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McDermott M, Li W, Wang YH, Chen AY, Lacruz R, Nadorp B, Feske S. Machine learning approach to single cell transcriptomic analysis of Sjogren's disease reveals altered activation states of B and T lymphocytes. J Autoimmun 2025; 154:103419. [PMID: 40318561 DOI: 10.1016/j.jaut.2025.103419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 03/17/2025] [Accepted: 04/04/2025] [Indexed: 05/07/2025]
Abstract
Sjogren's Disease (SjD) is an autoimmune disorder characterized by salivary and lacrimal gland dysfunction and immune cell infiltration leading to gland inflammation and destruction. Although SjD is a common disease, its pathogenesis is not fully understood. In this study, we conducted a single-cell transcriptome analysis of peripheral blood mononuclear cells (PBMC) from patients with SjD and symptomatic non-SjD controls to identify cell types and functional changes involved in SjD pathogenesis. All PBMCs populations showed marked differences in gene expression between SjD patients and controls, particularly an increase in interferon (IFN) signaling gene signatures. T and B cells of SjD patients displayed a depletion of ribosomal gene expression and pathways linked to protein translation. SjD patients had increased frequencies of naive B cells, which featured a unique gene expression profile (GEP) distinct from controls and had hallmarks of B cell hyperactivation. Non-negative matrix factorization (NMF) also identified several non-overlapping GEPs in CD4+ and CD8+ T cells with differential usage in SjD patients and controls. Of these, only the Th1 activation GEP was enriched in T cells of SjD patients whereas the other two GEPs were depleted in T cells, emphasizing the important role of Th1 cells in SjD. Our study provides evidence for aberrant and unique gene expression patterns in both B and T lymphocytes of SjD patients that point to their altered activation states and may provide new insights into the pathogenesis of SjD.
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Affiliation(s)
- Maxwell McDermott
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Wenyi Li
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Yin-Hu Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Allen Y Chen
- Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Rodrigo Lacruz
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY, 10010, USA
| | - Bettina Nadorp
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA; Department of Medicine, New York University Grossman School of Medicine, New York, NY, 10016, USA
| | - Stefan Feske
- Department of Pathology, New York University Grossman School of Medicine, New York, NY, 10016, USA.
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2
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Chuang TL, Koo M, Lee YM, Tung CH, Wang YF. Association Between Quantitative Sialoscintigraphy and Antibody Profiles in Patients With Sjögren or Sicca Syndrome. Clin Nucl Med 2025; 50:109-118. [PMID: 39625850 DOI: 10.1097/rlu.0000000000005602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
PURPOSE This study analyzed the association between anti-Ro/SSA and anti-La/SSB antibody levels with quantitative and visual sialoscintigraphy patterns in patients suspected of having Sjögren or sicca syndrome. PATIENTS AND METHODS Medical records of patients who underwent sialoscintigraphy between April 2020 and May 2022 were reviewed. Associations between antibody levels and sialoscintigraphy parameters were evaluated using linear regression. Receiver operating characteristic curve analysis was used to identify antibody cutoff values for predicting flat-type patterns and the risk of Sjögren or sicca syndrome. RESULTS Of the 170 patients (mean age, 56.6 years; 78.8% female), 95.3% had dry mouth and eyes, 30% experienced polyarthralgia, and 66.5% were prescribed hydroxychloroquine. The most common sialoscintigraphy finding was the median-type time-activity curve (TAC) pattern. Anti-Ro/SSA and anti-La/SSB levels were significantly correlated with maximum accumulation or maximum secretion in the salivary glands. Receiver operating characteristic analysis for anti-Ro/SSA predicting a flat-type TAC pattern showed an area under the curve (AUC) of 0.659 to 0.780, with specificity between 82.1% and 86.3% for antibody levels greater than 85.2 units. Anti-Ro/SSA levels greater than 49.75 units predicted a higher risk of Sjögren or sicca syndrome, with an AUC of 0.622 and 83.9% specificity. Anti-La/SSB levels had no significant predictive value, with an AUC of 0.554. CONCLUSIONS Anti-Ro/SSA levels greater than 85.2 units were strong predictors of flat-type TAC patterns, indicating near-total salivary gland dysfunction and supporting their diagnostic utility in Sjögren or sicca syndrome.
