|
1
|
Gong Y, Xu R, Gao G, Li S, Liu Y. The role of fatty acid metabolism on B cells and B cell-related autoimmune diseases. Inflamm Res 2025; 74:75. [PMID: 40299047 DOI: 10.1007/s00011-025-02042-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 04/08/2025] [Accepted: 04/15/2025] [Indexed: 04/30/2025] Open
Abstract
Fatty acid metabolism plays a critical role in regulating immune cell function, including B cells, which are central to humoral immunity and the pathogenesis of autoimmune diseases. Emerging evidence suggests that fatty acid metabolism influences B cell development, activation, differentiation, and antibody production, thereby impacting B cell-related autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS). In this review, we discuss the mechanisms by which fatty acid metabolism modulates B cell biology, including energy provision, membrane composition, and signaling pathways. We highlight how alterations in fatty acid synthesis, oxidation, and uptake affect B cell function and contribute to autoimmune pathogenesis. Additionally, we explore the therapeutic potential of targeting fatty acid metabolism in B cells to treat autoimmune diseases. Understanding the interplay between fatty acid metabolism and B cell immunity may provide novel insights into the development of precision therapies for B cell-mediated autoimmune disorders.
Collapse
Affiliation(s)
- Yanmei Gong
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Ruiqi Xu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Guohui Gao
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Simiao Li
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China
| | - Ying Liu
- Department of Neurology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Institute of Neuroimmunology, Jinan, Shandong, China.
- Shandong Institute of Neuroimmunology, Jinan, 250014, People's Republic of China, China.
- Shandong Provincial Medicine and Health Key Laboratory of Neuroimmunology, Jinan, Shandong, China.
| |
Collapse
|
|
2
|
Zhang K, Luo Z, Yao X, Lu D, Hong T, Zhu X, Chen M, Wang X. Identification of Epigenetic Alteration of the IFI44L Gene in B Cells of Sjogren's Syndrome as a Clinical Biomarker and Molecular Significance. J Inflamm Res 2025; 18:2499-2512. [PMID: 39991660 PMCID: PMC11847453 DOI: 10.2147/jir.s503309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 02/05/2025] [Indexed: 02/25/2025] Open
Abstract
Objective Type 1 interferon (IFN-I)-related genes play a critical role in Sjögren's syndrome (SS). However, study on its role and impact in peripheral blood B cells of SS is limited. This study investigated gene expression and epigenetic changes in IFI44L, analyzing its correlation with disease activity and clinical indicators. Methods Differentially expressed genes (DEGs) were identified from the GSE199868 dataset, while IFN-I-related genes were collected from GeneCards. Intersection analysis revealed IFN-I-related DEGs in SS. ClueGO, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, PPI network construction, and hub gene identification were conducted, with hub genes validated in GSE135809. Following this, we recruited 30 SS patients as the disease group and 11 healthy individuals as the control group. Clinical information and peripheral blood samples were collected from all participants. After isolating B cells from the peripheral blood, we used quantitative real-time polymerase chain reaction (RT-qPCR) and pyrosequencing to examine the mRNA expression and DNA methylation status of the IFI44L gene. Further analyses were conducted in conjunction with clinical indicators. Results GSE199868 analysis revealed 125 upregulated and 16 downregulated DEGs. Among 2794 IFN-I-related genes from GeneCards, 26 DEGs overlapped, enriched in viral genome replication and IFN-I pathways. 14 hub genes were identified, with 7 genes confirmed in GSE135809: ISG15, IFIT1, OASL, IFI6, RSAD2, IFI44L, and USP18. IFI44L mRNA expression was significantly higher in SS B cells (P < 0.05), while its DNA methylation status was significantly lower (P < 0.05). IFI44L expression correlated positively with ESSDAI, ESSPRI, and IgG levels, while methylation correlated negatively with ESSDAI and ESSPRI (P < 0.05). ROC analysis revealed that the IFI44L gene had high diagnostic value (AUC = 0.8515). Conclusion The study highlights the clinical relevance of IFI44L mRNA expression and DNA hypomethylation in SS, underscoring its potential as a biomarker for disease activity and progression.
Collapse
Affiliation(s)
- Kaiyuan Zhang
- School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Ziyue Luo
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Xinyi Yao
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Dingqi Lu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Tao Hong
- Department of Respiratory, People’s Hospital of Changshan County, Quzhou, Zhejiang Province, 324200, People’s Republic of China
| | - Xinchao Zhu
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Mei Chen
- Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310053, People’s Republic of China
| | - Xinchang Wang
- Department of Rheumatology, The Second Affiliated Hospital, Zhejiang Chinese Medical University, Hangzhou, Zhejiang Province, 310005, People’s Republic of China
| |
Collapse
|
|
3
|
Kang H, Jung YH, Moon J, Ryu JS, Yoon CH, Kim YH, Kim MK, Kim DH. Efficacy of RCI001 as a Therapeutic Candidate in a Primary Sjögren Syndrome Mouse Model. Cornea 2025; 44:226-233. [PMID: 39288434 PMCID: PMC11676593 DOI: 10.1097/ico.0000000000003696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/24/2024] [Accepted: 08/01/2024] [Indexed: 09/19/2024]
Abstract
PURPOSE The aim of this study was to investigate the efficacy of RCI001 (RCI) in a mouse model of primary Sjögren syndrome. METHODS Eight 12-week-old NOD.B10-H2b mice were used in this study. All experimental animals were randomly divided into phosphate-buffered saline (PBS) and RCI groups in NOD.B10-H2b mice. The eyes of mice were topically treated with PBS or RCI twice a day for a week. Ocular surface staining (OSS) and tear secretion were compared between before and after treatment. The transcript levels of inflammatory cytokines and nicotinamide adenine dinucleotide phosphate oxidase (NOX) in the conjunctiva and cornea (CC) and lacrimal gland were assayed. In addition, immunofluorescence staining of the conjunctiva was assessed. RESULTS The RCI group showed significant clinical improvement in OSS and tear secretion after 1 week of treatment compared with the baseline (both P < 0.001) and showed better improvement in OSS and tear secretion than the PBS group after 1 week of treatment (both P < 0.05). The levels of IL-1β and IL-17 in CC and IL-6 in the lacrimal gland were also significantly reduced in the RCI group compared with the PBS group (each P < 0.05). Transcript levels of NOX2 and NOX4 were also significantly reduced in CC of the RCI group compared with those of the PBS group ( P < 0.05). The RCI group also resulted in lower conjunctival expression of oxidative stress markers (4-hydroxy-2-nonenal, hexanoyl-lysine, and NOX4) than the PBS group. CONCLUSIONS Topical RCI001 demonstrated excellent therapeutic efficacy in a mouse model of primary Sjögren syndrome by inhibiting inflammation and oxidative stress.
Collapse
Affiliation(s)
| | - Young-ho Jung
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jayoon Moon
- Department of Ophthalmology, Saevit Eye Hospital, Goyang, Republic of Korea
| | - Jin Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Chang Ho Yoon
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yong Ho Kim
- RudaCure Co, Ltd, Incheon, Republic of Korea
- Gachon Pain Center, Department of Physiology, Gachon University College of Medicine, Incheon, Republic of Korea; and
| | - Mee Kum Kim
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
| | - Dong Hyun Kim
- RudaCure Co, Ltd, Incheon, Republic of Korea
- Department of Ophthalmology, Korea University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
4
|
Caraba A, Roman D, Crișan V, Iurciuc S, Iurciuc M. Salivary Flow Rate in Patients with Sjögren's Syndrome: Correlations with Salivary Gland Ultrasound Findings and Biomarkers of Disease Activity. Int J Mol Sci 2024; 26:101. [PMID: 39795957 PMCID: PMC11720050 DOI: 10.3390/ijms26010101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/21/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Sjögren's syndrome (SS) is a slowly progressive, chronic autoimmune inflammatory condition characterized by the affliction of the exocrine glands, with issues that derive from it markedly decreasing the quality of life of these patients. Salivary gland involvement can be identified through imaging methods. Among them, salivary gland ultrasonography (SGUS) is used as a diagnostic and prognostic tool in pSS. The aim of the present study was to assess the salivary flow rate and correlations between it and SGUS findings and markers of pSS activity. A total of 112 patients with pSS and 56 healthy subjects were included in this study. All patients underwent investigations including the measurement of serum autoantibodies, salivary flow rate determination, and ultrasonographic evaluation. SGUS modifications had a strong inverse correlation with salivary flow (r = -68.002, p < 0.0001) and a positive, strong correlation with IL-6 and Beta-2-microglobulin (r = -0.78 and r = -0.84, respectively, p < 0.001 in both cases). The SGUS findings were also strongly and positively correlated with the ESSDAI (r = -0.88, p < 0.0001) and Focus scores (r = -0.82, p < 0.0001). SGUS represents a non-invasive means of assessing the state of the salivary glands and, implicitly, the salivary flow of patients, offering valuable insights into disease progression and steps that can be taken in order to improve patients' quality of life.
Collapse
Affiliation(s)
- Alexandru Caraba
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
- Railway Clinical Hospital, 300041 Timisoara, Romania;
| | - Deiana Roman
- Second Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Viorica Crișan
- Emergency Clinical Municipal Hospital, Rheumatology Department, 300041 Timisoara, Romania;
| | - Stela Iurciuc
- Railway Clinical Hospital, 300041 Timisoara, Romania;
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Mircea Iurciuc
- Cardiology Department, “Victor Babes” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| |
Collapse
|
|
5
|
Wu PC, Chao YH, Zhang X, Chen TT, Kuo YH, Lin CC, Chang HH. Evaluation of the potential of Ergostatrien-3β-ol for treating Sjögren's syndrome. Int J Rheum Dis 2024; 27:e15341. [PMID: 39498888 DOI: 10.1111/1756-185x.15341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 06/26/2024] [Accepted: 09/08/2024] [Indexed: 11/07/2024]
Abstract
AIM Ergostatrien-3β-ol (EK100) is a bioactive compound found in the fruiting bodies and mycelia of Antrodia cinnamomea and has anti-inflammatory and immunomodulatory properties. This study aims to evaluate the potential of EK100 as a treatment for Sjögren's syndrome (SS). METHODS We employed a spontaneous SS model in non-obese diabetic (NOD)/Ltj mice to assess the therapeutic potential of EK100. The effects of EK100 were evaluated based on stimulated salivary flow rates, sialadenitis, expression of inflammatory cytokines in salivary glands, and profiles of T cell subsets in the spleen. Additionally, in vitro experiments were conducted to assess the impact of EK100 on Th17 cell differentiation and dendritic cell (DC) maturation. RESULTS EK100 treatment significantly increased salivary flow rates, suppressed lymphocyte infiltration, and decreased the concentrations of anti-SSA/Ro and anti-SSB/La autoantibodies. EK100 also downregulated the expression of various inflammatory cytokines in the salivary glands and reduced the populations of Th1 and Th17 cells in the spleens of NOD/Ltj mice. In vitro experiments confirmed that EK100 inhibited the differentiation of Th17 cells and the maturation of DCs. CONCLUSION Our findings suggest that EK100 may offer a promising therapeutic avenue for the treatment of SS by modulating the interaction between Th17 cells and DCs.
Collapse
Affiliation(s)
- Po-Chang Wu
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Rong Hsing Translational Medicine Research Center, National Chung Hsing University, Taichung, Taiwan
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
| | - Ya-Husan Chao
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
| | - Xiang Zhang
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Tzu-Ting Chen
- Institute of Bioinformatics and Structural Biology, National Tsing Hua University, Hsinchu, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, College of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
| | - Chih-Chen Lin
- Doctoral Program in Translational Medicine, National Chung Hsing University, Taichung, Taiwan
- Advanced Plant and Food Crop Biotechnology Center, National Chung Hsing University, Taichung, Taiwan
- Department of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hen-Hong Chang
- Chinese Medicine Research Center, China Medical University, Taichung, Taiwan
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan
- Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
6
|
Zhou J, Felix FA, Jiang Y, Li D, Kim MC, Jang D, Cha S, Yu Q. Altered characteristics of regulatory T cells in target tissues of Sjögren's syndrome in murine models. Mol Immunol 2024; 174:47-56. [PMID: 39197397 PMCID: PMC11500054 DOI: 10.1016/j.molimm.2024.08.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2024] [Revised: 07/31/2024] [Accepted: 08/15/2024] [Indexed: 09/01/2024]
Abstract
Sjӧgren's syndrome (SS), also known as Sjögren's disease, is a chronic autoimmune condition predominantly affecting the salivary and lacrimal glands. The disease is driven by autoimmune responses involving the activation and actions of major innate- and adaptive immune cell subsets. However, the specific characteristics and roles of regulatory T cells (Tregs) in SS remain elusive. This study seeks to clarify the main phenotypic and functional attributes of Tregs in the salivary glands and their draining lymph nodes in murine models of SS. Our flow cytometric analysis revealed that Tregs in the salivary gland-draining lymph nodes of female non-obese diabetic (NOD) mice, a spontaneous model of SS, exhibited a greater proportion of activated Tregs and fewer resting Tregs compared to Balb/c mice. Furthermore, Tregs from the salivary gland-draining lymph nodes of female C57BL/6.NOD-Aec1Aec2 (B6.NOD-Aec) mice, a model for primary SS, demonstrated significantly lower IL-10 production but markedly higher IFNγ- and IL-17 production than their C57BL/6 counterparts. Additionally, treatment of C57BL/6 Tregs with IL-7, a cytokine critical for SS pathogenesis, resulted in diminished IL-10 production and enhanced IFNγ and IL-17 production in these cells. Notably, the alterations in B6.NOD-Aec Tregs also included an increased expression of the immune-inhibitory molecule CTLA-4 compared to the C57BL/6 Tregs. Intriguingly, in vitro co-cultures of Tregs with conventional CD4 T cells and other key immune populations from lymph nodes indicated that Tregs from salivary gland-draining lymph nodes of both B6.NOD-Aec and C57BL/6 strains exhibited comparable and limited immunosuppressive effects on the proliferation and function of conventional CD4 T cells. The ability of B6.NOD-Aec Tregs to directly inflict damages to salivary gland epithelial tissues and contribute to SS pathologies through IFNγ and IL-17 that they produce warrants further investigations. In addition, enhancing the relatively weak immunosuppressive capacities of these Tregs may also serve as a viable strategy to alleviate the SS phenotype in the mouse models and potentially in patients.
