ROS). Additionally, transcriptome sequencing, PCR, and Western blotting were utilized to examine the expression of glycolytic genes. Our investigation revealed that activated CD4+ T cells from pSS patients exhibited elevated aerobic glycolysis, rather than oxidative phosphorylation, resulting in excessive production of IFN-γ and IL-17A. Inhibition of glycolysis by 2-Deoxy-D-glucose reduced the expression of IFN-γ and IL-17A in activated CD4+ T cells and mitigated the differentiation of Th1 and Th17 cells. Furthermore, the expression of glycolytic genes, including CD3E, CD28, PIK3CA, AKT1, mTOR, MYC, LDHA, PFKL, PFKFB3, and PFKFB4, was upregulated in activated CD4+ T cells from pSS patients. Specifically, the expression and activity of LDHA were enhanced, contributing to an increased level of intracellular ROS. Targeting LDHA with FX-11 or inhibiting ROS with N-acetyl-cysteine had a similar effect on reversing the dysfunction of activated CD4+ T cells from pSS patients. Our study unveils heightened aerobic glycolysis in activated CD4+ T cells from pSS patients, and inhibition of glycolysis or its metabolite normalizes the dysfunction of activated CD4+ T cells. These findings suggest that aerobic glycolysis may be a promising therapeutic target for the treatment of pSS.


Assuntos
Linfócitos T CD4-Positivos , Glicólise , Espécies Reativas de Oxigênio , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Células Th17/imunologia , Diferenciação Celular , Interferon gama/metabolismo , Interleucina-17/metabolismo , Células Th1/imunologia
4.
Head Neck Pathol ; 18(1): 64, 2024 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-38958850

RESUMO

PURPOSE: There are a number of diagnostic criteria that can be used to support a diagnosis of Sjögren's syndrome (SS), a chronic autoimmune condition often characterised by xerostomia and xerophthalmia. Of the available investigations, the most invasive is the labial gland biopsy (LGB) for histopathology, which is associated with a risk of long-term altered sensation to the lip. A positive histological diagnosis is currently considered to be one of the most objective criteria, however there is debate about the interobserver agreement between pathologists, as well as the sensitivity and specificity of this test. We aim to determine if the diagnostic value of the LGB is significant enough to warrant the surgical procedure and its associated risks. METHODS: This study involved assessing the degree of agreement between members of a pathology team for a cohort of 50 LGBs taken for the purpose of confirming or excluding SS. The Tarpley system was used, which involves the allocation of a 'focus score'. Additionally, the histological diagnoses were compared to the relevant serological findings where available. RESULTS: All cases within the cohort had adequate tissue for assessment. 84% agreement (Cohen's Kappa = 0.585) was seen between the current team's consensus and the original reporting pathologist on whether the appearance was supportive of SS. However, only 58% agreement was seen for focus scores (Weighted Kappa = 0.496). The agreement between the serology result and whether the histology was supportive of SS was 79% (Cohen's Kappa = 0.493). CONCLUSION: The findings raise the possibility that undue emphasis is placed on the value of a histological SS diagnosis. The current system for assessing and grading these biopsies is ambiguous in nature, with a low threshold considered indicative of SS. Due to the risk of complications associated with a LGB, alternative minimally invasive investigations should always be considered. The histological findings in isolation, particularly when a low focus score is seen, may not be predictive of a diagnosis of SS.


Assuntos
Glândulas Salivares Menores , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia , Biópsia , Glândulas Salivares Menores/patologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Masculino , Sensibilidade e Especificidade
5.
Eur J Med Res ; 29(1): 371, 2024 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-39014509

RESUMO

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disease primarily affecting exocrine glands such as the salivary glands, leading to impaired secretion and sicca symptoms. As the mainstay of salivation, salivary gland epithelial cells (SGECs) have an important role in the pathology of pSS. Emerging evidence suggests that the interplay between immunological factors and SGECs may not be the initial trigger or the sole mechanism responsible for xerostomia in pSS, challenging conventional perceptions. To deepen our understanding, current research regarding SGECs in pSS was reviewed. Among the extensive aberrations in cellular architecture and function, this review highlighted certain alterations of SGECs that were identified to occur independently of or in absence of lymphocytic infiltration. In particular, some of these alterations may serve as upstream factors of immuno-inflammatory responses. These findings underscore the significance of introspecting the pathogenesis of pSS and developing interventions targeting SGECs in the early stages of the disease.