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Affiliation(s)
| | - Malcolm Koo
- Department of Nursing, Tzu Chi University, Hualien
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3
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Du ZH, Chu WX, Peng X, Wu LL, Liu Y, Yu GY, Ding C. SHED-Derived Exosomes Ameliorate Sjögren's Syndrome-Induced Hyposalivation by Suppressing Th1 Cell Response via the miR-29a-3p/T-bet Axis. ACS APPLIED MATERIALS & INTERFACES 2025; 17:5752-5761. [PMID: 39803988 PMCID: PMC11788986 DOI: 10.1021/acsami.4c16595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 01/03/2025] [Accepted: 01/06/2025] [Indexed: 01/31/2025]
Abstract
Background: Sjögren's syndrome (SS), an autoimmune disease, was characterized by sicca syndrome and systemic manifestations, presenting significant treatment challenges. Exosomes, naturally derived nanoparticles containing bioactive molecules, have garnered interest in regenerative medicine. The present study aimed to elucidate the immunoregulatory properties and mechanism of exosomes obtained from the stem cells derived from human exfoliated deciduous teeth (SHED-exos) in SS-induced sialadenitis. Methods: SHED-exo nanoparticles were injected into submandibular glands (SMGs) of 14-week-old nonobese diabetic (NOD) mice, a classic animal model of SS. At 21 weeks, the saliva flow rate (SFR) was measured. Lymphocyte proportions were examined via flow cytometry. Inflammatory cytokine levels were examined by the Quantibody mouse Th1/Th2/Th17 array and ELISA. miR-29a-3p expression and its regulatory effect on T-bet was detected using FISH and luciferase reporter gene assay, respectively. Results: SHED-exos injected into SMGs increased SFR, reduced lymphocytic infiltration, and decreased inflammatory cytokine levels in serum, SMG tissues, and saliva. Mechanistically, SHED-exos suppressed the Th1 proportion in spleen lymphocytes in NOD mice. Exosomal miR-29a-3p targeted and suppressed T-bet expression, which is a Th1-specific transcription factor. In vitro, SHED-exos (but not miR-29a-3p-inhibited exosomes) decreased the level of Th1 differentiation and IFN-γ and TNF-α production. Furthermore, SHED-exos (but not miR-29a-3p-inhibited exosomes) blocked the increase in IFN-γ and TNF-α production induced by T-bet overexpression. In vivo, miR-29a-3p-inhibited exosomes neither increase saliva secretion in NOD mice nor decrease lymphocytic infiltration, T-bet expression, and IFN-γ and TNF-α levels in SMGs. Conclusion: SHED-exos suppress Th1 cell differentiation and response through the miR-29a-3p/T-bet axis, contributing to amelioration of SS-induced hyposalivation.
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Affiliation(s)
- Zhi-hao Du
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Wei-xia Chu
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
- Shanghai
General Hospital, Shanghai 200080, P. R. China
| | - Xin Peng
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Li-ling Wu
- Department
of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular
Sciences, Ministry of Education, and Beijing Key Laboratory of Cardiovascular
Receptors Research, Peking University School
of Basic Medical Sciences, Beijing 100191, P. R. China
| | - Yan Liu
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Guang-yan Yu
- Department
of Oral and Maxillofacial Surgery, Peking
University School and Hospital of Stomatology & National Center
for Stomatology & National Clinical Research Center for Oral Diseases
& National Engineering Research Center of Oral Biomaterials and
Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology
& NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
| | - Chong Ding
- Center
Laboratory, Peking University School and
Hospital of Stomatology & National Center for Stomatology &
National Clinical Research Center for Oral Diseases & National
Engineering Research Center of Oral Biomaterials and Digital Medical
Devices & Beijing Key Laboratory of Digital Stomatology &
NHC Key Laboratory of Digital Stomatology & NMPA Key Laboratory
for Dental Materials, No. 22, Zhongguancun South Avenue, Haidian District, Beijing 100081, P. R. China
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Wang YH, Li W, McDermott M, Son GY, Maiti G, Zhou F, Tao AY, Raphael D, Moreira AL, Shen B, Vaeth M, Nadorp B, Chakravarti S, Lacruz RS, Feske S. IFN-γ-producing T H1 cells and dysfunctional regulatory T cells contribute to the pathogenesis of Sjögren's disease. Sci Transl Med 2024; 16:eado4856. [PMID: 39693412 DOI: 10.1126/scitranslmed.ado4856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 08/06/2024] [Accepted: 10/02/2024] [Indexed: 12/20/2024]
Abstract