Collapse
Affiliation(s)
- Jing Zhou
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA
| | - Fernanda Aragão Felix
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Surgery, Pathology, and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Yuqiao Jiang
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA
| | - Dongfang Li
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA
| | - Myung-Chul Kim
- Veterinary Diagnostic Laboratory Medicine, College of Veterinary Medicine, Jeju National University, 102, Jejudaehak-ro, Jeju-si, Jeju-do 63243, South Korea
| | - Daesong Jang
- Department of Oral & Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA; Center for Orphaned Autoimmune Disorders, University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Seunghee Cha
- Department of Oral & Maxillofacial Diagnostic Sciences, University of Florida College of Dentistry, Gainesville, FL 32610, USA; Center for Orphaned Autoimmune Disorders, University of Florida College of Medicine, Gainesville, FL 32610, USA
| | - Qing Yu
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.
| |
Collapse
|
|
7
|
Felix FA, Zhou J, Li D, Onodera S, Yu Q. Endogenous IL-22 contributes to the pathogenesis of salivary gland dysfunction in the non-obese diabetic model of Sjögren's syndrome. Mol Immunol 2024; 173:20-29. [PMID: 39018744 PMCID: PMC11343657 DOI: 10.1016/j.molimm.2024.06.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Revised: 06/13/2024] [Accepted: 06/29/2024] [Indexed: 07/19/2024]
Abstract
Sjӧgren's syndrome is a systemic autoimmune disease primarily targeting the salivary and lacrimal glands. Our previous investigations have shown that administration of interleukin-22 (IL-22), an IL-10 family cytokine known for its complex and context-dependent effects on tissues, either protective- or detrimental, to salivary glands leads to hypofunction and pathological changes of salivary glands in C57BL/6 mice and in non-obese diabetic (NOD) mice, the latter being a commonly used model of Sjӧgren's syndrome. This study aims to delineate the pathophysiological roles of endogenously produced IL-22 in the development of salivary gland pathologies and dysfunction associated with Sjӧgren's disease in the NOD mouse model. Our results reveal that neutralizing IL-22 offered a protective effect on salivary gland function without significantly affecting the immune cell infiltration of salivary glands or the autoantibody production. Blockade of IL-22 reduced the levels of phosphorylated STAT3 in salivary gland tissues of NOD mice, while its administration to salivary glands had the opposite effect. Correspondingly, the detrimental impact of exogenously applied IL-22 on salivary glands was almost completely abrogated by a specific STAT3 inhibitor. Moreover, IL-22 blockade led to a downregulation of protein amounts of Ten-Eleven-Translocation 2, a methylcytosine dioxygenase critical for mediating interferon-induced responses, in salivary gland epithelial cells. IL-22 neutralization also exerted a protective effect on the salivary gland epithelial cells that express high levels of surface EpCAM and bear the stem cell potential, and IL-22 treatment in vitro hampered the survival/expansion of these salivary gland stem cells, indicating a direct negative impact of IL-22 on these cells. In summary, this study has uncovered a critical pathogenic role of the endogenous IL-22 in the pathogenesis of Sjögren's disease-characteristic salivary gland dysfunction and provided initial evidence that this effect is dependent on STAT3 activation and potentially achieved through fostering Tet2-mediated interferon responses in salivary gland epithelial cells and negatively affecting the EpCAMhigh salivary gland stem cells.
Collapse
Affiliation(s)
- Fernanda Aragão Felix
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States; Department of Oral Surgery, Pathology, and Clinical Dentistry, School of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Jing Zhou
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States
| | - Dongfang Li
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States
| | - Shoko Onodera
- Department of Biochemistry, Tokyo Dental College, 2-9-18 Kanda Misaki-chou, Chiyoda-ku, Tokyo 101-0061, Japan
| | - Qing Yu
- The ADA Forsyth Institute, 245 First Street, Cambridge, MA 02142, United States.
| |
Collapse
|
|
8
|
Zhang Z, Bahabayi A, Liu D, Hasimu A, Zhang Y, Guo S, Liu R, Zhang K, Li Q, Xiong Z, Wang P, Liu C. KLRB1 defines an activated phenotype of CD4+ T cells and shows significant upregulation in patients with primary Sjögren's syndrome. Int Immunopharmacol 2024; 133:112072. [PMID: 38636371 DOI: 10.1016/j.intimp.2024.112072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Revised: 04/07/2024] [Accepted: 04/09/2024] [Indexed: 04/20/2024]
Abstract
OBJECTIVE This study aimed to investigate the role of KLRB1 (CD161) in human CD4+ T cells and elucidate its significance in primary Sjögren's syndrome (pSS). METHODS Peripheral blood samples from 37 healthy controls and 44 pSS patients were collected. The publicly available single-cell RNA-Seq data from pSS patient PBMCs were utilized to analyse KLRB1 expression in T cells. KLRB1-expressing T lymphocyte subset proportions in pSS patients and healthy controls were determined by flow cytometry. CD25, Ki-67, cytokine secretion, and chemokine receptor expression in CD4+ KLRB1+ T cells were detected and compared with those in CD4+ KLRB1- T cells. Correlation analysis was conducted between KLRB1-related T-cell subsets and clinical indicators. ROC curves were generated to explore the diagnostic potential of KLRB1 for pSS. RESULTS KLRB1 was significantly upregulated following T-cell activation, and Ki-67 and CD25 expression was significantly greater in CD4+ KLRB1+ T cells than in CD4+ KLRB1- T cells. KLRB1+ CD4+ T cells exhibited greater IL-17A, IL-21, IL-22, and IFN-γ secretion upon stimulation, and there were significantly greater proportions of CCR5+, CCR2+, CX3CR1+, CCR6+, and CXCR3+ cells among CD4+ KLRB1+ T cells than among CD4+ KLRB1- T cells. Compared with that in HCs, KLRB1 expression in CD4+ T cells was markedly elevated in pSS patients and significantly correlated with clinical disease indicators. CONCLUSION KLRB1 is a characteristic molecule of the CD4+ T-cell activation phenotype. The increased expression of KLRB1 in the CD4+ T cells of pSS patients suggests its potential involvement in the pathogenesis of pSS and its utility as an auxiliary diagnostic marker for pSS.
Collapse
Affiliation(s)
- Zhonghui Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ayibaota Bahabayi
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Danni Liu
- School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ainizati Hasimu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Yangyang Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Siyu Guo
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ruiqing Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ke Zhang
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Qi Li
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Ziqi Xiong
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China
| | - Pingzhang Wang
- Department of Immunology, NHC Key Laboratory of Medical Immunology (Peking University), Medicine Innovation Center for Fundamental Research on Major Immunology-related Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Peking University Center for Human Disease Genomics, Peking University Health Science Center, Beijing, China.
| | - Chen Liu
- Department of Clinical Laboratory, Peking University People's Hospital, Beijing, China.
| |
Collapse
|
|
9
|
Punnanitinont A, Kasperek EM, Zhu C, Yu G, Miecznikowski JC, Kramer JM. TLR7 activation of age-associated B cells mediates disease in a mouse model of primary Sjögren's disease. J Leukoc Biol 2024; 115:497-510. [PMID: 37930711 PMCID: PMC10990110 DOI: 10.1093/jleuko/qiad135] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/07/2023] Open
Abstract
Primary Sjögren's disease (pSD) (also referred to as Sjögren's syndrome) is an autoimmune disease that primarily occurs in women. In addition to exocrine gland dysfunction, pSD patients exhibit B cell hyperactivity. B cell-intrinsic TLR7 activation is integral to the pathogenesis of systemic lupus erythematosus, a disease that shares similarities with pSD. The role of TLR7-mediated B cell activation in pSD, however, remains poorly understood. We hypothesized that age-associated B cells (ABCs) were expanded in pSD and that TLR7-stimulated ABCs exhibited pathogenic features characteristic of disease. Our data revealed that ABC expansion and TLR7 expression were enhanced in a pSD mouse model in a Myd88-dependent manner. Splenocytes from pSD mice showed enhanced sensitivity to TLR7 agonism as compared with those derived from control animals. Sort-purified marginal zone B cells and ABCs from pSD mice showed enhanced inflammatory cytokine secretion and were enriched for antinuclear autoantibodies following TLR7 agonism. Finally, IgG from pSD patient sera showed elevated antinuclear autoantibodies, many of which were secreted preferentially by TLR7-stimulated murine marginal zone B cells and ABCs. These data indicate that pSD B cells are hyperresponsive to TLR7 agonism and that TLR7-activated B cells contribute to pSD through cytokine and autoantibody production. Thus, therapeutics that target TLR7 signaling cascades in B cells may have utility in pSD patients.
Collapse
Affiliation(s)
- Achamaporn Punnanitinont
- Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY USA
| | - Eileen M. Kasperek
- Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY USA
| | - Chengsong Zhu
- Department of Immunology, Microarray & Immune Phenotyping Core Facility, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Guan Yu
- Department of Biostatistics, School of Public Health and Health Professions, The University at Buffalo, State University of New York, Buffalo, NY USA
| | - Jeffrey C. Miecznikowski
- Department of Biostatistics, School of Public Health and Health Professions, The University at Buffalo, State University of New York, Buffalo, NY USA
| | - Jill M. Kramer
- Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY USA
| |
Collapse
|
|
10
|
Shi W, Xu Y, Zhang A, Jia X, Liu S, Hu Z. Inflammatory cytokines and their potential role in Sjogren's syndrome risk: insights from a mendelian randomization study. Adv Rheumatol 2024; 64:14. [PMID: 38365917 DOI: 10.1186/s42358-024-00354-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 02/03/2024] [Indexed: 02/18/2024] Open
Abstract
AIM This study aimed to investigate the causal impact of inflammatory cytokines on Sjogren's Syndrome (SS) and to identify potential biomarkers for SS clinical management using Mendelian Randomization (MR). MATERIALS AND METHODS Leveraging GWAS summary data of inflammatory cytokines and SS, we executed the first two-sample MR analysis. Genetic variants from prior GWASs associated with circulating inflammatory cytokines served as instrumental variables (IVs). Data regarding cytokines were analyzed using the Olink Target-96 Inflammation panel, synthesizing data from 14,824 participants. GWAS summary statistics for SS were procured from the UK Biobank, focusing on samples of European ancestry. To discern the causal relationship between inflammatory cytokines and SS, several MR methodologies, including inverse variance weighted (IVW) and MR-Egger regression, were applied. RESULTS After rigorous IV quality control, 91 cytokines were incorporated into the MR analysis. The IVW analysis identified 8 cytokines with a positive association to SS: Axin-1 (OR 2.56, 95% CI 1.07-6.10), T-cell surface glycoprotein CD5 (OR 1.81, 95% CI 1.08-3.02), CUDP1 (OR 1.61, 95% CI 1.00-2.58), CXCL10 (OR 1.92, 95% CI 1.25-2.95), IL-4 (OR 2.18, 95% CI 1.22-3.91), IL-7 (OR 2.35, 95% CI 1.27-4.33), MCP-2 (OR 1.27, 95% CI 1.05-1.54), and TNFRSF9 (OR 1.83, 95% CI 1.03-3.24), suggesting their potential in increasing SS risk. CONCLUSION Our study conducted through MR, identified various inflammatory cytokines associated with SS risk, validating some previous research results and offering some new potential biomarkers for SS. However, these findings necessitate further research for validation and exploration of their precise role in the onset and progression of SS.
Collapse
Affiliation(s)
- Wenbin Shi
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Shenzhen City, Guangdong Province, 518110, P. R. China
| | - Yuli Xu
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Shenzhen City, Guangdong Province, 518110, P. R. China
| | - Anan Zhang
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Shenzhen City, Guangdong Province, 518110, P. R. China
| | - Xiqun Jia
- Department of Pediatrics, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Guangdong Province, Shenzhen Cit, 518110, P. R. China
| | - Shuhua Liu
- Department of Neonatalogy, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Shenzhen City, Guangdong Province, 518110, P. R. China.
- Department of Pediatrics, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Guangdong Province, Shenzhen Cit, 518110, P. R. China.
| | - Ziyang Hu
- Department of Stomatology, Shenzhen Longhua District Central Hospital, Guanlan Avenue 187, Shenzhen City, Guangdong Province, 518110, P. R. China.
| |
Collapse
|
|
11
|
Yu Y, Lu C, Yu W, Lei Y, Sun S, Liu P, Bai F, Chen Y, Chen J. B Cells Dynamic in Aging and the Implications of Nutritional Regulation. Nutrients 2024; 16:487. [PMID: 38398810 PMCID: PMC10893126 DOI: 10.3390/nu16040487] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2024] [Revised: 02/01/2024] [Accepted: 02/06/2024] [Indexed: 02/25/2024] Open
Abstract
Aging negatively affects B cell production, resulting in a decrease in B-1 and B-2 cells and impaired antibody responses. Age-related B cell subsets contribute to inflammation. Investigating age-related alterations in the B-cell pool and developing targeted therapies are crucial for combating autoimmune diseases in the elderly. Additionally, optimal nutrition, including carbohydrates, amino acids, vitamins, and especially lipids, play a vital role in supporting immune function and mitigating the age-related decline in B cell activity. Research on the influence of lipids on B cells shows promise for improving autoimmune diseases. Understanding the aging B-cell pool and considering nutritional interventions can inform strategies for promoting healthy aging and reducing the age-related disease burden.