Assuntos
Células Epiteliais , Glândulas Salivares , Síndrome de Sjogren , Síndrome de Sjogren/patologia , Síndrome de Sjogren/imunologia , Humanos , Células Epiteliais/patologia , Glândulas Salivares/patologia
6.
Sci Rep ; 14(1): 17256, 2024 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-39060324

RESUMO

Sjögren syndrome (SS) is an autoimmune disease characterized by chronic inflammatory infiltrates in the salivary and lacrimal glands. Mucosal-associated invariant T (MAIT) cells are a subset of innate-like T-cells, predominantly found in mucosal tissues with crucial role in epithelial homeostasis. Thus, MAIT cells may be implicated in mucosal alterations of SS patients. Activation markers, inflammatory and cytotoxic cytokines were examined in 23 SS patients and compared to 23 healthy controls (HC). Tissular MAIT cells in salivary gland (SG) biopsies were also analyzed. Circulating MAIT cells were decreased in SS patients with a higher expression of CD69 and a higher CD4/CD8 ratio of MAIT cells. MAIT cells showed a higher production of IFNγ, TNFα and GzB in SS compare to HC. Tissular MAIT cells were present within inflamed SG of SS patients, while they were absent in SG of HC. Overall, circulating MAIT cells are decreased in the peripheral blood of SS albeit producing higher amounts of IFNγ, TNFα, and GzB. Tissular MAIT cells are detected in salivary glands from SS with a proinflammatory tissular cytokine environment. MAIT cells with abnormal phenotype, functions and tissular homeostasis may contribute to epithelial damage in SS.


Assuntos
Células T Invariantes Associadas à Mucosa , Glândulas Salivares , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Células T Invariantes Associadas à Mucosa/imunologia , Células T Invariantes Associadas à Mucosa/metabolismo , Feminino , Pessoa de Meia-Idade , Masculino , Glândulas Salivares/patologia , Glândulas Salivares/imunologia , Glândulas Salivares/metabolismo , Adulto , Citocinas/metabolismo , Idoso , Estudos de Casos e Controles
7.
Clin Exp Med ; 24(1): 133, 2024 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-38900301

RESUMO

This study aimed to investigate the serum and expression levels of C-X-C motif chemokine ligand 9 (CXCL9), CXCL10, CXCL11, and CXC receptor 3 (CXCR3) in minor salivary glands (MSGs) of patients with primary Sjögren's syndrome (pSS), and to explore their correlations with clinical parameters. Serum samples from 49 patients diagnosed with pSS, 33 patients with rheumatoid arthritis (RA), and 30 healthy controls (HCs) were collected for measurements of CXCL9, CXCL10, CXCL11, and CXCR3. Additionally, CXCL levels in the MSG tissues were measured in 41 patients who underwent MSG biopsy. Correlations between CXCL and CXCL/CXCR levels in serum/MSG tissues and clinical factors/salivary scintigraphy parameters were analyzed. Serum CXCL11 and CXCR3 showed statistically significant differences among patients with pSS and RA and HCs (serum CXCL11, pSS:RA:HC = 235.6 ± 500.1 pg/mL:90.0 ± 200.3 pg/mL:45.9 ± 53.6 pg/mL; p = 0.041, serum CXCR3, pSS:RA:HC = 3.27 ± 1.32 ng/mL:3.29 ± 1.17 ng/mL:2.00 ± 1.12 ng/mL; p < 0.001). Serum CXCL10 showed a statistically significant difference between pSS (64.5 ± 54.2 pg/mL) and HCs (18.6 ± 18.1 pg/mL, p < 0.001), while serum CXCL9 did not exhibit a significant difference among the groups. Correlation analysis of clinical factors revealed that serum CXCL10 and CXCL11 levels positively correlated with erythrocyte sedimentation rate (r = 0.524, p < 0.001 and r = 0.707, p < 0.001, respectively), total protein (r = 0.375, p = 0.008 and r = 0.535, p < 0.001, respectively), globulin (r = 0.539, p < 0.001 and r = 0.639, p < 0.001, respectively), and European Alliance of Associations for Rheumatology SS Disease Activity Index (r = 0.305, p = 0.033 and r = 0.321, p = 0.025). Additionally, serum CXCL10 negatively correlated with the Schirmer test score (r = - 0.354, p = 0.05), while serum CXCL11 positively correlated with the biopsy focus score (r = 0.612, p = 0.02). In the MSG tissue, the percentage of infiltrating CXCL9-positive cells was highest (75.5%), followed by CXCL10 (29.1%) and CXCL11 (27.9%). In the correlation analysis, CXCL11-expressing cells were inversely related to the mean washout percentage on salivary gland scintigraphy (r = - 0.448, p = 0.007). Our study highlights distinct serum and tissue chemokine patterns in pSS, emphasizing CXCL9's potential for early diagnosis. This suggests that CXCL10 and CXCL11 are indicators of disease progression, warranting further investigation into their roles in autoimmune disorders beyond pSS.