Sjögren's disease (SjD) is an autoimmune disorder characterized by progressive salivary and lacrimal gland dysfunction, inflammation, and destruction, as well as extraglandular manifestations. SjD is associated with autoreactive B and T cells, but its pathophysiology remains incompletely understood. Abnormalities in regulatory T (Treg) cells occur in several autoimmune diseases, but their role in SjD is ambiguous. We had previously shown that the function and development of Treg cells depend on store-operated Ca2+ entry (SOCE), which is mediated by ORAI1 Ca2+ channels and stromal interaction protein 1 (STIM1) and STIM2. Here, we show that mice with a Foxp3+ Treg cell-specific deletion of Stim1 and Stim2 develop a phenotype that fulfills all classification criteria of human SjD. Mutant mice have salivary and lacrimal gland inflammation characterized by strong lymphocyte infiltration and transcriptional signatures dominated by T helper 1 (TH1) and interferon (IFN) signaling. CD4+ T cells from mutant mice are sufficient to induce SjD-like disease in an IFN-γ-dependent manner. Inhibition of IFN signaling with the JAK1/2 inhibitor baricitinib alleviated CD4+ T cell-induced SjD in mice. These findings are consistent with the transcriptional profiles of CD4+ T cells from patients with SjD, which indicate enhanced TH1 but reduced memory Treg cell function. Together, our study provides evidence for a critical role of dysfunctional Treg cells and IFN-γ-producing TH1 cells in the pathogenesis of SjD.
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Affiliation(s)
- Yin-Hu Wang
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Wenyi Li
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Maxwell McDermott
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Ga-Yeon Son
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - George Maiti
- Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Fang Zhou
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Anthony Y Tao
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Dimitrius Raphael
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Andre L Moreira
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Boheng Shen
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Martin Vaeth
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Bettina Nadorp
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Shukti Chakravarti
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
- Department of Ophthalmology, New York University Grossman School of Medicine, New York, NY 10016, USA
| | - Rodrigo S Lacruz
- Department of Molecular Pathobiology, New York University College of Dentistry, New York, NY 10010, USA
| | - Stefan Feske
- Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA
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Desvaux E, Hemon P, Soret P, Le Dantec C, Chatzis L, Cornec D, Devauchelle-Pensec V, Elouej S, Duguet F, Laigle L, Poirier N, Moingeon P, Bretin S, Pers JO. High-content multimodal analysis supports the IL-7/IL-7 receptor axis as a relevant therapeutic target in primary Sjögren's syndrome. J Autoimmun 2024; 149:103147. [PMID: 38114349 DOI: 10.1016/j.jaut.2023.103147] [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: 09/25/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 12/21/2023]
Abstract
OBJECTIVE While the involvement of IL-7/IL-7R axis in pSS has been described in relation to T cells, little is known about the contribution of this pathway in relationship with other immune cells, and its implication in autoimmunity. Using high-content multiomics data, we aimed at characterizing IL-7R expressing cells and the involvement of IL-7/IL-7R pathway in pSS pathophysiology. METHODS An IL-7 signature established using RNA-sequencing of human PBMCs incubated with IL-7 was applied to 304 pSS patients, and on RNA-Seq datasets from tissue biopsies. High-content immunophenotyping using flow and imaging mass cytometry was developed to characterize peripheral and in situ IL-7R expression. RESULTS We identified a blood 4-gene IL-7 module (IKZF4, KIAA0040, PGAP1 and SOS1) associated with anti-SSA/Ro positiveness in patients as well as disease activity, and a tissue 5-gene IL-7 module (IL7R, PCED1B, TNFSF8, ADAM19, MYBL1) associated with infiltration severity. We confirmed expression of IL-7R on T cells subsets, and further observed upregulation of IL-7R on double-negative (DN) B cells, and especially DN2 B cells. IL-7R expression was increased in pSS compared to sicca patients with variations seen according to the degree of infiltration. When expressed, IL-7R was mainly found on epithelial cells, CD4+ and CD8+ T cells, switched memory B cells, DN B cells and M1 macrophages. CONCLUSION This exhaustive characterization of the IL-7/IL-7R pathway in pSS pathophysiology established that two IL-7 gene modules discriminate pSS patients with a high IL-7 axis involvement. Their use could guide the implementation of an anti-IL-7R targeted therapy in a precision medicine approach.