Collapse
Affiliation(s)
| | | | | | | | | | | | | | | | - Juan Chen
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing 100091, China; (Y.Y.)
| |
Collapse
|
|
12
|
Benchabane S, Sour S, Zidi S, Hadjimi Z, Nabila L, Acheli D, Bouzenad A, Belguendouz H, Touil-Boukoffa C. Exploring the relationship between oxidative stress status and inflammatory markers during primary Sjögren's syndrome: A new approach for patient monitoring. Int J Immunopathol Pharmacol 2024; 38:3946320241263034. [PMID: 38901876 PMCID: PMC11191624 DOI: 10.1177/03946320241263034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Accepted: 05/31/2024] [Indexed: 06/22/2024] Open
Abstract
INTRODUCTION Primary Sjögren's syndrome (pSS) is a chronic inflammatory disease primarily affects exocrine glands dysfunction. Oxidative stress (OS) is a phenomenon occurring as a result of an imbalance between the generation of free radicals and antioxidant defense system. Hence, we aimed to establish the status of OS and inflammatory response according to the pSS disease activity index. In this context, we investigated malondialdehyde (MDA), and antioxidant enzymes during pSS. The possible association between MDA and nitric oxide (NO) levels and between MDA and some pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-33). METHODS The study has been conducted on 53 pSS patients. The antioxidant enzymes, represented by glutathione peroxidase (GSH-Px), catalase (CAT) and superoxide dismutase (SOD), were estimated by a colorimetric activity kit. Whereas, MDA value was assessed by measuring thiobarbituric acid reactive substances. Moreover, pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, and IL-33) and NO were respectively quantified by enzyme-linked immunosorbent assays (ELISA) and the modified Griess. RESULTS Interestingly, we report a notable reduction in our pSS patients' antioxidant enzyme activity, while NO, MDA and proinflammatory cytokines values were significantly increased. pSS patients with higher disease activity had much stronger increases in NO and MDA levels. No significant difference was assessed in CRP level. Additionally, substantial significant correlations between plasmatic NO and MDA levels and between MDA, NO and IL-1β, IL-6, TNF-α cytokines were reported. However, no significant association was found between NO, MDA and IL-33 concentrations. CONCLUSION Collectively, our data showed altered oxidant-antioxidant balance in pSS patients. MDA, NO, IL-1β, IL-6, TNF-α seem to be good indicators in monitoring disease activity. Oxidative stress was closely related to inflammation in pSS. Exploiting this relationship might provide valuable indicators in the follow-up and prognosis of pSS with a potential therapeutic value.
Collapse
Affiliation(s)
- Sarah Benchabane
- Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
- Faculty of Natural Sciences and Life, Department of Biology, Saad Dahlab’s University of Blida, Blida, Algeria
| | - Souad Sour
- Faculty of Natural Sciences and Life, Department of Biology, Saad Dahlab’s University of Blida, Blida, Algeria
| | - Sourour Zidi
- Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
- Department of Natural Sciences, Guelma University, Guelma, Algeria
| | - Zohra Hadjimi
- Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Lyazidi Nabila
- Internal Medicine Department, Issad Hassani Hospital- Algiers 1 University of Medicine, Algiers, Algeria
| | - Dahbia Acheli
- Internal Medicine Department, Douera Hospital- Algiers 1 University of Medicine, Algiers, Algeria
| | - Amel Bouzenad
- Medical Biology Laboratory, Pasteur Institut- Algiers 1 University of Medicine, Algiers, Algeria
| | - Houda Belguendouz
- Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| | - Chafia Touil-Boukoffa
- Laboratory of Cellular and Molecular Biology (LBCM), Cytokines and NO Synthases Team, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene (USTHB), Algiers, Algeria
| |
Collapse
|
|
13
|
Liu R, Zhang Y, Li K, Xu H, Cheng Z, Pang F, Wu H, Guo Z, He J, Tang X, Zhou X, Jiang Q. Effect of acupuncture on regulating IL-17, TNF-ɑ and AQPs in Sjögren's syndrome. Oral Dis 2024; 30:50-62. [PMID: 37518974 DOI: 10.1111/odi.14680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 06/19/2023] [Accepted: 07/06/2023] [Indexed: 08/01/2023]
Abstract
AIM The aim of the study was to observe the effect of acupuncture on regulating interleukin (IL)-17, tumor necrosis factor (TNF)-ɑ, and aquaporins (AQPs) in Sjögren's syndrome (SS) on patients and on non-obese diabetic (NOD) models. METHODS Levels of anti-AQP 1, 5, 8, and 9 antibodies, IL-17, and TNF-ɑ in the serum of SS patients were compared prior and following 20 acupuncture treatment visits during 8 weeks. While in murine model, five groups were divided to receive interventions for 4 weeks, including control, model, acupuncture, isoflurane, and hydroxychloroquine. The submaxillofacial gland index, histology, immunohistochemistry of AQP1, 5, salivary flow, together with IL-17, and TNF-ɑ expression in peripheral blood were compared among the groups. RESULTS Acupuncture reduced IL-17, TNF-ɑ, and immunoglobin A levels, and numeric analog scale of dryness in 14 patients with SS (p < 0.05). The salivary flow was increased, and the water intake decreased in NOD mice receiving acupuncture treatments. IL-17 and TNF-ɑ levels in peripheral serum were down-regulated (p < 0.05) and AQP1, 5 expression in the submandibular glands up-regulated in mice. CONCLUSION The effect on relieving xerostomia with acupuncture may be achieved by up-regulating the expression of AQP1. AQP5, down-regulating levels of IL-17 and TNF-ɑ, and a decrease in inflammation of glands.
Collapse
Affiliation(s)
- Ruihua Liu
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yi Zhang
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, China
| | - Kesong Li
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Haodong Xu
- Department of Rheumatology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Jiangsu, China
| | - Zengyu Cheng
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Fengtao Pang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hengbo Wu
- Department of Rheumatology, Xi'an Hospital of Traditional Chinese Medicine, Shanxi, China
| | - Zilin Guo
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jiale He
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaopo Tang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xinyao Zhou
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Quan Jiang
- Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| |
Collapse
|
|
14
|
Gao M, Zhao L, Liang R, Zhu Q, Zhao Q, Kong X. Evaluation of the Efficacy and Safety of Topical 0.05% Cyclosporine Eye Drops (II) in the Treatment of Dry Eye Associated with Primary Sjögren's Syndrome. Ocul Immunol Inflamm 2023; 31:1662-1668. [PMID: 35914303 DOI: 10.1080/09273948.2022.2094812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 06/20/2022] [Indexed: 10/16/2022]
Abstract
PURPOSE To evaluate the efficacy and safety of 0.05% cyclosporine eye drops (II) for the treatment of primary Sjögren's syndrome-associated dry eye (PSSDE). METHODS Sixty patients with PSSDE were randomly divided into three groups, received treatment with 0.05% cyclosporine (C group), artificial tears (S group) or their combination (CS group). The evaluation indicators were evaluated at baseline and at weeks 2, 4 and 12. RESULTS The symptoms of C and CS groups were reduced significantly. The signs [schirmer I test (F = 4.838, p = .011), ocular staining score (F = 7.961, p = .001) and tear break-up time (F = 9.283, p < .001)] were significantly different between S and C groups as well as S and CS groups. The tear meniscus height (F = 3.197, p = .048) was significantly different between S and CS groups. No serious adverse events occurred. CONCLUSION 0.05% cyclosporine is an effective and safe treatment for patients with PSSDE.
Collapse
Affiliation(s)
- Mingjun Gao
- Department of Ophthalmology, Dalian Medical University, Dalian, China
| | - Lin Zhao
- Department of Rheumatology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Ran Liang
- Department of Ophthalmology, Dalian Medical University, Dalian, China
| | - Qing Zhu
- Department of Ophthalmology, Dalian Medical University, Dalian, China
| | - Qi Zhao
- Department of Ophthalmology, The Second Hospital of Dalian Medical University, Dalian, China
| | - Xiaodan Kong
- Department of Rheumatology, The Second Hospital of Dalian Medical University, Dalian, China
| |
Collapse
|
|
15
|
Alqahtani B, Daghestani M, Omair MA, Alhamad EH, Tashkandy Y, Othman N, Al Shahrani K, Paramasivam MP, Alenzi F, Halwani R, Alkhulaifi FM, Alomar SY. Association of Inflammatory Cytokine Levels with Extra Glandular Manifestations, Fatigue, and Disease Activity in Primary Sjögren's Syndrome in Saudi Patients: A Cross-Sectional Study. Diagnostics (Basel) 2023; 13:3036. [PMID: 37835779 PMCID: PMC10572739 DOI: 10.3390/diagnostics13193036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 09/01/2023] [Accepted: 09/15/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Primary Sjögren's syndrome (pSS) is an autoimmune disease that can cause fatigue and extraglandular manifestations (EGMs). pSS is associated with cytokine network dysregulation, which may be related to the immune-mediated destruction of exocrine glands. OBJECTIVE We determined cytokine levels and their relationship to EGMs, the European League Against Rheumatism (EULAR) Sjögren's syndrome disease activity index (ESSDAI), and fatigue in Saudi patients with pSS. METHODS This study was a cross-sectional, single-center study. We included forty-one patients and 71 controls. Serum samples were collected from random healthy people and pSS patients who were followed in the rheumatology and pulmonary clinics of King Saud University Medical City in Riyadh, Saudi Arabia. Levels of the frequently studied cytokines were measured using Luminex xMAP technology. Each ESSDAI score and EGM were recorded, and the Arabic version of the fatigue severity scale (FSS) was applied to assess fatigue. The main outcome measures were cytokine levels in pSS Saudi patients using/not using immune-suppressive medications (ISMs). RESULTS Thirty-six (87.8%) patients had one or more EGMs, and the mean ESSDAI score was 9.95 ± 7.73. There was a significant decrease in TNFα and IL-21 levels in the pSS group compared to those in the control group (p = 0.034 and p < 0.001, respectively), whereas IL-12 levels were significantly elevated in the pSS group (p = 0.002). Cytokine levels in patients who used ISMs were the same as those in patients who did not use medications. Decreased IL-1β (p = 0.014), IL-2 (p = 0.035), IL-6 (p = 0.014), and IL-35 (p = 0.010) levels were observed in patients who had EGMs. Patients who had low disease activity exhibited low IL-10 (p = 0.018) and high IFN-α (p = 0.049), IFN-β (p = 0.049), IL-1β (p = 0.006), and IL-35 (p = 0.032) levels compared to patients with high disease activity. A negative association between a positive fatigue score and IL-1β (p = 0.010), IL-2 (p = 0.037), IFN-α (p = 0.025), TNFα (p = 0.030), IL-17 (p = 0.029), IL-12 (p = 0.046), and IL-21 (p = 0.005) levels was found. CONCLUSIONS Cytokine profiles correlate with EGMs, ESSDAI, and fatigue. Patients with controlled disease activity have a normal cytokine profile that is similar to that of controls.
Collapse
Affiliation(s)
- Bashaer Alqahtani
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (B.A.); (M.D.)
| | - Maha Daghestani
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (B.A.); (M.D.)
| | - Mohammed A. Omair
- Rheumatology Unit, Department of Medicine, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Esam H. Alhamad
- Department of Medicine, Division of Pulmonary Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Yusra Tashkandy
- Department of Statistics and Operations Research, College of Sciences, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Nashwa Othman
- Central Laboratory, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Khalid Al Shahrani
- Rheumatology Division, Department of Medicine, Ad Diriyah Hospital, Ministry of Health, Riyadh 13717, Saudi Arabia;
| | - Muthurajan P. Paramasivam
- Pulmonary Division, Department of Medicine, College of Medicine, King Saud University, Riyadh 11451, Saudi Arabia;
| | - Fahidah Alenzi
- Department of Clinical Science, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia;
| | - Rabih Halwani
- Department of Clinical Sciences, Sharjah Institute for Medical Research (SIMR), College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates;
| | - Fadwa M. Alkhulaifi
- Biology Department, College of Science, Imam Abdulrahman bin Faisal University, Dammam 34212, Saudi Arabia;
| | - Suliman Yousef Alomar
- Department of Zoology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia; (B.A.); (M.D.)
| |
Collapse
|
|
16
|
Caraba A, Iurciuc S, Nicolin M, Iurciuc M. Endothelial Dysfunction in Primary Sjögren's Syndrome: Correlation with Serum Biomarkers of Disease Activity. Int J Mol Sci 2023; 24:13918. [PMID: 37762225 PMCID: PMC10531316 DOI: 10.3390/ijms241813918] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 08/31/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
To assess the relationship between endothelial dysfunction and serum cytokines, anti-SSA and anti-SSB antibodies, beta-2 microglobulin levels, focus score and EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) in primary Sjögren's syndrome (pSS) patients. The study included 90 patients with pSS and 45 healthy subjects, matched for age and gender, as controls. Serum beta-2 microglobulin, total cholesterol, HDL-cholesterol, triglycerides, TNF-α, and IL-6 were analyzed in both the groups. Patients with pSS were also tested for antinuclear antibodies, anti-SAA (anti-Sjögren's syndrome-related antigen A) antibodies, anti-SSB (anti-Sjögren syndrome related antigen B) antibodies, and focus score (the histopathologic one, based on minor salivary gland biopsy). Endothelial dysfunction was assessed by means of flow-mediated dilation (FMD) in the brachial artery. Data are presented as mean ± standard deviation. Statistical analysis was performed using the t-test and the Pearson's correlation. Differences were considered to be statistically significant if the value of p < 0.05. Endothelial dysfunction was identified in pSS patients (p < 0.00001). The serum levels of cytokines (TNF-α, respective IL-6) and beta-2 microglobulin were increased in pSS patients compared with controls (p < 0.00001). Endothelial dysfunction (expressed as FMD%) was correlated with focus score, ESSDAI, levels of anti-SSA and anti-SSB antibodies, beta-2 microglobulin, IL-6, and TNF-α, with statistical significance. Endothelial dysfunction is present in pSS patients and is associated with a high focus score and activity as well as increased concentrations of antibodies, pro-inflammatory cytokines, and beta 2-microglobulin.