Assuntos
Quimiocina CXCL10 , Quimiocina CXCL11 , Receptores CXCR3 , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/patologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/metabolismo , Feminino , Pessoa de Meia-Idade , Masculino , Receptores CXCR3/metabolismo , Adulto , Quimiocina CXCL11/sangue , Quimiocina CXCL10/sangue , Idoso , Glândulas Salivares Menores/patologia , Glândulas Salivares Menores/metabolismo , Quimiocina CXCL9/sangue , Soro/química , Soro/metabolismo
8.
Arch Biochem Biophys ; 758: 110063, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38880321

RESUMO

To investigate the potential molecular mechanism of miR-34a in Sjögren's syndrome (SS). Transmission electron microscopy was used to observe the salivary gland tissues of mild and severe SS patients. SS mouse model was constructed and injected with miR-34a antagonist. HSGE cells were transfected with miR-34a mimic. Starbase predicted miR-34a binding sites and validated them with dual-luciferase reporter assays. Immunohistochemistry, HE staining, CCK-8, TUNEL assay, flow cytometry, immunofluorescence and Western Blot were used to investigate the effects of miR-34a on NF-κB signaling and mitochondrial pathway of apoptosis in HSGE cells. Severe SS patients showed obvious mitochondrial damage and apoptosis in salivary glands. MiR-34a was overexpressed and NF-κB signaling is activated in salivary glands of severe SS patients. Inhibition of miR-34a alleviated salivary gland injury in SS mice, as well as inhibited the activation of NF-κB signaling and mitochondrial pathway of apoptosis. In conclusion, miR-34a promoted NF-κB signaling by targeting IκBα, thereby causing mitochondrial pathway apoptosis and aggravating SS-induced salivary gland damage.


Assuntos
Apoptose , Células Epiteliais , MicroRNAs , Mitocôndrias , NF-kappa B , Glândulas Salivares , Transdução de Sinais , Síndrome de Sjogren , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Animais , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Camundongos , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/genética , Síndrome de Sjogren/patologia , Feminino , Linhagem Celular , Masculino , Pessoa de Meia-Idade
9.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892170

RESUMO

Elevated oxidative stress can play a pivotal role in autoimmune diseases by exacerbating inflammatory responses and tissue damage. In Sjögren's disease (SjD), the contribution of oxidative stress in the disease pathogenesis remains unclear. To address this question, we created mice with a tamoxifen-inducible conditional knockout (KO) of a critical antioxidant enzyme, superoxide dismutase 2 (Sod2), in the salivary glands (i-sg-Sod2 KO mice). Following tamoxifen treatment, Sod2 deletion occurred primarily in the ductal epithelium, and the salivary glands showed a significant downregulation of Sod2 expression. At twelve weeks post-treatment, salivary glands from the i-sg-Sod2 KO mice exhibited increased 3-Nitrotyrosine staining. Bulk RNA-seq revealed alterations in gene expression pathways related to ribosome biogenesis, mitochondrial function, and oxidative phosphorylation. Significant changes were noted in genes characteristic of salivary gland ionocytes. The i-sg-Sod2 KO mice developed reversible glandular hypofunction. However, this functional loss was not accompanied by glandular lymphocytic foci or circulating anti-nuclear antibodies. These data demonstrate that although localized oxidative stress in salivary gland ductal cells was insufficient for SjD development, it induced glandular dysfunction. The i-sg-Sod2 KO mouse resembles patients classified as non-Sjögren's sicca and will be a valuable model for deciphering oxidative-stress-mediated glandular dysfunction and recovery mechanisms.


Assuntos
Células Epiteliais , Camundongos Knockout , Mitocôndrias , Estresse Oxidativo , Glândulas Salivares , Síndrome de Sjogren , Superóxido Dismutase , Animais , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Síndrome de Sjogren/genética , Camundongos , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Mitocôndrias/metabolismo , Modelos Animais de Doenças
10.
Int Immunopharmacol ; 135: 112274, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38772301

RESUMO

OBJECTIVE: The current treatment and mechanism of Sjogren's syndrome (SS) are unclear. The purpose of the present study was to potential molecular mechanisms of SS. METHODS: Immunohistochemical and immunofluorescence techniques reveal the targets and therapeutic approaches of SS. RESULTS: We found through molecular biology techniques such as immunoblotting and immunoprecipitation that USP5 is a novel regulator of NLRP3 involvement in the pathological process of SS. USP5 was significantly downregulated in submandibular gland tissue of SS. Meanwhile, it was found that USP5 is a negative regulator of NLRP3 via ubiquitination NLRP3. In addition, SalvianolicacidB (SaB), a natural USP5 agonist, can alleviate ss by regulating the USP5/NLRP3 signaling pathway. CONCLUSION: Therefore, this study provides a new mechanism for SS and also provides new therapeutic targets for treating SS.