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Affiliation(s)
- Emiko Desvaux
- LBAI, UMR1227, University of Brest, Inserm, Brest, France; Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | - Patrice Hemon
- LBAI, UMR1227, University of Brest, Inserm, Brest, France
| | - Perrine Soret
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | | | - Loukas Chatzis
- LBAI, UMR1227, University of Brest, Inserm, Brest, France; Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Divi Cornec
- LBAI, UMR1227, University of Brest, Inserm, Brest, France; CHU de Brest, Brest, France
| | | | - Sahar Elouej
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | - Fanny Duguet
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | - Laurence Laigle
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | | | - Philippe Moingeon
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | - Sylvie Bretin
- Institut de Recherches Internationales Servier, Research and Development, Suresnes, France
| | - Jacques-Olivier Pers
- LBAI, UMR1227, University of Brest, Inserm, Brest, France; CHU de Brest, Brest, France.
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6
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Liu Y, Kang J, Su Y, Fan X, Ma D, Wu Z, Gong X, Zhao J, Zhang L. The causal role of immune cells in primary Sjögren's syndrome: A two-sample Mendelian randomization. Int J Rheum Dis 2024; 27:e15350. [PMID: 39558620 DOI: 10.1111/1756-185x.15350] [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: 05/27/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 11/20/2024]
Abstract
BACKGROUND Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by the destruction of exocrine glands primarily via T-cell-mediated B-cell over-activation and cytokine production. This leads to pronounced dryness of the mouth and eyes and can result in multi-systemic involvement affecting the kidneys, lungs, and blood. In recent years, there has been increasing attention on the role of immune cells in pSS. However, studies investigating the causal role of immune cells in pSS have been relatively limited. METHODS In this study, we employed a two-way two-sample Mendelian randomization approach to assess the causal relationship between immune cells and pSS. Utilizing publicly available genome-wide association study (GWAS) data, we explored the causal links between 731 immunophenotypically labeled immune cells and the risk of pSS. RESULTS Through the use of instrumental variables derived from GWAS data and corrected for false discovery rate (FDR), we identified three immune cells with increased levels that were causally associated with pSS risk (FDR < 0.05). These included IgD+ CD38br AC B cells, CD27 on IgD+ CD38- unswitched memory B cells, and Granulocyte % leukocyte. Additionally, three immune cells with reduced levels were found to be causally associated with pSS risk, namely CD4+ CD8dim %lymphocyte, CD4+ CD8dim %leukocyte, and CD28 on activated and secreting regulatory T cells (Tregs). Furthermore, the development of pSS was associated with elevated levels of CD33br HLA DR+ CD14- % CD33br HLA DR+ in myeloid cells. CONCLUSION This study demonstrates that immune responses influence the progression of pSS in a complex pattern. Our findings may provide new insights into the immunology of pSS pathogenesis and more experimental studies should be conducted to further explore the potential mechanisms between identified immune features and pSS risk, which may provide a basis for exploring early intervention methods for pSS and developing targeted therapeutic strategies or even reshaping immune homeostasis.
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Affiliation(s)
- Yang Liu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Jie Kang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Yazhen Su
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xiuying Fan
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Zewen Wu
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Xueyan Gong
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Junkang Zhao
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
| | - Liyun Zhang
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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Ma D, Feng Y, Lin X. Immune and non-immune mediators in the fibrosis pathogenesis of salivary gland in Sjögren's syndrome. Front Immunol 2024; 15:1421436. [PMID: 39469708 PMCID: PMC11513355 DOI: 10.3389/fimmu.2024.1421436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 09/30/2024] [Indexed: 10/30/2024] Open
Abstract
Sjögren's syndrome (SS) or Sjögren's disease (SjD) is a systemic autoimmune disease clinically manifested as sicca symptoms. This disease primarily impacts the functionality of exocrine glands, specifically the lacrimal and salivary glands (SG). SG fibrosis, an irreversible morphological change, is a severe consequence that occurs in the later stages of the disease due to sustained inflammation. However, the mechanism underlying SG fibrosis in SS remains under-investigated. Glandular fibrosis may arise from chronic sialadenitis, in which the interactions between infiltrating lymphocytes and epithelial cells potentially contributes to fibrotic pathogenesis. Thus, both immune and non-immune cells are closely involved in this process, while their interplays are not fully understood. The molecular mechanism of tissue fibrosis is partly associated with an imbalance of immune responses, in which the transforming growth factor-beta (TGF-β)-dependent epithelial-mesenchymal transition (EMT) and extracellular matrix remodeling are recently investigated. In addition, viral infection has been implicated in the pathogenesis of SS. Viral-specific innate immune response could exacerbate the autoimmune progression, resulting in overt inflammation in SG. Notably, post-COVID patients exhibit typical SS symptoms and severe inflammatory sialadenitis, which are positively correlated with SG damage. In this review, we discuss the immune and non-immune risk factors in SG fibrosis and summarize the evidence to understand the mechanisms upon autoimmune progression in SS.