Collapse
Affiliation(s)
- Alexandru Caraba
- 3rd Internal Medicine, Diabetes and Rheumatology Department, University of Medicine and Pharmacy “Victor Babeș”, 300041 Timișoara, Romania;
| | - Stela Iurciuc
- Cardiology Department, University of Medicine and Pharmacy “Victor Babeș”, 300041 Timișoara, Romania;
| | - Mihaela Nicolin
- Cardiology Department, “Victor Popescu” Military Hospital, 300080 Timișoara, Romania;
| | - Mircea Iurciuc
- Cardiology Department, University of Medicine and Pharmacy “Victor Babeș”, 300041 Timișoara, Romania;
| |
Collapse
|
|
17
|
Yura Y, Hamada M. Outline of Salivary Gland Pathogenesis of Sjögren's Syndrome and Current Therapeutic Approaches. Int J Mol Sci 2023; 24:11179. [PMID: 37446355 DOI: 10.3390/ijms241311179] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 06/30/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Sjögren's syndrome (SS) is an autoimmune disease characterized by the involvement of exocrine glands such as the salivary and lacrimal glands. The minor salivary glands, from which tissue samples may be obtained, are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of SS. In the onset of SS, autoantigens derived from the salivary glands are recognized by antigen-presenting dendritic cells, leading to the activation of T and B cells, cytokine production, autoantibody production by plasma cells, the formation of ectopic germinal centers, and the destruction of salivary gland epithelial cells. A recent therapeutic approach with immune checkpoint inhibitors for malignant tumors enhances the anti-tumor activity of cytotoxic effector T cells, but also induces SS-like autoimmune disease as an adverse event. In the treatment of xerostomia, muscarinic agonists and salivary gland duct cleansing procedure, as well as sialendoscopy, are expected to ameliorate symptoms. Clinical trials on biological therapy to attenuate the hyperresponsiveness of B cells in SS patients with systemic organ involvement have progressed. The efficacy of treatment with mesenchymal stem cells and chimeric antigen receptor T cells for SS has also been investigated. In this review, we will provide an overview of the pathogenesis of salivary gland lesions and recent trends in therapeutic approaches for SS.
Collapse
Affiliation(s)
- Yoshiaki Yura
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
| | - Masakazu Hamada
- Department of Oral & Maxillofacial Oncology and Surgery, Osaka University Graduate School of Dentistry, Osaka 565-0871, Japan
| |
Collapse
|
|
18
|
Mihai A, Caruntu C, Jurcut C, Blajut FC, Casian M, Opris-Belinski D, Ionescu R, Caruntu A. The Spectrum of Extraglandular Manifestations in Primary Sjögren's Syndrome. J Pers Med 2023; 13:961. [PMID: 37373950 DOI: 10.3390/jpm13060961] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2023] [Revised: 06/02/2023] [Accepted: 06/05/2023] [Indexed: 06/29/2023] Open
Abstract
Extraglandular manifestations (EGMs) in primary Sjogren's syndrome (pSS) represent the clinical expression of the systemic involvement in this disease. EGMs are characterized by a wide heterogeneity; virtually any organ or system can be affected, with various degrees of dysfunction. The existing gaps of knowledge in this complex domain of extraglandular extension in pSS need to be overcome in order to increase the diagnostic accuracy of EGMs in pSS. The timely identification of EGMs, as early as from subclinical stages, can be facilitated using highly specific biomarkers, thus preventing decompensated disease and severe complications. To date, there is no general consensus on the diagnostic criteria for the wide range of extraglandular involvement in pSS, which associates important underdiagnosing of EGMs, subsequent undertreatment and progression to severe organ dysfunction in these patients. This review article presents the most recent basic and clinical science research conducted to investigate pathogenic mechanisms leading to EGMs in pSS patients. In addition, it presents the current diagnostic and treatment recommendations and the trends for future therapeutic strategies based on personalized treatment, as well as the latest research in the field of diagnostic and prognostic biomarkers for extraglandular involvement in pSS.
Collapse
Affiliation(s)
- Ancuta Mihai
- Department of Internal Medicine, Carol Davila Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Rheumatology, Faculty of General Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
| | - Constantin Caruntu
- Department of Physiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Department of Dermatology, Prof. N.C. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, 011233 Bucharest, Romania
| | - Ciprian Jurcut
- Department of Internal Medicine, Carol Davila Central Military Emergency Hospital, 010825 Bucharest, Romania
| | - Florin Cristian Blajut
- Department of General Surgery, Carol Davila Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Medical-Surgical Specialties, "Titu Maiorescu" University of Bucharest, 040441 Bucharest, Romania
| | - Mihnea Casian
- Emergency Institute for Cardiovascular Diseases Prof. Dr. C.C. Iliescu, 022328 Bucharest, Romania
- Department of Cardiology, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Daniela Opris-Belinski
- Internal Medicine and Rheumatology Department, Sfanta Maria Clinical Hospital, 011172 Bucharest, Romania
- Internal Medicine and Rheumatology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ruxandra Ionescu
- Internal Medicine and Rheumatology Department, Sfanta Maria Clinical Hospital, 011172 Bucharest, Romania
| | - Ana Caruntu
- Department of Oral and Maxillofacial Surgery, Carol Davila Central Military Emergency Hospital, 010825 Bucharest, Romania
- Department of Oral and Maxillofacial Surgery, Faculty of Dental Medicine, Titu Maiorescu University, 031593 Bucharest, Romania
| |
Collapse
|
|
19
|
Blinova VG, Vasilyev VI, Rodionova EB, Zhdanov DD. The Role of Regulatory T Cells in the Onset and Progression of Primary Sjögren's Syndrome. Cells 2023; 12:1359. [PMID: 37408193 DOI: 10.3390/cells12101359] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 07/07/2023] Open
Abstract
Regulatory T cells (Tregs) play a key role in maintaining immune balance and regulating the loss of self-tolerance mechanisms in various autoimmune diseases, including primary Sjögren's syndrome (pSS). With the development of pSS primarily in the exocrine glands, lymphocytic infiltration occurs in the early stages, mainly due to activated CD4+ T cells. Subsequently, in the absence of rational therapy, patients develop ectopic lymphoid structures and lymphomas. While the suppression of autoactivated CD4+ T cells is involved in the pathological process, the main role belongs to Tregs, making them a target for research and possible regenerative therapy. However, the available information about their role in the onset and progression of this disease seems unsystematized and, in certain aspects, controversial. In our review, we aimed to organize the data on the role of Tregs in the pathogenesis of pSS, as well as to discuss possible strategies of cell therapy for this disease. This review provides information on the differentiation, activation, and suppressive functions of Tregs and the role of the FoxP3 protein in these processes. It also highlights data on various subpopulations of Tregs in pSS, their proportion in the peripheral blood and minor salivary glands of patients as well as their role in the development of ectopic lymphoid structures. Our data emphasize the need for further research on Tregs and highlight their potential use as a cell-based therapy.
Collapse
Affiliation(s)
- Varvara G Blinova
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| | - Vladimir I Vasilyev
- Joint and Heart Treatment Center, Nizhnyaya Krasnoselskaya St. 4, 107140 Moscow, Russia
| | | | - Dmitry D Zhdanov
- Laboratory of Medical Biotechnology, Institute of Biomedical Chemistry, Pogodinskaya St. 10/8, 119121 Moscow, Russia
| |
Collapse
|
|
20
|
Xin X, Wang Q, Qing J, Song W, Gui Y, Li X, Li Y. Th17 cells in primary Sjögren’s syndrome negatively correlate with increased Roseburia and Coprococcus. Front Immunol 2022; 13:974648. [PMID: 36275752 PMCID: PMC9579428 DOI: 10.3389/fimmu.2022.974648] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 09/06/2022] [Indexed: 11/30/2022] Open
Abstract
Background Dysbiosis of the gut microbiota is closely related to chronic systemic inflammation and autoimmunity, playing an essential role in the pathogenesis of primary Sjögren’s syndrome (pSS). Abnormalities in the proportions of blood T lymphocyte subtype, that is Th17/Treg, were detected in pSS patients. We aimed to determine the associations between gut microbiota and Th17/Treg in pSS. Method 98 pSS patients and 105 healthy controls (NC) were enrolled between Dec 1, 2018, and Aug 31, 2019. The baseline information and clinical parameters on pSS patients and healthy controls were collected. 16S rRNA sequencing was performed to characterize the gut microbiome and identify gut microbes that are differentially abundant between patients and healthy controls. Lastly, associations between relative abundances of specific bacterial taxa in the gut and clinical outcome parameters were evaluated. Results Patients with pSS show decreased gut microbial diversity and richness, decreased abundance of butyrate producing bacteria, such as Roseburia and Coprococcus, and increased abundance of other taxa, such as Eubacterium rectale and Roseburia inulinivorans. These bacteria are enriched with functions related to glycolytic and lipogenic, energy, substance, galactose, pentose metabolism pathways and glucuronate interconversions, decreased with functions related to peptidoglycan biosynthesis, pyrimidine metabolism pathways. An integrative analysis identified pSS-related specific bacterial taxa in the gut, for which the abundance of Eubacterium rectale is negatively correlated with Th17/Treg. Furthermore, the pathways of biosynthesis of secondary metabolites, biosynthesis of amino acids, peptidoglycan biosynthesis and pyrimidine, galactose, pentose, microbial metabolism in diverse environments, glyoxylate and dicarboxylate metabolism are associated with Treg or Th17/Treg. Conclusions Primary Sjögren’s syndrome could lead to decreased gut microbial diversity and richness of intestinal flora in patients. The proportions of Th17 and Treg cells induced by microbiota were predictive pSS manifestations and accounted for the pSS severity.
Collapse
Affiliation(s)
- Xiaohong Xin
- Core Laboratory, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Qian Wang
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People’s Hospital (Fifth Hospital), Taiyuan, China
| | - Jianbo Qing
- Core Laboratory, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People’s Hospital (Fifth Hospital), Taiyuan, China
- Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
| | - Wenzhu Song
- Core Laboratory, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- School of Public Health, Shanxi Medical University, Taiyuan, China
| | - Yanni Gui
- Department of Rheumatology and Clinical Immunology, Peking University First Hospital, Beijing, China
| | - Xiaofeng Li
- Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
- Department of Rheumatology, The Second Hospital of Shanxi Medical University, Taiyuan, China
- Key Laboratory of Cellular Physiology, Ministry of Education, Taiyuan, China
- *Correspondence: Yafeng Li, ; Xiaofeng Li,
| | - Yafeng Li
- Core Laboratory, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People’s Hospital (Fifth Hospital), Taiyuan, China
- Department of Nephrology, Shanxi Provincial People’s Hospital (Fifth Hospital) of Shanxi Medical University, Taiyuan, China
- Academy of Microbial Ecology, Shanxi Medical University, Taiyuan, China
- *Correspondence: Yafeng Li, ; Xiaofeng Li,
| |
Collapse
|
|
21
|
Fasching PA, Liu D, Scully S, Ingle JN, Lyra PC, Rack B, Hein A, Ekici AB, Reis A, Schneeweiss A, Tesch H, Fehm TN, Heinrich G, Beckmann MW, Ruebner M, Huebner H, Lambrechts D, Madden E, Shen J, Romm J, Doheny K, Jenkins GD, Carlson EE, Li L, Fridley BL, Cunningham JM, Janni W, Monteiro ANA, Schaid DJ, Häberle L, Weinshilboum RM, Wang L. Identification of Two Genetic Loci Associated with Leukopenia after Chemotherapy in Patients with Breast Cancer. Clin Cancer Res 2022; 28:3342-3355. [PMID: 35653140 PMCID: PMC9357161 DOI: 10.1158/1078-0432.ccr-20-4774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/20/2022] [Accepted: 05/27/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE To identify molecular predictors of grade 3/4 neutropenic or leukopenic events (NLE) after chemotherapy using a genome-wide association study (GWAS). EXPERIMENTAL DESIGN A GWAS was performed on patients in the phase III chemotherapy study SUCCESS-A (n = 3,322). Genotyping was done using the Illumina HumanOmniExpress-12v1 array. Findings were functionally validated with cell culture models and the genotypes and gene expression of possible causative genes were correlated with clinical treatment response and prognostic outcomes. RESULTS One locus on chromosome 16 (rs4784750; NLRC5; P = 1.56E-8) and another locus on chromosome 13 (rs16972207; TNFSF13B; P = 3.42E-8) were identified at a genome-wide significance level. Functional validation revealed that expression of these two genes is altered by genotype-dependent and chemotherapy-dependent activity of two transcription factors. Genotypes also showed an association with disease-free survival in patients with an NLE. CONCLUSIONS Two loci in NLRC5 and TNFSF13B are associated with NLEs. The involvement of the MHC I regulator NLRC5 implies the possible involvement of immuno-oncological pathways.