Assuntos
Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Síndrome de Sjogren , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Humanos , Inflamassomos/metabolismo , Feminino , Glândula Submandibular/patologia , Glândula Submandibular/metabolismo , Ubiquitinação , Transdução de Sinais , Camundongos , Proteases Específicas de Ubiquitina/metabolismo , Proteases Específicas de Ubiquitina/genética , Camundongos Endogâmicos C57BL , Masculino
11.
J Neurol ; 271(7): 4610-4619, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38743089

RESUMO

BACKGROUND: While retinal vessel changes are evident in the eyes of patients with relapsing-remitting multiple sclerosis (RRMS), changes in the vasculature of possible MS mimics such as primary Sjögren's syndrome (pSS) remain to be determined. We investigated the potential of retinal optical coherence tomography (OCT) angiography (OCTA) as diagnostic tool to differentiate between patients with RRMS and pSS. METHODS: This cross-sectional study included patients with RRMS (n = 36), pSS (n = 36) and healthy controls (n = 30). Participants underwent clinical examination, assessment of visual acuity, retinal OCT, OCTA, and serum markers of glial and neuronal damage. We investigated the associations between OCTA parameters, visual functions, and serum markers. Eyes with a history of optic neuritis (ON) were excluded from analysis. RESULTS: We observed a significant thinning of the combined ganglion cell and inner plexiform layer in the eyes of patients with RRMS but not with pSS, when compared to healthy controls. Retinal vessel densities of the superficial vascular complex (SVC) were reduced in both patients with RRMS and pSS. However, retinal vessel rarefication of the deep vascular complex (DVC) was only evident in patients with pSS but not RRMS. Using multivariate regression analysis, we found that DVC vessel loss in pSS patients was associated with worse visual acuity. CONCLUSIONS: Compared to patients with RRMS, rarefication of deep retinal vessels is a unique characteristic of pSS and associated with worse visual function. Assuming a disease-specific retinal vessel pathology, these data are indicative of a differential affliction of the gliovascular complex in the retina of RRMS and pSS patients.


Assuntos
Síndrome de Sjogren , Tomografia de Coerência Óptica , Humanos , Feminino , Masculino , Estudos Transversais , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/complicações , Síndrome de Sjogren/patologia , Pessoa de Meia-Idade , Adulto , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/fisiopatologia , Esclerose Múltipla Recidivante-Remitente/patologia , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Retina/diagnóstico por imagem , Retina/patologia , Doenças Retinianas/diagnóstico por imagem , Doenças Retinianas/etiologia , Acuidade Visual/fisiologia
12.
Int J Mol Sci ; 25(9)2024 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-38732189

RESUMO

Sjögren's Disease (SjD) is an autoimmune disease of the exocrine tissues. Etiological events result in the loss of epithelial homeostasis alongside extracellular matrix (ECM) destruction within the salivary and lacrimal glands, followed by immune cell infiltration. In this review, we have assessed the current understanding of epithelial-mesenchymal transition (EMT)-associated changes within the salivary epithelium potentially involved in salivary dysfunction and SjD pathogenesis. We performed a PubMed literature review pertaining to the determination of pathogenic events that lead to EMT-related epithelial dysfunction and signaling in SjD. Molecular patterns of epithelial dysfunction in SjD salivary glands share commonalities with EMT mediating wound healing. Pathological changes altering salivary gland integrity and function may precede direct immune involvement while perpetuating MMP9-mediated ECM destruction, inflammatory mediator expression, and eventual immune cell infiltration. Dysregulation of EMT-associated factors is present in the salivary epithelium of SjD and may be significant in initiating and perpetuating the disease. In this review, we further highlight the gap regarding mechanisms that drive epithelial dysfunction in salivary glands in the early or subclinical pre-lymphocytic infiltration stages of SjD.