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Affiliation(s)
- Danbao Ma
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yun Feng
- Department of Ophthalmology, Peking University Third Hospital, Beijing, China
| | - Xiang Lin
- School of Chinese Medicine, The University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Chinese Medicine, the University of Hong Kong-Shenzhen Hospital (HKU-SZH), Shenzhen, China
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8
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Li XX, Maitiyaer M, Tan Q, Huang WH, Liu Y, Liu ZP, Wen YQ, Zheng Y, Chen X, Chen RL, Tao Y, Yu SL. Emerging biologic frontiers for Sjogren's syndrome: Unveiling novel approaches with emphasis on extra glandular pathology. Front Pharmacol 2024; 15:1377055. [PMID: 38828450 PMCID: PMC11140030 DOI: 10.3389/fphar.2024.1377055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 04/29/2024] [Indexed: 06/05/2024] Open
Abstract
Primary Sjögren's Syndrome (pSS) is a complex autoimmune disorder characterized by exocrine gland dysfunction, leading to dry eyes and mouth. Despite growing interest in biologic therapies for pSS, FDA approval has proven challenging due to trial complications. This review addresses the absence of a molecular-target-based approach to biologic therapy development and highlights novel research on drug targets and clinical trials. A literature search identified potential pSS treatment targets and recent advances in molecular understanding. Overlooking extraglandular symptoms like fatigue and depression is a notable gap in trials. Emerging biologic agents targeting cytokines, signal pathways, and immune responses have proven efficacy. These novel therapies could complement existing methods for symptom alleviation. Improved grading systems accounting for extraglandular symptoms are needed. The future of pSS treatment may involve gene, stem-cell, and tissue-engineering therapies. This narrative review offers insights into advancing pSS management through innovative biologic interventions.
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Affiliation(s)
- Xiao Xiao Li
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Maierhaba Maitiyaer
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Qing Tan
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Wen Hui Huang
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yu Liu
- Department of Clinical Medicine, The First Clinical Medical School of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Zhi Ping Liu
- Ophthalmic Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yue Qiang Wen
- Department of Nephrology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yu Zheng
- Department of Urology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Xing Chen
- Department of Geriatrics, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Rui Lin Chen
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Yi Tao
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
| | - Shui Lian Yu
- Department of Rheumatology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
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Yin J, Fu J, Xu J, Chen C, Zhu H, Wang B, Yu C, Yang X, Cai R, Li M, Ji K, Wu W, Zhao Y, Zheng Z, Pu Y, Zheng L. Integrated analysis of m6A regulator-mediated RNA methylation modification patterns and immune characteristics in Sjögren's syndrome. Heliyon 2024; 10:e28645. [PMID: 38596085 PMCID: PMC11002070 DOI: 10.1016/j.heliyon.2024.e28645] [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: 01/23/2023] [Revised: 03/17/2024] [Accepted: 03/21/2024] [Indexed: 04/11/2024] Open
Abstract
The epigenetic modifier N6-methyladenosine (m6A), recognized as the most prevalent internal modification in messenger RNA (mRNA), has recently emerged as a pivotal player in immune regulation. Its dysregulation has been implicated in the pathogenesis of various autoimmune conditions. However, the implications of m6A modification within the immune microenvironment of Sjögren's syndrome (SS), a chronic autoimmune disorder characterized by exocrine gland dysfunction, remain unexplored. Herein, we leverage an integrative analysis combining public database resources and novel sequencing data to investigate the expression profiles of m6A regulatory genes in SS. Our cohort comprised 220 patients diagnosed with SS and 62 healthy individuals, enabling a comprehensive evaluation of peripheral blood at the transcriptomic level. We report a significant association between SS and altered expression of key m6A regulators, with these changes closely tied to the activation of CD4+ T cells. Employing a random forest (RF) algorithm, we identified crucial genes contributing to the disease phenotype, which facilitated the development of a robust diagnostic model via multivariate logistic regression analysis. Further, unsupervised