Collapse
Affiliation(s)
- Peter A Fasching
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
| | - Duan Liu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Steve Scully
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - James N Ingle
- Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota
| | - Paulo C Lyra
- Biotechnology/RENORBIO Program, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Brigitte Rack
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Alexander Hein
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
| | - Arif B Ekici
- Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Andre Reis
- Institute of Human Genetics, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Andreas Schneeweiss
- National Center for Tumor Diseases, Division of Gynecologic Oncology, Heidelberg University Hospital and German Cancer Research Center, Heidelberg, Germany
| | - Hans Tesch
- Onkologie Bethanien, Frankfurt am Main, Germany
| | - Tanja N Fehm
- Department of Gynecology and Obstetrics, Düsseldorf University Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Georg Heinrich
- Schwerpunktpraxis für Gynäkologische Onkologie, Fürstenwalde, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
| | - Matthias Ruebner
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
| | - Hanna Huebner
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
| | - Diether Lambrechts
- VIB Center for Cancer Biology, VIB and Laboratory for Translational Genetics, KU Leuven, Leuven, Belgium
| | - Ebony Madden
- Division of Genomic Medicine, National Human Genome Research Institute, Bethesda, Maryland
| | - Jess Shen
- Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Jane Romm
- McKusick-Nathans Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland
| | - Kim Doheny
- McKusick-Nathans Department of Genetic Medicine, Center for Inherited Disease Research, Johns Hopkins University, Baltimore, Maryland
| | - Gregory D Jenkins
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Erin E Carlson
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Liang Li
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
- Department of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Tiantan Xili, Beijing, China
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, Florida
| | - Julie M Cunningham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Wolfgang Janni
- Department of Gynecology and Obstetrics, Ulm University Hospital, Ulm, Germany
| | - Alvaro N A Monteiro
- Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Daniel J Schaid
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Lothar Häberle
- Department of Gynecology and Obstetrics, University Breast Center for Franconia, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Comprehensive Cancer Center Erlangen EMN, Erlangen, Germany
- Department of Gynecology and Obstetrics, Unit of Biostatistics, Erlangen University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Richard M Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Liewei Wang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
22
|
Li P, Han M, Zhao X, Ren G, Mei S, Zhong C. Abnormal Epigenetic Regulations in the Immunocytes of Sjögren's Syndrome Patients and Therapeutic Potentials. Cells 2022; 11:1767. [PMID: 35681462 PMCID: PMC9179300 DOI: 10.3390/cells11111767] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 05/22/2022] [Accepted: 05/26/2022] [Indexed: 02/01/2023] Open
Abstract
Sjögren's syndrome (SjS), characterized by keratoconjunctivitis sicca and dry mouth, is a common autoimmune disease, especially in middle-aged women. The immunopathogenesis of SjS is caused by the sequential infiltration of T and B cells into exocrine glands, including salivary and lacrimal glands. Effector cytokines produced by these immunocytes, such as interferons (IFNs), IL-17, IL-22, IL-21, IL-4, TNF-α, BAFF and APRIL, play critical roles in promoting autoimmune responses and inducing tissue damages. Epigenetic regulations, including DNA methylation, histone modification and non-coding RNAs, have recently been comprehensively studied during the activation of various immunocytes. The deficiency of key epigenetic enzymes usually leads to aberrant immune activation. Epigenetic modifications in T and B cells are usually found to be altered during the immunopathogenesis of SjS, and they are closely correlated with autoimmune responses. In particular, the important role of methylation in activating IFN pathways during SjS progression has been revealed. Thus, according to the involvement of epigenetic regulations in SjS, target therapies to reverse the altered epigenetic modifications in auto-responsive T and B cells are worthy of being considered as a potential therapeutic strategy for SjS.
Collapse
Affiliation(s)
- Peng Li
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
| | - Mengwei Han
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
| | - Xingyu Zhao
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
| | - Guanqun Ren
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
| | - Si Mei
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
| | - Chao Zhong
- Beijing Key Laboratory of Tumor Systems Biology, School of Basic Medical Sciences, Institute of Systems Biomedicine, Peking University Health Science Center, 38 Xueyuan Road, Beijing 100191, China; (P.L.); (M.H.); (X.Z.); (G.R.); (S.M.)
- NHC Key Laboratory of Medical Immunology, Peking University, Beijing 100191, China
- Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing 100191, China
| |
Collapse
|
|
23
|
Garriz A, Morokuma J, Bowman M, Pagni S, Zoukhri D. Effects of proinflammatory cytokines on lacrimal gland myoepithelial cells contraction. FRONTIERS IN OPHTHALMOLOGY 2022; 2:873486. [PMID: 36147586 PMCID: PMC9491489 DOI: 10.3389/fopht.2022.873486] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
In the lacrimal gland, myoepithelial cells (MEC) express muscle contractile proteins such as alpha smooth muscle actin (SMA) and calponin and therefore can contract to help expel lacrimal fluid. In a previous study, we demonstrated that lacrimal gland MEC express the oxytocin receptor (OXTR) and they contract under oxytocin (OXT) stimulation. Using NOD and MRL/lpr mice (animal models of Sjogren's syndrome), we reported a decrease in SMA and calponin protein levels plus a decline in acini contraction after stimulation with OXT. It is known that proinflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α) or interferon gamma (IFN-γ), can affect OXTR expression and signaling capacity and inhibit MEC contraction. The aim of the current study was to investigate if proinflammatory cytokines are implicated in the loss of MEC contractile ability. Thus, lacrimal gland MEC from a SMA-GFP transgenic mouse were treated with IL-1β (10 ng/ml) for a total of 7 days. At days 0, 2, 4 and 7, GFP intensity, cell size/area, contractile proteins amounts and MEC contraction were assessed. At day 0, control and treated cells showed no differences in GFP intensity and cell size. GFP intensity started to decrease in treated MEC at day 2 (20%; p=0.02), continuing after day 4 (25%; p=0.007) and 7 (30%; p=0.0001). Mean cell area was also reduced at day 2 (34%; p=0.0005), and after 4 (51%; p<0.0001) and 7 days (30%; p=0.0015). The contraction assay at day 2 showed a 70% decrease of contraction in treated MEC (p<0.0001), 73% (p<0.0001) at day 4 and 82% (p=0.0015) at day 7 when compared to control. Levels of contractile proteins were measured on day 7 showing a decrease in SMA and calponin amount in treated MEC compared with the control group (around 30%; p=0.0016 and p=0.0206; respectively). Similar results were observed when TNF-α and IFN-γ were added along with IL-1β. Taken together the present data and those from our previous studies with Sjogren's syndrome mouse models, they strongly suggest that proinflammatory cytokines affect lacrimal gland MEC contractile ability that may account for the reduced tear secretion associated with Sjogren's syndrome dry eye disease.
Collapse
Affiliation(s)
- Angela Garriz
- Department of Comprehensive Care, Tufts University School
of Dental Medicine, Boston, MA, USA
| | - Junji Morokuma
- Department of Comprehensive Care, Tufts University School
of Dental Medicine, Boston, MA, USA
| | - Maytal Bowman
- Department of Comprehensive Care, Tufts University School
of Dental Medicine, Boston, MA, USA
| | - Sarah Pagni
- Public Health and Community Service, Tufts University
School of Dental Medicine, Boston, MA, USA
| | - Driss Zoukhri
- Department of Comprehensive Care, Tufts University School
of Dental Medicine, Boston, MA, USA
- Department of Ophthalmology, Tufts University School of
Medicine, Boston, MA, USA
| |
Collapse
|
|
24
|
Guo H, Ju Y, Choi M, Edman MC, Louie SG, Hamm-Alvarez SF, MacKay JA. Supra-lacrimal protein-based carriers for cyclosporine A reduce Th17-mediated autoimmunity in murine model of Sjögren's syndrome. Biomaterials 2022; 283:121441. [PMID: 35306230 PMCID: PMC8982551 DOI: 10.1016/j.biomaterials.2022.121441] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 01/17/2022] [Accepted: 02/24/2022] [Indexed: 01/11/2023]
Abstract
Sjögren's syndrome (SS) is a multifactorial autoimmune disease with principal symptoms including inflammation and loss of function of lacrimal glands (LG) and salivary glands. While glandular infiltrates includes both B- and T-cells, CD4+ T cells are strongly implicated. Utilizing the male non-obese diabetic (NOD) mouse model of SS, this work: 1) identifies clinically-relevant elevations in cytokines (IL-17A, IL-2) in LG-derived CD4+ T cells; and 2) explores tissue-specific immunosuppression of SS using a novel protein-based drug carrier to concentrate cyclosporine A (CsA) directly in the LG. As a potent immunosuppressant, topical ophthalmic CsA is approved for dry eye disorders; however, it cannot effectively resolve inflammation due to limited accumulation in the LG. Systemic CsA has dose-limiting side effects that also limit its ability to block LG inflammation. Using elastin-like polypeptides (ELPs) fused genetically to cyclophilin, the intracellular cognate receptor of CsA, this manuscript reports a sustained-release formulation of CsA that maintains therapeutic drug concentrations in the LG and extends intervals between doses. This formulation blocked both in vitro Th17 cell differentiation and IL-17A secretion. In vivo treatment significantly decreased the abundance of Th17.1 cells, a helper cell population sharing phenotypes of both Th17 and Th1, in the LG of diseased NOD mice. Treatment with even a single dose of the sustained-release formulation was effective enough to improve basal levels of tear production. Thus, this sustained-release formulation suppressed local LG inflammation driven through IL-17 dependent pathways, while improving ocular surface function.
Collapse
Affiliation(s)
- Hao Guo
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States.
| | - Yaping Ju
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States; Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Room 4900, Mail Code 6103, Los Angeles, CA, 90033, United States.
| | - Minchang Choi
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States.
| | - Maria C Edman
- Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Room 4900, Mail Code 6103, Los Angeles, CA, 90033, United States.
| | - Stan G Louie
- Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States.
| | - Sarah F Hamm-Alvarez
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States; Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Room 4900, Mail Code 6103, Los Angeles, CA, 90033, United States.
| | - J Andrew MacKay
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, 1985 Zonal Ave, Los Angeles, CA, 90033, United States; Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, 1450 San Pablo St., Room 4900, Mail Code 6103, Los Angeles, CA, 90033, United States; Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, 3650 McClintock Ave, Los Angeles, CA, 90089, United States.
| |
Collapse
|
|
25
|
The Clinical and Immunological Activity Depending on the Presence of Interferon γ in Primary Sjögren’s Syndrome—A Pilot Study. J Clin Med 2021; 11:jcm11010003. [PMID: 35011744 PMCID: PMC8745422 DOI: 10.3390/jcm11010003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/06/2021] [Accepted: 12/18/2021] [Indexed: 12/16/2022] Open
Abstract
The upregulation of IFN pathways and their stimulated genes is associated with primary Sjögren’s syndrome (pSS). The recent studies also indicate the involvement of interferon γ (IFNγ) in the pathogenesis of pSS. The study aimed to assess the clinical and immunological activity depending on the concentration of IFNγ in the peripheral blood in pSS patients. Methods: The study group consisted of patients over 18 years of age with a confirmed diagnosis of pSS. Based on the collected data, disease activity was assessed using the EULAR Sjögren’s syndrome disease activity index (ESSDAI) and the EULAR Sjögren’s syndrome patient reported index (ESSPRI). Results: Among 40 pSS patients, 33 (82%) showed increased levels of IFNγ. The group with positive IFNγ was younger (43 years) than the group with negative IFNγ (57 years) (p < 0.05). In the positive IFNγ group, the time to diagnosis was shorter (p < 0.05). There was a difference in ESSDAI among patients with and without IFNγ (p < 0.05). There were no differences between the groups in ESSPRI and the presence of cryoglobulins, specific anti-SSA, and anti-SSB antibodies and in C3 and C4 hypocomplementemia. RF occurred in both groups with a similar frequency (p = 0.6), but in patients with IFNγ presence, significantly higher RF titers were observed (34.9 vs. 10.5; p < 0.05). Conclusion: In the group of patients with positive IFNγ, the mean value of RF and ESSDAI was higher. This group was also younger than patients with pSS without IFNγ.
Collapse
|
|
26
|
Qi X, Wang XQ, Jin L, Gao LX, Guo HF. Uncovering potential single nucleotide polymorphisms, copy number variations and related signaling pathways in primary Sjogren's syndrome. Bioengineered 2021; 12:9313-9331. [PMID: 34723755 PMCID: PMC8809958 DOI: 10.1080/21655979.2021.2000245] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Primary Sjogren’s syndrome (pSS) is a complex systemic autoimmune disease, which is difficult to accurately diagnose due to symptom diversity in patients, especially at earlier stages. We tried to find potential single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and related signaling pathways. Genomic DNA was extracted from peripheral blood of 12 individuals (7 individuals from 3 pSS pedigrees and 5 sporadic cases) for whole-exome sequencing (WES) analysis. SNPs and CNVs were identified, followed by functional annotation of genes with SNPs and CNVs. Gene expression profile (involving 64 normal controls and 166 cases) was downloaded from the Gene Expression Omnibus database (GEO) dataset for differentially expression analysis. Sanger sequencing and in vitro validation was used to validate the identified SNPs and differentially expressed genes, respectively. A total of 5 SNPs were identified in both pedigrees and sporadic cases, such as FES, PPM1J, and TRAPPC9. A total of 3402 and 19 CNVs were identified in pedigrees and sporadic cases, respectively. Fifty-one differentially expressed genes were associated with immunity, such as BATF3, LAP3, BATF2, PARP9, and IL15RA. AMPK signaling pathway and cell adhesion molecules (CAMs) were the most significantly enriched signaling pathways of identified SNPs. Identified CNVs were associated with systemic lupus erythematosus, mineral absorption, and HTLV-I infection. IL2-STAT5 signaling, interferon-gamma response, and interferon-alpha response were significantly enriched immune related signaling pathways of identified differentially expressed genes. In conclusion, our study found some potential SNPs, CNVs, and related signaling pathways, which could be useful in understanding the pathological mechanism of pSS.