Assuntos
Transição Epitelial-Mesenquimal , Glândulas Salivares , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/patologia , Síndrome de Sjogren/metabolismo , Glândulas Salivares/patologia , Glândulas Salivares/metabolismo , Animais , Epitélio/patologia , Epitélio/metabolismo , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Transdução de Sinais , Matriz Extracelular/metabolismo
13.
Arthritis Res Ther ; 26(1): 101, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745331

RESUMO

BACKGROUND: The purpose of this study was to investigate the role of macrophage polarization in the pathogenesis of primary Sjogren's syndrome (pSS). METHODS: Peripheral venous blood samples were collected from 30 patients with pSS and 30 healthy controls. Minor salivary gland samples were abtainted from 10 of these patients and 10 non-pSS controls whose minor salivary gland didn't fulfill the classification criteria for pSS. Enzyme-linked immuno sorbent assay was used to examine the serum concentration of M1/M2 macrophage related cytokines (TNF-a, IL-6, IL-23, IL-4, IL-10 and TGF-ß). Flow cytometry was used to examine the numbers of CD86+ M1 macrophages and CD206+ M2 macrophages in peripheral blood mononuclear cells (PBMCs). Immunofluorescence was used to test the infiltration of macrophages in minor salivary glands. RESULTS: This study observed a significant increase in pSS patients both in the numbers of M1 macrophages in peripheral blood and serum levels of M1-related pro-inflammatory cytokines (IL-6, IL-23 and TNF-α). Conversely, M2 macrophages were downregulated in the peripheral blood of pSS patients. Similarly, in the minor salivary glands of pSS patients, the expression of M1 macrophages was increased, and that of M2 macrophages was decreased. Furthermore, a significantly positive correlation was found between the proportions of M1 macrophages in PBMCs and serum levels of IgG and RF. CONCLUSIONS: This study reveals the presence of an significant imbalance in M1/M2 macrophages in pSS patients. The M1 polarization of macrophages may play an central role in the pathogenesis of pSS.


Assuntos
Citocinas , Macrófagos , Síndrome de Sjogren , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/sangue , Síndrome de Sjogren/patologia , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Feminino , Pessoa de Meia-Idade , Citocinas/sangue , Citocinas/metabolismo , Masculino , Adulto , Citometria de Fluxo , Idoso , Polaridade Celular , Ensaio de Imunoadsorção Enzimática , Ativação de Macrófagos/imunologia , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/imunologia
14.
Clin Exp Med ; 24(1): 96, 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38717644

RESUMO

Primary Sjögren's Syndrome (pSS) falls within the category of connective tissue diseases, characterized by the presence of autoantibodies such as antinuclear antibodies (ANA). However, according to the classification criteria for pSS, some patients may exhibit a negative result for autoantibodies. Patients with a negative result for autoantibodies may lack typical features of connective tissue diseases, and the immunological state as well as the extent of organ involvement and damage may differ from those with positive autoantibodies. This study aims to compare the clinical phenotypes of patients with positive and negative autoantibodies, providing insights for disease classification and treatment selection for clinicians. Patients with pSS were grouped based on the presence and titers of their autoantibodies. Subsequently, differences in organ damage and laboratory indicators were compared between these groups, aiming to analyze the value of autoantibody titers in assessing the condition of pSS. (1) Patients with positive ANA exhibited elevated levels of inflammatory indicators, including ESR, IgG levels, lip gland biopsy pathology grade, and overall organ involvement, in comparison with patients with negative ANA (P < 0.05). Furthermore, ANA-positivity correlated with a higher occurrence of multi-organ damage, particularly affecting the skin, mucous membranes, and the hematological system (P < 0.05). (2) As ANA titers increased, patients demonstrated elevated levels of IgG and an escalation in organ involvement (P < 0.05). (3) Patients in the positive autoantibody group (positive for antinuclear antibodies, anti-SSA, or anti-SSB antibodies) had higher IgG levels compared to the negative group (P < 0.05). (4) Patients with positive anti-SSA and anti-SSB antibodies exhibited higher levels of inflammatory indicators and IgG compared to other patients (P < 0.05); however, no significant differences were observed in terms of organ involvement and organ damage. Patients with positive ANA in pSS typically exhibit higher levels of inflammation and an increased likelihood of experiencing multi-organ damage. Furthermore, as the ANA titers increase, both inflammation levels and the risk of multi-organ damage also escalate. Additionally, the presence of anti-SSA and anti-SSB antibodies may contribute to an elevated risk of increased inflammation levels, but does not increase the risk of organ damage.