clustering revealed two distinct m6A modification patterns, which were significantly associated with variations in immunocyte infiltration, immune response activity, and biological function enrichment in SS. Subsequently, we proceeded with a screening process aimed at identifying genes that were differentially expressed (DEGs) between the two groups distinguished by m6A modification. Leveraging these DEGs, we employed weight gene co-expression network analysis (WGCNA) to uncover sets of genes that exhibited strong co-variance and hub genes that were closely linked to m6A modification. Through rigorous analysis, we identified three critical m6A regulators - METTL3, ALKBH5, and YTHDF1 - alongside two m6A-related hub genes, COMMD8 and SRP9. These elements collectively underscore a complex but discernible pattern of m6A modification that appears to be integrally linked with SS's pathogenesis. Our findings not only illuminate the significant correlation between m6A modification and the immune microenvironment in SS but also lay the groundwork for a deeper understanding of m6A regulatory mechanisms. More importantly, the identification of these key regulators and hub genes opens new avenues for the diagnosis and treatment of SS, presenting potential targets for therapeutic intervention.
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Affiliation(s)
- Junhao Yin
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Jiayao Fu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Jiabao Xu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Changyu Chen
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Hanyi Zhu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Baoli Wang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Chuangqi Yu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Xiujuan Yang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Ruiyu Cai
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Mengyang Li
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Kaihan Ji
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Wanning Wu
- College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
| | - Yijie Zhao
- Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, 1258 Fuxin Zhong Road, Shanghai 200031, China
| | - Zhanglong Zheng
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Yiping Pu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
| | - Lingyan Zheng
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
- Shanghai Institute of Stomatology, Shanghai, China
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10
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Zhou J, Pathak JL, Cao T, Chen B, Wei W, Hu S, Mao T, Wu X, Watanabe N, Li X, Li J. CD4 T cell-secreted IFN-γ in Sjögren's syndrome induces salivary gland epithelial cell ferroptosis. Biochim Biophys Acta Mol Basis Dis 2024; 1870:167121. [PMID: 38471652 DOI: 10.1016/j.bbadis.2024.167121] [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: 08/07/2023] [Revised: 03/05/2024] [Accepted: 03/06/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Sjögren's syndrome (SS) is a chronic autoimmune disease that predominantly affects exocrine glands. Previous studies have demonstrated that upregulated interferon-gamma (IFN-γ) in SS triggers ferroptosis in salivary gland epithelial cells (SGECs), resulting in impaired salivary gland secretion. However, the immune cells responsible for secreting IFN-γ remain unclear. Therefore, this study conducted bioinformatics analysis and molecular validation to identify the origin of IFN-γ in SS salivary gland. METHODS The 'limma' package in R software was utilized to identify differentially expressed genes (DEGs) in the human SS dataset. Subsequently, the identified DEGs were compared with the ferroptosis database and screened through Cytoscape to determine candidate genes. The cellular localization and expression patterns of candidate genes were further confirmed in the salivary gland single-cell RNA sequence (scRNA-seq) data set from healthy control and SS mice. Furthermore, in vitro and in vivo studies were performed to analyze the effect of CD4 T-secreted IFN-γ on SGECs' ferroptosis and functions. RESULTS Upregulated TLR4, IFNG, and IL33 were screened as candidates ferroptosis ferroptosis-inducing genes in SS salivary glands. The association of IFNG and IL33 with CD4 T cells was established through immune infiltration analysis. The expression of IFN-γ on CD4 T cells was robustly higher compared with that of IL33 as evidenced by scRNA-seq and immunofluorescence co-localization. Subsequent experiments conducted on candidate genes consistently demonstrated the potent ability of IFN-γ to induce SGECs' ferroptosis and inhibit AQP5 expression. CONCLUSIONS Our findings indicate that CD4 T cell-secreted IFN-γ in SS induces SGECs' ferroptosis and inhibits AQP5 expression.