Collapse
Affiliation(s)
- Xuan Qi
- Department of Rheumatism and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xi-Qin Wang
- Internal Medicine, Yuhua Yunfang Integrated Traditional Chinese and Western Medicine Clinic, Shijiazhuang, Hebei, China
| | - Lu Jin
- Department of Rheumatism and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Li-Xia Gao
- Department of Rheumatism and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hui-Fang Guo
- Department of Rheumatism and Immunology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| |
Collapse
|
|
27
|
Autoimmune Epithelitis and Chronic Inflammation in Sjögren's Syndrome-Related Dry Eye Disease. Int J Mol Sci 2021; 22:ijms222111820. [PMID: 34769250 PMCID: PMC8584177 DOI: 10.3390/ijms222111820] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 10/07/2021] [Accepted: 10/09/2021] [Indexed: 12/18/2022] Open
Abstract
Autoimmune epithelitis and chronic inflammation are one of the characteristic features of the immune pathogenesis of Sjögren’s syndrome (SS)-related dry eye disease. Autoimmune epithelitis can cause the dysfunction of the excretion of tear fluid and mucin from the lacrimal glands and conjunctival epithelia and meibum from the meibomian glands. The lacrimal gland and conjunctival epithelia express major histocompatibility complex class II or human leukocyte antigen-DR and costimulatory molecules, acting as nonprofessional antigen-presenting cells for T cell and B cell activation in SS. Ocular surface epithelium dysfunction can lead to dry eye disease in SS. Considering the mechanisms underlying SS-related dry eye disease, this review highlights autoimmune epithelitis of the ocular surface, chronic inflammation, and several other molecules in the tear film, cornea, conjunctiva, lacrimal glands, and meibomian glands that represent potential targets in the treatment of SS-related dry eye disease.
Collapse
|
|
28
|
Chang CM, Wu PC, Lin JR, Jan Wu YJ, Luo SF, Hsue YT, Lan JL, Pan TL, Wu YT, Yu KH, Wei YH, Chang HH. Herbal Formula SS-1 Increases Tear Secretion for Sjögren's Syndrome. Front Pharmacol 2021; 12:645437. [PMID: 34630072 PMCID: PMC8498214 DOI: 10.3389/fphar.2021.645437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 09/13/2021] [Indexed: 11/21/2022] Open
Abstract
Background: Sjögren’s syndrome (SS) is an autoimmune inflammatory disease that primarily affects the exocrine glands, leading to glandular dysfunction. The hallmark symptoms of SS are dry eyes and mouth, compromising the quality of life of patients and decreasing their capacity to perform their daily activities. Objective: This study aims to evaluate the efficacy of the herbal formula SS-1 for its potential therapeutic benefits for patients with Sjögren’s syndrome. Materials and Methods: The bioactivity profile of SS-1 was determined using four different SS-1 concentrations across 12 human primary cell systems of the BioMAP profile. After that, a randomized, double-blind, crossover, placebo-controlled trial was performed including 57 patients treated with SS-1 for 28 weeks. Results: Biologically multiplexed activity profiling in cell-based models indicated that SS-1 exerted anti-proliferative activity in B cells and promoted anti-inflammatory and immunomodulatory activity. In the clinical trial, Schirmer’s test results revealed significant improvements in both eyes, with increases of 3.42 mm (95% CI, 2.44–4.41 mm) and 3.45 mm (95% CI, 2.32–4.59 mm), respectively, and a significant reduction in artificial tear use, which was −1.38 times/day, 95% CI, −1.95 to −0.81 times/day. Moreover, the increases in B-cell activating factor (BAFF) and B-cell maturation antigen (BCMA) levels were dampened by 53.20% (295.29 versus 555.02 pg/ml) and 58.33% (99.16 versus 169.99 pg/ml), respectively. Conclusion: SS-1 treatment significantly inhibited B-cell maturation antigen. No serious drug-related adverse effects were observed. Oral SS-1 administration may be a complementary treatment for Sjögren’s syndrome.
Collapse
Affiliation(s)
- Ching-Mao Chang
- Center for Traditional Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Institute of Traditional Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
| | - Po-Chang Wu
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Jr-Rung Lin
- Clinical Informatics and Medical Statistics Research Center, Graduate Institute of Clinical Medical, Chang Gung University, Taoyuan, Taiwan
| | - Yeong-Jian Jan Wu
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Shue-Fen Luo
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yin-Tzu Hsue
- Department of Internal Medicine, Division of Rheumatology, Allergy and Immunology, Changhua Christian Hospital, Changhua, Taiwan
| | - Joung-Liang Lan
- Rheumatology and Immunology Center, China Medical University Hospital, Taichung, Taiwan.,College of Medicine, China Medical University, Taichung, Taiwan
| | - Tai-Long Pan
- School of Traditional Chinese Medicine and Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan, Taiwan.,Research Center for Chinese Herbal Medicine and Research Center for Food and Cosmetic Safety, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan.,Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Yu-Ting Wu
- Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua, Taiwan
| | - Kuang-Hui Yu
- Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yau-Huei Wei
- Center for Mitochondrial Medicine and Free Radical Research, Changhua Christian Hospital, Changhua, Taiwan.,Department of Biochemistry and Molecular Biology, School of Life Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan.,Department of Medicine, Mackay Medical College, Taipei, Taiwan
| | - Hen-Hong Chang
- Graduate Institute of Integrated Medicine, College of Chinese Medicine, and Chinese Medicine Research Center, China Medical University, Taichung, Taiwan.,Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan
| |
Collapse
|
|
29
|
Chihaby N, Orliaguet M, Le Pottier L, Pers JO, Boisramé S. Treatment of Sjögren's Syndrome with Mesenchymal Stem Cells: A Systematic Review. Int J Mol Sci 2021; 22:10474. [PMID: 34638813 PMCID: PMC8508641 DOI: 10.3390/ijms221910474] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 09/23/2021] [Accepted: 09/23/2021] [Indexed: 01/10/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are ubiquitous in the human body. Mesenchymal stem cells were initially isolated from bone marrow and later from other organs such as fatty tissues, umbilical cords, and gingiva. Their secretory capacities give them interesting immunomodulatory properties in cell therapy. Some studies have explored the use of MSCs to treat Sjögren's syndrome (SS), a chronic inflammatory autoimmune disease that mainly affects exocrine glands, including salivary and lacrimal glands, although current treatments are only palliative. This systematic review summarizes the current data about the application of MSCs in SS. Reports show improvements in salivary secretions and a decrease in lymphocytic infiltration in salivary glands in patients and mice with SS after intravenous or infra-peritoneal injections of MSCs. MSC injections led to a decrease in inflammatory cytokines and an increase in anti-inflammatory cytokines. However, the intrinsic mechanism of action of these MSCs currently remains unknown.
Collapse
Affiliation(s)
- Najwa Chihaby
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
| | - Marie Orliaguet
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
| | - Laëtitia Le Pottier
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- Inserm, LBAI, University of Western Brittany, UMR1227, 29609 Brest, France
| | - Jacques-Olivier Pers
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
- Inserm, LBAI, University of Western Brittany, UMR1227, 29609 Brest, France
| | - Sylvie Boisramé
- UFR d’Odontologie, University of Western Brittany, 29200 Brest, France; (N.C.); (M.O.); (L.L.P.); (S.B.)
- CHU de Brest, 29609 Brest, France
| |
Collapse
|
|
30
|
Abstract
Sjögren's syndrome (SjS) is a systemic autoimmune disease marked by xerostomia (dry mouth), keratoconjunctivitis sicca (eye dryness), and other systematic disorders. Its pathogenesis involves an inflammatory process that is characterized by lymphocytic infiltration into exocrine glands and other tissues. Although the development of ectopic lymphoid tissue and overproduction of autoantibodies by hyperactive B cells suggest that they may promote SjS development, treatment directed towards them fails to induce significant laboratory or clinical improvement. T cells are overwhelming infiltrators in most phases of the disease, and the involvement of multiple T cell subsets of suggests the extraordinary complexity of SjS pathogenesis. The factors, including various cellular subtypes and molecules, regulate the activation and suppression of T cells. T cell activation induces inflammatory cell infiltration, B cell activation, tissue damage, and metabolic changes in SjS. Knowledge of the pathways that link these T cell subtypes and regulation of their activities are not completely understood. This review comprehensively summarizes the research progress and our understanding of T cells in SjS, including CD4+ T cells, CD8+ TRM cells, and innate T cells, to provide insights into for clinical treatment.
Collapse
|
|
31
|
Du W, Han M, Zhu X, Xiao F, Huang E, Che N, Tang X, Zou H, Jiang Q, Lu L. The Multiple Roles of B Cells in the Pathogenesis of Sjögren's Syndrome. Front Immunol 2021; 12:684999. [PMID: 34168653 PMCID: PMC8217880 DOI: 10.3389/fimmu.2021.684999] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Accepted: 05/21/2021] [Indexed: 12/12/2022] Open
Abstract
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by lymphocytic infiltration and tissue destruction of exocrine glands such as salivary glands. Although the formation of ectopic lymphoid tissue in exocrine glands and overproduction of autoantibodies by autoreactive B cells highlight the critical involvement of B cells in disease development, the precise roles of various B cell subsets in pSS pathogenesis remain partially understood. Current studies have identified several novel B cell subsets with multiple functions in pSS, among which autoreactive age-associated B cells, and plasma cells with augmented autoantibody production contribute to the disease progression. In addition, tissue-resident Fc Receptor-Like 4 (FcRL4)+ B cell subset with enhanced pro-inflammatory cytokine production serves as a key driver in pSS patients with mucosa-associated lymphoid tissue (MALT)-lymphomas. Recently, regulatory B (Breg) cells with impaired immunosuppressive functions are found negatively correlated with T follicular helper (Tfh) cells in pSS patients. Further studies have revealed a pivotal role of Breg cells in constraining Tfh response in autoimmune pathogenesis. This review provides an overview of recent advances in the identification of pathogenic B cell subsets and Breg cells, as well as new development of B-cell targeted therapies in pSS patients.
Collapse
Affiliation(s)
- Wenhan Du
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China
| | - Man Han
- Division of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Xiaoxia Zhu
- Department of Rheumatology, Huashan Hospital and Fudan University, Shanghai, China
| | - Fan Xiao
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.,Chongqing International Institute for Immunology, Chongqing, China
| | - Enyu Huang
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.,Chongqing International Institute for Immunology, Chongqing, China
| | - Nan Che
- Department of Rheumatology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu, China
| | - Xiaopo Tang
- Division of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Hejian Zou
- Department of Rheumatology, Huashan Hospital and Fudan University, Shanghai, China
| | - Quan Jiang
- Division of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Liwei Lu
- Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong, China.,Chongqing International Institute for Immunology, Chongqing, China
| |
Collapse
|
|
32
|
Effect of the Chinese Herbal Medicine SS-1 on a Sjögren's Syndrome-Like Disease in Mice. Life (Basel) 2021; 11:life11060530. [PMID: 34200223 PMCID: PMC8229783 DOI: 10.3390/life11060530] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2021] [Revised: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 12/17/2022] Open
Abstract
Sjögren’s syndrome (SS) is an inflammatory autoimmune disease primarily affecting the exocrine glands; it has a major impact on patients’ lives. The Chinese herbal formula SS-1 is composed of Gan Lu Yin, Sang Ju Yin, and Xuefu Zhuyu decoction, which exerts anti-inflammatory, immunomodulatory, and antifibrotic effects. Our previous study demonstrated that SS-1 alleviates clinical SS. This study aimed to evaluate the efficacy and mechanism of the Chinese herbal formula SS-1 for salivary gland protein-induced experimental Sjögren’s syndrome (ESS). These results showed that ESS treatment with the Chinese herbal formula SS-1 (1500 mg/kg) significantly alleviated the severity of ESS. We found that SS-1 substantially improved saliva flow rates in SS mice and ameliorated lymphocytic infiltrations in submandibular glands. In addition, salivary gland protein-induced SS in mice treated with SS-1 significantly lowered proinflammatory cytokines (including IFN-γ, IL-6, and IL-17A) in mouse salivary glands and decreased serum anti-M3R autoantibody levels. In addition, we found that CD4+ T cells isolated from SS-1-treated SS mice significantly reduced the percentages of IFN-γ-producing CD4+ T cells (Th1) and IL-17A-producing CD4+ T cells (Th17). Our data show that SS-1 alleviates ESS through anti-inflammatory and immunomodulatory effects, which provides new insight into the clinical treatment of SS.