Assuntos
Anticorpos Antinucleares , Síndrome de Sjogren , Humanos , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/imunologia , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Síndrome de Sjogren/sangue , Feminino , Pessoa de Meia-Idade , Masculino , Adulto , Idoso , Inflamação/imunologia , Inflamação/patologia , Imunoglobulina G/sangue
15.
J Rheumatol ; 51(7): 687-695, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38561184

RESUMO

OBJECTIVE: Vaginal dryness is an important factor influencing sexual function in women with primary Sjögren syndrome (pSS). Previous studies showed a higher degree of inflammation in vaginal biopsies from patients with pSS compared to non-pSS controls. However, the molecular pathways that drive this inflammation remain unclear. Therefore, the aim of this study was to investigate inflammatory pathway activity in the vaginal tissue of patients with pSS. METHODS: Vaginal biopsies of 8 premenopausal patients with pSS experiencing vaginal dryness and 7 age-matched non-pSS controls were included. Expression of genes involved in inflammation and tissue homeostasis was measured using NanoString technology and validated using TaqMan Real-Time PCR. Vaginal tissue sections were stained by immunohistochemistry for myxovirus resistance protein 1 (MxA) and CD123 (plasmacytoid dendritic cells [pDCs]). RESULTS: The most enriched pathway in vaginal biopsies from patients with pSS compared to non-pSS controls was the interferon (IFN) signaling pathway (P < 0.01). Pathway scores for Janus kinase and signal transducer and activator of transcription (JAK-STAT) and Notch signaling were also higher (P < 0.01 for both pathways). Conversely, transforming growth factor-ß signaling and angiogenesis pathway scores were lower in pSS (P = 0.02 and P = 0.04, respectively). Differences in IFN signaling between patients with pSS and non-pSS controls were confirmed by PCR and MxA tissue staining. No CD123+ pDCs were detected in vaginal biopsies. IFN-stimulated gene expression levels correlated positively with CD45+ cell numbers in vaginal biopsies and serum anti-SSA/Ro positivity. CONCLUSION: Upregulation of IFN signaling in vaginal tissue of women with pSS, along with its association with tissue pathology, suggests that IFNs contribute to inflammation of the vaginal wall and potentially also to clinical symptomatology (ie, vaginal dryness).


Assuntos
Interferons , Transdução de Sinais , Síndrome de Sjogren , Vagina , Humanos , Feminino , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/patologia , Vagina/patologia , Vagina/imunologia , Vagina/metabolismo , Adulto , Pessoa de Meia-Idade , Interferons/metabolismo , Proteínas de Resistência a Myxovirus/genética , Proteínas de Resistência a Myxovirus/metabolismo , Biópsia , Doenças Vaginais/metabolismo , Doenças Vaginais/patologia , Doenças Vaginais/imunologia
16.
Zhonghua Jie He He Hu Xi Za Zhi ; 47(4): 346-351, 2024 Apr 12.
Artigo em Chinês | MEDLINE | ID: mdl-38599810

RESUMO

A 58-year-old woman presented with a six-month history of nasal congestion, sore throat and cough, and a five-month history of dyspnea. She had a history of xerostomia for one year. On examination, the bilateral submandibular gland and parotid glands were enlarged. Parotid and anterior cervical lymph nodes were palpable. There were rales in both lungs. The rest of the physical examination was unremarkable. Sialographic analysis showed normal caliber in the main duct, stenosis in secondary ducts, and dilation in the proximal ducts. Minor salivary gland biopsy demonstrated periductal lymphocytic infiltration. Chest computed tomography (CT) showed diffuse thickening of the tracheal and bilateral bronchial walls. Bronchoscopy revealed macroscopic multiple nodules mainly in the trachea and bilateral main bronchus. Endobronchial biopsy showed lymphocytic infiltration in the bronchial submucosa. She was diagnosed with Sjögren's syndrome and treated with glucocorticoids. The dose of prednisone was started at 30 mg/d and tapered gradually. Following treatment, the patient's clinical condition improved dramatically, with shrinkage of the enlarged lymph nodes, bilateral submandibular and parotid glands. A repeated chest CT scan revealed improvement of the tracheal and bilateral bronchial thickening. Multiple nodules in the airway regressed, as evidenced by repeated bronchoscopic examination. The final diagnosis was a large-airway disease associated with Sjögren's syndrome.Among airway diseases in Sjögren's syndrome, peripheral airway diseases including bronchiolitis and bronchiectasis are common; however, central airway lesions in Sjögren's syndrome, especially with macroscopic nodules, are rare. In this case, we demonstrated tracheal and endobronchial nodules in Sjögren's syndrome as determined by clinical features, CT scan, bronchoscopy, and response to therapy.