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Affiliation(s)
- Jiannan Zhou
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Janak L Pathak
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Tingting Cao
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Bo Chen
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Wei Wei
- Hospital of Stomatology, Jilin University, Changchun 130021, China
| | - Shilin Hu
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Tianjiao Mao
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Xiaodan Wu
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China
| | - Nobumoto Watanabe
- Chemical Resource Development Research Unit, RIKEN CSRS, Wako, Saitama, 351-0198, Japan
| | - Xiaomeng Li
- KingMed School of Laboratory Medicine, Guangzhou Medical University, Guangzhou, Guangdong 510182, China.
| | - Jiang Li
- School and Hospital of Stomatology, Guangdong Engineering Research Center of Oral Restoration and Reconstruction & Guangzhou Key Laboratory of Basic and Applied Research of Oral Regenerative Medicine, Guangzhou Medical University, Guangzhou 510182, China.
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11
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Wang YH, Li W, McDermott M, Son GY, Maiti G, Zhou F, Tao A, Raphael D, Moreira AL, Shen B, Vaeth M, Nadorp B, Chakravarti S, Lacruz RS, Feske S. Regulatory T cells and IFN-γ-producing Th1 cells play a critical role in the pathogenesis of Sjögren's Syndrome. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.23.576314. [PMID: 38328096 PMCID: PMC10849570 DOI: 10.1101/2024.01.23.576314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Objectives Sjögren's Disease (SjD) is an autoimmune disorder characterized by progressive dysfunction, inflammation and destruction of salivary and lacrimal glands, and by extraglandular manifestations. Its etiology and pathophysiology remain incompletely understood, though a role for autoreactive B cells has been considered key. Here, we investigated the role of effector and regulatory T cells in the pathogenesis of SjD. Methods Histological analysis, RNA-sequencing and flow cytometry were conducted on glands, lungs, eyes and lymphoid tissues of mice with regulatory T cell-specific deletion of stromal interaction proteins (STIM) 1 and 2 ( Stim1/2 Foxp3 ), which play key roles in calcium signaling and T cell function. The pathogenicity of T cells from Stim1/2 Foxp3 mice was investigated through adoptively transfer into lymphopenic host mice. Additionally, single-cell transcriptomic analysis was performed on peripheral blood mononuclear cells (PBMCs) of patients with SjD and control subjects. Results Stim1/2 Foxp3 mice develop a severe SjD-like disorder including salivary gland (SG) and lacrimal gland (LG) inflammation and dysfunction, autoantibodies and extraglandular symptoms. SG inflammation in Stim1/2 Foxp3 mice is characterized by T and B cell infiltration, and transcriptionally by a Th1 immune response that correlates strongly with the dysregulation observed in patients with SjD. Adoptive transfer of effector T cells from Stim1/2 Foxp3 mice demonstrates that the SjD-like disease is driven by interferon (IFN)-γ producing autoreactive CD4 + T cells independently of B cells and autoantiboodies. scRNA-seq analysis identifies increased Th1 responses and attenuated memory Treg function in PBMCs of patients with SjD. Conclusions We report a more accurate mouse model of SjD while providing evidence for a critical role of Treg cells and IFN-γ producing Th1 cells in the pathogenesis of SjD, which may be effective targets for therapy.
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12
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Yin J, Fu J, Shao Y, Xu J, Li H, Chen C, Zhao Y, Zheng Z, Yu C, Zheng L, Wang B. CYP51-mediated cholesterol biosynthesis is required for the proliferation of CD4 + T cells in Sjogren's syndrome. Clin Exp Med 2023; 23:1691-1711. [PMID: 36413274 DOI: 10.1007/s10238-022-00939-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Accepted: 11/02/2022] [Indexed: 11/23/2022]
Abstract
CYtochrome P450, family 51 (CYP51) is an important enzyme for de novo cholesterol synthesis in mammalian cells. In the present study, we found that the expression of CYP51 positively correlated with CD4+ T cell activation both in vivo and in vitro. The addition of ketoconazole, a pharmacological inhibitor of CYP51, prevented the proliferation and activation of anti-CD3/CD28-expanded mouse CD4+ T cells in a dose-dependent fashion. Liquid chromatography-tandem mass spectrometry indicated an increase in levels of lanosterol in T cells treated with ketoconazole during activation. Ketoconazole-induced blockade of the cholesterol synthesis pathway also caused Sterol regulatory element binding protein 2 (SREBP2) activation in CD4+ T cells. Additionally, ketoconazole treatment elicited an integrated stress response in T cells that up-regulated activating transcription factor 4 (ATF4) and DNA-damage inducible transcript 3 (DDIT3/CHOP) at the translational level. Furthermore, treatment with ketoconazole significantly decreased the amount of CD4+ T cells infiltrating lesions in the submandibular glands of NOD/Ltj mice. In summary, our results suggest that CYP51 plays an essential role in the proliferation and survival of CD4+ T cells, which makes ketoconazole an inhibitor of CD4+ T cell proliferation and of the SS-like autoimmune response through regulating the biosynthesis of cholesterol and inducing the integrated stress response.