Collapse
|
|
33
|
Liang Y, Xian Z, Fu D, Liu S, Yao Y, Jin Y, Gao C, Shen L, Shi G, He J. IL-14α as a Putative Biomarker for Stratification of Dry Eye in Primary Sjögren's Syndrome. Front Immunol 2021; 12:673658. [PMID: 34012457 PMCID: PMC8126710 DOI: 10.3389/fimmu.2021.673658] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 04/13/2021] [Indexed: 11/24/2022] Open
Abstract
Background Dry eye is often the first presenting manifestation of primary Sjögren’s syndrome (pSS). Because of the high prevalence of dry eye disease in normal population, ophthalmologists urgently need a non-invasive and reliable screening test to diagnose dry eye associated SS patients, other than ocular symptoms and signs. Currently, there is no single test available. The correlation of serum IL-14α with pSS has been found in pSS mouse model. Purpose To evaluate whether IL-14α can serve as a biomarker to stratify dry eye in primary Sjögren’s syndrome and its correlation to BAFF in a cohort of patients with non-SS dry eye (NSDE), pSS with dry eye disease, rheumatoid arthritis (RA), and healthy controls (HC). Methods Retrospective study based on serum levels of IL-14α (defined by Western Blot) and BAFF (measured by ELISA) were evaluated among pSS with dry eye disease, NSDE, RA, and HC groups. Serum levels of SS related autoantibodies (Ro, La, SP1, PSP, and CA6) were also measured by ELISA. Results One hundred and eighty patients were included for the current study, patients were separated into four groups as defined by pSS (n=65), NSDE (n=20), RA (n=50) and HC (n=45). The level of serum IL-14α in pSS was significantly higher compared to NSDE, RA, and HC (p=0.0011, p=0.0052 and p<0.0001, respectively). The levels of serum BAFF in pSS was significantly higher than in NSDE and HC (p=0.0148 and p<0.0001, respectively, whereas the levels of serum BAFF in RA was only significantly higher than in HC (p=0.001), but the level of BAFF was no significant difference between pSS and RA. In pSS, there was a decrease in the serum levels of IL-14α associated with a longer duration of the disease. Also, there was a correlation between the serum levels of IL-14α and SS related autoantibodies such as anti-SSA/Ro and anti-SSB/La in pSS patients. Conclusions This is the first paper to report both IL-14α and BAFF could serve as a critical cytokine biomarker for the stratification of dry eye in primary Sjögren’s syndrome. This may help ophthalmologists to develop non-invasive metrics for the diagnosis of dry eye associated pSS.
Collapse
Affiliation(s)
- Yichen Liang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Zhenhua Xian
- Department of Gastrointestinal Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Dehua Fu
- Department of Gastrointestinal Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Shuang Liu
- Department of Gastrointestinal Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Yang Yao
- Department of Gastrointestinal Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Yuebo Jin
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| | - Chun Gao
- Department of Gastrointestinal Surgery, Tongji Hospital of Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
| | - Long Shen
- Department of Oncology, Northern Jiangsu People's Hospital, Yangzhou, China.,Department of Oncology, Cancer Institute Affiliated to Northern Jiangsu People's Hospital, Yangzhou, China.,Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Guixiu Shi
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xiamen University, Xiamen, China
| | - Jing He
- Department of Rheumatology and Immunology, Peking University People's Hospital, Beijing, China
| |
Collapse
|
|
34
|
The Involvement of Innate and Adaptive Immunity in the Initiation and Perpetuation of Sjögren's Syndrome. Int J Mol Sci 2021; 22:ijms22020658. [PMID: 33440862 PMCID: PMC7826728 DOI: 10.3390/ijms22020658] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/01/2021] [Accepted: 01/06/2021] [Indexed: 02/07/2023] Open
Abstract
Sjogren’s syndrome (SS) is a chronic autoimmune disease characterized by the infiltration of exocrine glands including salivary and lachrymal glands responsible for the classical dry eyes and mouth symptoms (sicca syndrome). The spectrum of disease manifestations stretches beyond the classical sicca syndrome with systemic manifestations including arthritis, interstitial lung involvement, and neurological involvement. The pathophysiology underlying SS is not well deciphered, but several converging lines of evidence have supported the conjuncture of different factors interplaying together to foster the initiation and perpetuation of the disease. The innate and adaptive immune system play a cardinal role in this process. In this review, we discuss the inherent parts played by both the innate and adaptive immune system in the pathogenesis of SS.
Collapse
|
|
35
|
Parisis D, Chivasso C, Perret J, Soyfoo MS, Delporte C. Current State of Knowledge on Primary Sjögren's Syndrome, an Autoimmune Exocrinopathy. J Clin Med 2020; 9:E2299. [PMID: 32698400 PMCID: PMC7408693 DOI: 10.3390/jcm9072299] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2020] [Revised: 07/15/2020] [Accepted: 07/16/2020] [Indexed: 12/13/2022] Open
Abstract
Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3-3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the "autoimmune epithelitis" still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin's lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.
Collapse
Affiliation(s)
- Dorian Parisis
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
- Department of Rheumatology, Erasme Hospital, Université Libre de Bruxelles, 1070 Brussels, Belgium;
| | - Clara Chivasso
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
| | - Jason Perret
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
| | | | - Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 1070 Brussels, Belgium; (D.P.); (C.C.); (J.P.)
| |
Collapse
|
|
36
|
Pilson Q, Smith S, Jefferies CA, Ní Gabhann-Dromgoole J, Murphy CC. miR-744-5p contributes to ocular inflammation in patients with primary Sjogrens Syndrome. Sci Rep 2020; 10:7484. [PMID: 32366870 PMCID: PMC7198540 DOI: 10.1038/s41598-020-64422-5] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 12/11/2019] [Indexed: 01/15/2023] Open
Abstract
In primary Sjögren’s syndrome (pSS) the exocrine glands become infiltrated with lymphocytes instigating severe damage to the salivary and lacrimal glands causing dry eyes and dry mouth. Previous investigations have suggested that dysregulated localized and systemic inflammation contributes to the development and pathogenesis of pSS. A miR microarray performed in primary human conjunctival epithelial cells (PECs) demonstrated significant differences in miR expression at the ocular surface between pSS patients and healthy controls. MicroRNA-744-5p (miR-744-5p) was identified as being of particular interest, as its top predicted target is Pellino3 (PELI3), a known negative regulator of inflammation. Validation studies confirmed that miR-744-5p expression is significantly increased in PECs from pSS patients, whilst PELI3 was significantly reduced. We validated the miR-744 binding site in the 3’ untranslated region (UTR) of PELI3 and demonstrated that increasing PELI3 levels with a miR-744-5p antagomir in an inflammatory environment resulted in reduced levels of IFN dependent chemokines Rantes (CCL5) and CXCL10. These results reveal a novel role for miR-744-5p in mediating ocular inflammation via Pellino3 expression in pSS patients and suggest that miR-744-5p may be a potential therapeutic target for the management of severe dry eye disease and ocular inflammation in pSS patients.
Collapse
Affiliation(s)
- Qistina Pilson
- Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland.,Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland
| | - Siobhan Smith
- School of Pharmacy and Biomolecular Sciences (PBS) and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Caroline A Jefferies
- Division of Rheumatology, Department of Medicine, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, California, 90048, USA.,Department of Biomedical Sciences, Cedars-Sinai Medical Centre, 8700 Beverly Blvd, Los Angeles, California, 90048, USA
| | - Joan Ní Gabhann-Dromgoole
- School of Pharmacy and Biomolecular Sciences (PBS) and RSCI Research Institute, Royal College of Surgeons in Ireland, Dublin 2, Ireland.,Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland
| | - Conor C Murphy
- Department of Ophthalmology, Royal College of Surgeons in Ireland, Dublin 2, Ireland. .,Department of Ophthalmology, Royal Victoria Eye and Ear Hospital, Dublin 2, Ireland.
| |
Collapse
|
|
37
|
Zhou J, You BR, Yu Q. Agonist-induced 4-1BB activation prevents the development of Sjӧgren's syndrome-like sialadenitis in non-obese diabetic mice. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165605. [PMID: 31740402 DOI: 10.1016/j.bbadis.2019.165605] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 10/15/2019] [Accepted: 11/01/2019] [Indexed: 11/19/2022]
Abstract
Activation of costimulatory receptor 4-1BB enhances T helper 1 (Th1) and CD8 T cell responses in protective immunity, and prevents or attenuates several autoimmune diseases by increasing Treg numbers and suppressing Th17 or Th2 effector response. We undertook this study to elucidate the impact of enforced 4-1BB activation on the development of Sjögren's syndrome (SS)-like sialadenitis in non-obese diabetic (NOD) model of this disease. An anti-4-1BB agnostic antibody was intraperitoneally injected to female NOD mice aged 7 weeks, prior to the disease onset that occurs around 10-11 weeks of age, 3 times weekly for 2 weeks, and the mice were analyzed for SS pathologies at age 11 weeks. The salivary flow rate was markedly higher in the anti-4-1BB-treated NOD mice compared to the IgG-treated controls. Anti-4-1BB treatment significantly reduced the leukocyte infiltration of the submandibular glands (SMGs) and the levels of serum antinuclear antibodies. Flow cytometric analysis showed that the percentages of CD4 T cells, Th17 cells and plasmacytoid dendritic cells among SMG leukocytes were markedly reduced by anti-4-1BB treatment, in conjunction with a reduction in SMG IL-23p19 mRNA levels and serum IL-17 concentrations. Although the proportion of Tregs and IL-10 mRNA levels in SMGs were not altered by 4-1BB activation, IL-10 mRNA levels in salivary gland-draining lymph nodes and serum IL-10 concentrations were both markedly increased. While anti-4-1BB treatment did not affect the amount of Th1 cells and IFNγ mRNA in the SMGs, it increased these measurables in salivary gland-draining lymph nodes. Hence, agonistic activation of 4-1BB impedes the development of SS-like sialadenitis and hyposalivation.
Collapse
Affiliation(s)
- Jing Zhou
- The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
| | - Bo Ra You
- The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA
| | - Qing Yu
- The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA; Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA.
| |
Collapse
|
|
38
|
Choi SS, Jang E, Jang K, Jung SJ, Hwang KG, Youn J. Autoantibody-Mediated Dysfunction of Salivary Glands Leads to Xerostomia in SKG Mice. Immune Netw 2019; 19:e44. [PMID: 31921474 PMCID: PMC6943169 DOI: 10.4110/in.2019.19.e44] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/29/2019] [Accepted: 12/13/2019] [Indexed: 01/10/2023] Open
Abstract
Sjögren's syndrome (SS) is a chronic heterogeneous disease that mainly affects exocrine glands, leading to sicca syndromes such as xerostomia. Despite the second highest prevalence rate among systemic autoimmune diseases, its pathophysiology remains largely unknown. Here we report that SKG mice, a cardinal model of Th17 cell-mediated arthritis, also develop a secondary form of SS-like disorder upon systemic exposure to purified curdlan, a type of β-glucan. The reduced production of saliva was not caused by focal immune cell infiltrates but was associated with IgG deposits in salivary glands. Sera from curdlan-injected SKG mice contained elevated titers of IgG (predominantly IgG1), autoantibody to the muscarinic type 3 receptor (M3R) and inhibited carbachol-induced Ca2+ signaling in salivary acinar cells. These results suggest that the Th17 cells that are elicited in SKG mice promote the production of salivary gland-specific autoantibodies including anti-M3R IgG; the antibodies are then deposited on acinar cells and inhibit M3R-mediated signaling required for salivation, finally leading to hypofunction of the salivary glands. This type II hypersensitivity reaction may explain the origin of secondary SS occurring without focal leukocyte infiltrates.
Collapse
Affiliation(s)
- Suk San Choi
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Eunkyeong Jang
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Kiseok Jang
- Department of Pathology, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Sung Jun Jung
- Department of Physiology, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Kyung-Gyun Hwang
- Division of Oral & Maxillofacial Surgery, Department of Dentistry, Hanyang University College of Medicine, Seoul 04763, Korea
| | - Jeehee Youn
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul 04763, Korea
| |
Collapse
|
|
39
|
Abstract
PURPOSE OF REVIEW The purpose of this article is to draw attention to the role of Epstein-Barr virus (EBV) virus in the pathogenesis of the primary Sjögren's syndrome. The article introduces the problem of consequences of EBV acute infection, and its reactivation, in association with the immune response modulation by the virus and with an increased risk of developing systemic autoimmune diseases and EBV-associated cancers. RECENT FINDINGS The knowledge about the mechanisms by which the virus may stay for years in a latent phase, unrecognized by the host response immune cells is constantly expanding. There are several mechanisms and theories about EBV influence on the autoimmune process in Sjogren's syndrome (pSS), including the similarity (molecular mimicry) between viral EBNA-2 protein and Ro-60 antigen or EBER-1 and EBER-2 viral proteins and La antigen. SUMMARY The influence of EBV infection on the development and course of pSS has been proven. It has also been established that both EBV and pSS result in the increased risk of tumor (especially lymphoma) development. In the light of these findings, new ways to manage EBV infections are being sought. Optimal methods for assessing EBV infection status are being devised. Research also aims at finding therapies, which target EBV through the inhibition of the autoimmune process and of viral activity. The present article is an attempt to discuss the most important phenomena and elements linking EBV infection to the primary Sjögren's syndrome.