Assuntos
Síndrome de Sjogren , Feminino , Humanos , Pessoa de Meia-Idade , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/patologia , Traqueia/patologia , Glândula Parótida/patologia , Pulmão/patologia , Brônquios/patologia
17.
Clin Rheumatol ; 43(5): 1683-1692, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38568436

RESUMO

To identify the value of salivary gland ultrasound (SGUS) combined with magnetic resonance imaging (MRI) and magnetic resonance sialography (MRS) in predicting the results of labial salivary gland biopsy (LSGB) in patients with suspected primary Sjögren syndrome (pSS), and construct a nomogram model to predict LSGB results. A total of 181 patients who were admitted with suspected pSS from December 2018 to April 2023 were examined and divided into a training set (n = 120) and a validation set (n = 61). Baseline data of the two groups were examined, and the value of SGUS, MRI, and MRS in predicting LSGB was analyzed. Multivariate logistic analysis was used to screen for risk factors, and nomogram prediction models were constructed using these results. In the training set, the SGUS, MRI, and MRS scores of patients in the LSGB + group were higher than those in the LSGB - group (all P < 0.001). The positive prediction value (PPV) was 91% for an SGUS score of 3, and 82% for MRI and MRS scores of 2 or more. We developed a nomogram prediction model based on SGUS, MRI, and MRS data, and it had a concordance index (C-index) of 0.94. The Hosmer-Lemeshow test (χ2 = 3.17, P = 0.92) also indicated the nomogram prediction model had good accuracy and calibration for prediction of LSGB results. A nomogram model based on SGUS, MRI, and MRS results can help rheumatologists decide whether LSGB should be performed in patients with suspected pSS.


Assuntos
Síndrome de Sjogren , Humanos , Síndrome de Sjogren/diagnóstico por imagem , Síndrome de Sjogren/patologia , Glândulas Salivares/diagnóstico por imagem , Glândulas Salivares/patologia , Biópsia , Glândulas Salivares Menores/diagnóstico por imagem , Glândulas Salivares Menores/patologia , Ultrassonografia/métodos
18.
DNA Cell Biol ; 43(5): 207-218, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38635961

RESUMO

Sjogren's syndrome (SS) is a complex systemic autoimmune disease. This study aims to elucidate a humanized NOD-PrkdcscidIl2rgem1/Smoc (NSG) murine model to better clarify the pathogenesis of SS. NSG female mice were adoptively transferred with 10 million peripheral blood mononuclear cells (PBMCs) through the tail vein from healthy controls (HCs), primary Sjogren's syndrome (pSS), and systemic lupus erythematosus (SLE) patients on D0. The mice were subcutaneously injected with C57/B6j submandibular gland (SG) protein or phosphate-buffered saline on D3, D17 and D31, respectively. NSG mice were successfully transplanted with human PBMCs. Compared with NSG-HC group, NSG-pSS and NSG-SLE mice exhibited a large number of lymphocytes infiltration in the SG, decreased salivary flow rate, lung involvement, decreased expression of genes related to salivary secretion, and the production of autoantibodies. Type I interferon-related genes were increased in the SG of NSG-pSS and NSG-SLE mice. The ratio of BAX/BCL2, BAX, cleaved caspase3, and TUNEL staining were increased in the SG of NSG-pSS and NSG-SLE mice. The expressions of p-MLKL and p-RIPK3 were increased in the SG of NSG-pSS and NSG-SLE mice. Increased expression of type I interferon-related genes, PANoptosis (apoptosis and necroptosis) were identified in the SG of this typical humanized NSG murine model of SS.


Assuntos
Modelos Animais de Doenças , Camundongos Endogâmicos NOD , Síndrome de Sjogren , Síndrome de Sjogren/patologia , Síndrome de Sjogren/imunologia , Animais , Humanos , Feminino , Camundongos , Apoptose , Leucócitos Mononucleares/metabolismo , Leucócitos Mononucleares/transplante , Glândula Submandibular/patologia , Glândula Submandibular/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/imunologia , Camundongos Endogâmicos C57BL , Autoanticorpos/imunologia , Interferon Tipo I/metabolismo
19.
Free Radic Biol Med ; 218: 1-15, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38574973