Collapse
Affiliation(s)
- Maria Maślińska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Early Arthritis Clinic, Spartanska1, Warsaw, Poland
| |
Collapse
|
|
40
|
Scuron MD, Fay B, Oliver J, Smith P. Spontaneous Model of Sjögren's Syndrome in NOD Mice. ACTA ACUST UNITED AC 2019; 86:e65. [DOI: 10.1002/cpph.65] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
|
|
41
|
Lopes AP, van Roon JAG, Blokland SLM, Wang M, Chouri E, Hartgring SAY, van der Wurff-Jacobs KMG, Kruize AA, Burgering BMT, Rossato M, Radstake TRDJ, Hillen MR. MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and Stress-Activated Protein Kinase-1. Front Immunol 2019; 10:1335. [PMID: 31281310 PMCID: PMC6595962 DOI: 10.3389/fimmu.2019.01335] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 05/28/2019] [Indexed: 12/14/2022] Open
Abstract
Objectives: Considering the critical role of microRNAs (miRNAs) in regulation of cell activation, we investigated their role in circulating type-2 conventional dendritic cells (cDC2s) of patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC). Methods: CD1c-expressing cDC2s were isolated from peripheral blood. A discovery cohort (15 pSS, 6 HC) was used to screen the expression of 758 miRNAs and a replication cohort (15 pSS, 11 HC) was used to confirm differential expression of 18 identified targets. Novel targets for two replicated miRNAs were identified by SILAC in HEK-293T cells and validated in primary cDC2s. Differences in cytokine production between pSS and HC cDC2s were evaluated by intracellular flow-cytometry. cDC2s were cultured in the presence of MSK1-inhibitors to investigate their effect on cytokine production. Results: Expression of miR-130a and miR-708 was significantly decreased in cDC2s from pSS patients compared to HC in both cohorts, and both miRNAs were downregulated upon stimulation via endosomal TLRs. Upstream mediator of cytokine production MSK1 was identified as a novel target of miR-130a and overexpression of miR-130a reduced MSK1 expression in cDC2s. pSS cDC2s showed higher MSK1 expression and an increased fraction of IL-12 and TNF-α-producing cells. MSK1-inhibition reduced cDC2 activation and production of IL-12, TNF-α, and IL-6. Conclusions: The decreased expression of miR-130a and miR-708 in pSS cDC2s seems to reflect cell activation. miR-130a targets MSK1, which regulates pro-inflammatory cytokine production, and we provide proof-of-concept for MSK1-inhibition as a therapeutic avenue to impede cDC2 activity in pSS.
Collapse
Affiliation(s)
- Ana P Lopes
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Joel A G van Roon
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Sofie L M Blokland
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Maojie Wang
- Department of Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Eleni Chouri
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Sarita A Y Hartgring
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Kim M G van der Wurff-Jacobs
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Aike A Kruize
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Boudewijn M T Burgering
- Department of Molecular Cancer Research, Center Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Marzia Rossato
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Biotechnology, University of Verona, Verona, Italy
| | - Timothy R D J Radstake
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Maarten R Hillen
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| |
Collapse
|
|
42
|
Maślińska M, Mańczak M, Kwiatkowska B. Usefulness of rheumatoid factor as an immunological and prognostic marker in PSS patients. Clin Rheumatol 2019; 38:1301-1307. [PMID: 30810912 DOI: 10.1007/s10067-019-04438-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 12/30/2018] [Accepted: 01/07/2019] [Indexed: 10/27/2022]
Abstract
INTRODUCTION The rheumatoid factor (RF) is present in numerous autoimmune disorders, although its role in many of them remains a subject of research. The study assesses the role of RF as an immunological and prognostic factor in the primary Sjögren's syndrome (pSS). METHODS Seventy-five pSS patients (mean age 50.03 ± 15.1), 65 (87%) females, and 10 (13%) males. WBC, CRP, RF, ESR, gammaglobulins, C4, C3 component of complement, cryoglobulins, ANA, anti-SS-A, and anti-SS-B antibodies were determined. The disease activity assessed with ESSDAI. Minor salivary gland biopsy (focus score and immunochemistry) was conducted. Results were analyzed with U Mann-Whitney (continuous variables) tests, correlations between quantitative variables assessed with the Spearman correlation coefficient with statistical significance set at p < 0.05. The approval of the Bioethics Committee was obtained. RESULTS Two subgroups I-RF(+) (61%) and II-RF(-) (39%) were established, with lower WBC (p = 0.012) and higher ESR (p = 0.016), gammaglobulin concentration (p = 0.007) in group I. Conjunctivitis sicca was more severe in group I. There was positive correlation between RF and lnANA (rho = 0.496), anti-SS-A, anti-SS-B antibodies (rho = 0.448; rho = 0.397 respectively). There was higher disease activity ESSDAI in group I than in group II (Me, 3.0 vs 2.0; p < 0.003). RF correlated negatively with WBC (rho = - 0.374). RF did not correlate with serum concentrations of BAFF, APRIL, CRP, and C3, C4 and with CD19+, CD3+, CD4+, CD 21+, and CD35+. CONCLUSIONS RF should be considered as a prognostic, but not diagnostic, factor in patients with pSS, as it is associated with more severe disease course (sicca eye symptoms, ESSDAI) and parameters (production of gammaglobulins, ANA, anti SS-A, anti-SS-B autoantibodies) indicating increased B cell activity.
Collapse
Affiliation(s)
- Maria Maślińska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Early Arthritis Clinic, Warsaw, Poland.
| | - Małgorzata Mańczak
- Department of Gerontology and Public Health, National Institute of Geriatrics, Rheumatology and Rehabilitation, Warsaw, Poland
| | - Brygida Kwiatkowska
- National Institute of Geriatrics, Rheumatology and Rehabilitation, Early Arthritis Clinic, Warsaw, Poland
| |
Collapse
|
|
43
|
Affiliation(s)
- Toshio Odani
- Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - John A. Chiorini
- Adeno-Associated Virus Biology Section, Molecular Physiology and Therapeutics Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| |
Collapse
|
|
44
|
Subgroups of Sjögren's syndrome patients categorised by serological profiles: clinical and immunological characteristics. Reumatologia 2018; 56:346-353. [PMID: 30647480 PMCID: PMC6330679 DOI: 10.5114/reum.2018.80711] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Accepted: 11/30/2018] [Indexed: 11/17/2022] Open
Abstract
Objectives Sjögren's syndrome (SS) is an autoimmune disease characterised by heterogeneous clinical presentation and presence of various autoantibodies - anti-SSA/Ro of diagnostic value, less specific anti-SSB/La and others. We searched for biomarker(s) and potential therapeutic target(s) of SS subsets that vary in their autoantibody profile. Material and methods Eighty-one patients with SS (70 female and 11 male) and 38 healthy volunteers (28 female and 10 male) were included in the study. Patients were categorised according to absence (group 1) or presence of anti-SSA/Ro antibody which occurred either alone (group 2) or together with anti-SSB/La (group 3). Clinical evaluation was performed, and presence of autoantibodies and concentrations of cytokines relevant to SS pathogenesis, i.e. a proliferation inducing ligand (APRIL), B-lymphocyte activating factor (BAFF), interleukin (IL) 4, IL-10, interferon α (IFN-α) and thymic stromal lymphopoietin (TSLP), in sera were determined. Results Frequency of autoantibodies other than anti-SSA/Ro and anti-SSB/La, the number of autoantibody specificities and anti-nuclear antibody titres were higher in group 2 and/or 3 than in group 1 of SS patients. Moreover, SS patients of groups 2 and 3 developed disease symptoms at younger age, and more often had positive Schirmer's test and skin lesions. In addition, serum concentrations of APRIL, but not other tested cytokines, were significantly higher in the patients of both groups 2 and 3 than those of group 1 and healthy volunteers. Conclusions Sjögren's syndrome patients with signs of B-cell epitope spreading are characterised by early disease onset, more frequent xerophthalmia and skin involvement, and up-regulated serum APRIL level. We suggest that therapeutic neutralisation of APRIL may be beneficial for these patients.
Collapse
|
|
45
|
Current and Emerging Evidence for Toll-Like Receptor Activation in Sjögren's Syndrome. J Immunol Res 2018; 2018:1246818. [PMID: 30671484 PMCID: PMC6317121 DOI: 10.1155/2018/1246818] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Accepted: 10/30/2018] [Indexed: 02/06/2023] Open
Abstract
While the importance of Toll-like receptor (TLR) signaling is well established in many autoimmune diseases, the role of TLR activation in Sjögren's syndrome (SS) is poorly understood. Studies in mice and humans reveal that TLRs are potent mediators of inflammation in SS. TLRs are expressed and functional in salivary tissue, and TLRs in peripheral blood cells of SS patients are also upregulated and hyperresponsive to ligation. In this review, we will detail observations in mouse models regarding the importance of TLR activation in both local and systemic disease. We will then discuss studies in SS patients that provide evidence of the importance of TLR-mediated signaling in disease. While the ligands that activate TLRs in the context of SS are unknown, emerging data suggest that damage-associated molecular patterns (DAMPs) may be significant drivers of the chronic and unremitting inflammation that is characteristic of SS. We will discuss putative DAMPs that may be of clinical significance in disease. Therapies that target TLR signaling cascades will likely reduce both exocrine-specific and systemic manifestations of SS.
Collapse
|
|
46
|
Chen FY, Gaylord E, McNamara N, Knox S. 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:E3628. [PMID: 30453645 PMCID: PMC6274681 DOI: 10.3390/ijms19113628] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/13/2018] [Accepted: 11/13/2018] [Indexed: 01/10/2023] Open
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 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.
Collapse
Affiliation(s)
- Feeling YuTing Chen
- Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
| | - Eliza Gaylord
- Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
| | - Nancy McNamara
- School of Optometry and Vision Science Graduate Program, University of California, Berkeley, CA 94720, USA.
- Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.
| | - Sarah Knox
- Department of Cell & Tissue Biology, University of California San Francisco, San Francisco, CA 94143, USA.
| |
Collapse
|
|
47
|
Ogawa Y, Shimizu E, Tsubota K. Interferons and Dry Eye in Sjögren's Syndrome. Int J Mol Sci 2018; 19:E3548. [PMID: 30423813 PMCID: PMC6274689 DOI: 10.3390/ijms19113548] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/24/2018] [Accepted: 11/01/2018] [Indexed: 02/07/2023] Open
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 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.
Collapse
Affiliation(s)
- Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
| | - Eisuke Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.
| |
Collapse
|
|
48
|
Zhang LW, Zhou PR, Wei P, Cong X, Wu LL, Hua H. Expression of interleukin-17 in primary Sjögren's syndrome and the correlation with disease severity: A systematic review and meta-analysis. Scand J Immunol 2018; 87:e12649. [PMID: 29476557 DOI: 10.1111/sji.12649] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 02/15/2018] [Indexed: 12/26/2022]
Affiliation(s)
- L.-W. Zhang
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - P.-R. Zhou
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - P. Wei
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| | - X. Cong
- Department of Physiology and Pathophysiology; Peking University Health Science Center; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research; Beijing China
| | - L.-L. Wu
- Department of Physiology and Pathophysiology; Peking University Health Science Center; Key Laboratory of Molecular Cardiovascular Sciences; Ministry of Education, and Beijing Key Laboratory of Cardiovascular Receptors Research; Beijing China
| | - H. Hua
- Department of Oral Medicine; Peking University School and Hospital of Stomatology; Beijing China
| |
Collapse
|
|
49
|
Wang C, Zaheer M, Bian F, Quach D, Swennes AG, Britton RA, Pflugfelder SC, de Paiva CS. Sjögren-Like Lacrimal Keratoconjunctivitis in Germ-Free Mice. Int J Mol Sci 2018; 19:E565. [PMID: 29438346 PMCID: PMC5855787 DOI: 10.3390/ijms19020565] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 02/10/2018] [Accepted: 02/12/2018] [Indexed: 02/06/2023] Open
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 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.
Collapse
Affiliation(s)
- Changjun Wang
- Eye Institute of Zhejiang University School of Medicine, Zhejiang Provincial Key Lab of Ophthalmology, Hangzhou 310009, China.
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Mahira Zaheer
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Fang Bian
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Darin Quach
- Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Alton G Swennes
- Center for Comparative Medicine and Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Robert A Britton
- Center for Metagenomics and Microbiome Research, Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Stephen C Pflugfelder
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Cintia S de Paiva
- Ocular Surface Center, Department of Ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, TX 77030, USA.
| |
Collapse
|
|
50
|
Kim D, Kim JY, Jun HS. Smad4 in T cells plays a protective role in the development of autoimmune Sjögren's syndrome in the nonobese diabetic mouse. Oncotarget 2018; 7:80298-80312. [PMID: 27880731 PMCID: PMC5348321 DOI: 10.18632/oncotarget.13437] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 11/07/2016] [Indexed: 12/11/2022] Open
Abstract
We investigated the role of Smad4, a signaling molecule of the TGF-beta pathway, in T cells on the pathology of Sjögren's syndrome (SS) in nonobese diabetic (NOD) mice, an animal model of SS. T cell-specific Smad4-deleted (Smad4fl/fl,CD4-Cre; Smad4 tKO) NOD mice had accelerated development of SS compared with wild-type (Smad4+/+,CD4-Cre; WT) NOD mice, including increased lymphocyte infiltration into exocrine glands, decreased tear and saliva production, and increased levels of autoantibodies at 12 weeks of age. Activated/memory T cells and cytokine (IFN-γ, IL-17)-producing T cells were increased in Smad4 tKO NOD mice, however the proportion and function of regulatory T (Treg) cells were not different between Smad4 tKO and WT NOD mice. Effector T (Teff) cells from Smad4 tKO NOD mice were less sensitive than WT Teff cells to suppression by Treg cells. Th17 differentiation capability of Teff cells was similar between Smad4 tKO and WT NOD mice, but IL-17 expression was increased under inducible Treg skewing conditions in T cells from Smad4 tKO NOD mice. Our results demonstrate that disruption of the Smad4 pathway in T cells of NOD mice increases Teff cell activation resulting in upregulation of Th17 cells, indicating that Smad4 in T cells has a protective role in the development of SS in NOD mice.
Collapse
Affiliation(s)
- Donghee Kim
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea
| | - Jae Young Kim
- Department of Life Science, Gachon University, Seongnam, Gyeonggi-Do, Republic of Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon, Republic of Korea.,College of Pharmacy and Gachon Institute Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.,Gil Medical Research Institute, Gil Hospital, Incheon, Republic of Korea
| |
Collapse
|