RESUMO

Sjogren's syndrome (SS) is an autoimmune disease characterized by dysfunction of exocrine glands, such as salivary glands. However, the molecular mechanism of salivary secretion dysfunction in SS is still unclear. Given the significance of glutathione peroxidase 4 (GPX4) in cellular redox homeostasis, we hypothesized that dysregulation of GPX4 may play a pivotal role in the pathogenesis of salivary secretion dysfunction observed in SS. The salivary gland of SS patients and the SS mouse model exhibited reduced expression of the ferroptosis inhibitor GPX4 and the important protein aquaporin 5 (AQP5), which is involved in salivary secretion. GPX4 overexpression upregulated and GPX4 knockdown downregulated AQP5 expression in salivary gland epithelial cells (SGECs) and salivary secretion. Bioinformatics analysis of GSE databases from SS patients' salivary glands revealed STAT4 as a key intermediary regulator between GPX4 and AQP5. A higher level of nuclear pSTAT4 was observed in the salivary gland of the SS mouse model. GPX4 overexpression inhibited and GPX4 knockdown promoted STAT4 phosphorylation and nuclear translocation in SGECs. CHIP assay confirmed the binding of pSTAT4 within the promoter of AQP5 inhibiting AQP5 transcription. GPX4 downregulation accumulates intracellular lipid ROS in SGECs. Lipid ROS inhibitor ferrostatin-1 treatment during in vitro and in vivo studies confirmed that lipid ROS activates STAT4 phosphorylation and nuclear translocation in SGECs. In summary, the downregulated GPX4 in SGECs contributes to salivary secretion dysfunction in SS via the lipid ROS/pSTAT4/AQP5 axis. This study unraveled novel targets to revitalize the salivary secretion function in SS patients.


Assuntos
Aquaporina 5 , Células Epiteliais , Fosfolipídeo Hidroperóxido Glutationa Peroxidase , Espécies Reativas de Oxigênio , Fator de Transcrição STAT4 , Glândulas Salivares , Síndrome de Sjogren , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/genética , Síndrome de Sjogren/patologia , Animais , Humanos , Camundongos , Glândulas Salivares/metabolismo , Glândulas Salivares/patologia , Aquaporina 5/metabolismo , Aquaporina 5/genética , Células Epiteliais/metabolismo , Células Epiteliais/patologia , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/genética , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT4/metabolismo , Fator de Transcrição STAT4/genética , Modelos Animais de Doenças , Feminino , Regulação para Baixo , Masculino , Transdução de Sinais , Regulação da Expressão Gênica , Ferroptose/genética , Saliva/metabolismo , Pessoa de Meia-Idade
20.
In Vitro Cell Dev Biol Anim ; 60(4): 411-419, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38587579

RESUMO

Sjogren's syndrome (SS) is an autoimmune disease. Its mechanism and treatment methods are unclear. The purpose of this study was to investigate the effects of rutin (Ru) on SS. Proteomics was used to detect differential proteins in the submandibular glands of normal mice and SS mice. Salivary secretion (SAS) and salivary gland index (SGI) were detected. Oxidative stress and inflammatory cytokine in submandibular glands were detected. The levels of NLRP3, ASC, Caspase-1, IL-1ß, and p-NF-κBp65 in submandibular gland tissues and submandibular gland cells of overexpressed calcium-sensing receptor (over-CaR) mice and overexpressed CaR primary submandibular gland cells (over-CaR-PSGs) were detected. In total, 327 differential proteins were identified in the submandibular gland tissues of SS mice compared to control mice. CaR was one of the most differential proteins and significantly increased compared to control mice. Ru could significantly increase SGI and SGI, and inhibit oxidative stress and inflammatory cytokine in submandibular glands. In addition, Ru was shown to further improve SS via regulation of the CaR/NOD-like receptor thermal protein domain associated protein 3 (NLRP3)/nuclear factor kappa-B (NF-κB) signal pathway. Overexpression of CaR counteracted partial activity of Ru. CaR may be an important target for the treatment of SS. In addition, Ru improved the SS via the CaR/NLRP3/NF-κB signal pathway. This study provides a basis for the treatments for SS.


Assuntos
NF-kappa B , Proteína 3 que Contém Domínio de Pirina da Família NLR , Estresse Oxidativo , Rutina , Transdução de Sinais , Síndrome de Sjogren , Glândula Submandibular , Animais , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/metabolismo , Síndrome de Sjogren/patologia , Transdução de Sinais/efeitos dos fármacos , NF-kappa B/metabolismo , Rutina/farmacologia , Rutina/uso terapêutico , Camundongos , Glândula Submandibular/metabolismo , Glândula Submandibular/efeitos dos fármacos , Glândula Submandibular/patologia , Estresse Oxidativo/efeitos dos fármacos , Feminino , Citocinas/metabolismo , Camundongos Endogâmicos C57BL
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