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Affiliation(s)
- Junhao Yin
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jiayao Fu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Yanxiong Shao
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jiabao Xu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Hui Li
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Changyu Chen
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Yijie Zhao
- Department of Oral and Maxillofacial Surgery, Shanghai Stomatological Hospital, Fudan University, 1258 Fuxin Zhong Road, Shanghai, China
| | - Zhanglong Zheng
- Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, China
| | - Chuangqi Yu
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China
- Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Lingyan Zheng
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China.
- Shanghai Key Laboratory of Stomatology, Shanghai, China.
| | - Baoli Wang
- Department of Oral Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
- National Center for Stomatology & National Clinical Research Center for Oral Disease, Shanghai, China.
- Shanghai Key Laboratory of Stomatology, Shanghai, China.
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13
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Cai T, Xu J, Fang Y, Wu Y, Qin Q, Zhang JA. Shared biomarkers of multi-tissue origin for primary Sjogren's syndrome and their importance in immune microenvironment alterations. Immunobiology 2023; 228:152726. [PMID: 37591179 DOI: 10.1016/j.imbio.2023.152726] [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: 04/21/2023] [Revised: 07/18/2023] [Accepted: 08/07/2023] [Indexed: 08/19/2023]
Abstract
With the recent advancement in omics and molecular techniques, a wealth of new molecular biomarkers have become available for the diagnosis and classification of primary Sjögren's syndrome (pSS) patients. However, whether these biomarkers are universal is of great interest to us. In this study, we used various methods to obtain shared biomarkers derived from multiple tissue in pSS patients and to explore their relationship with immune microenvironment alterations. First we identified differentially expressed genes (DEGs) between pSS and healthy controls utilizing nine mRNA microarray datasets obtained from the Gene Expression Omnibus (GEO). Then, shared biomarkers were filtered out using robust rank aggregation (RRA), data integration analysis, weighted gene co-expression network analysis (WGCNA), and least absolute selection and shrinkage operator (LASSO) regression; their roles in pSS and association with changes in the immune microenvironment were also analyzed. In addition, these biomarkers were further confirmed with both the testing set and immunohistochemistry (IHC). As a result, ten biomarkers, i.e., EPSTI1, IFI44, IFIT1, IFIT2, IFIT3, MX1, OAS1, PARP9, SAMD9L and TRIM22, were identified. Receiver operating characteristic (ROC) curves showed that the ten genes could discriminate pSS from controls. Gene set enrichment analysis (GSEA) showed that the enrichment of immune-related gene sets was significant in pSS patients with high expression of either biomarker. Furthermore, the association between some immunocytes and these biomarkers was identified. In the two distinct molecular patterns of pSS patients based on the expressions of these biomarkers, the proportions of immunocytes were significantly different. Our study identified shared biomarkers of multi-tissue origin and revealed their relationship with altered immune microenvironment in pSS patients. These markers not only have diagnostic implications but also provide potential immunotherapeutic targets for the clinical treatment of pSS patients.
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Affiliation(s)
- Tiantian Cai
- Graduate School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China; Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Jianbin Xu
- Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Yudie Fang
- Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Yuqing Wu
- Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China
| | - Qiu Qin
- Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China.
| | - Jin-An Zhang
- Department of Endocrinology & Rheumatology, Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, Shanghai 201318, People's Republic of China; Shanghai University of Traditional Chinese Medicine, Shanghai 201203, People's Republic of China.
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14
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Hamkour S, van der Heijden EH, Lopes AP, Blokland SLM, Bekker CPJ, Van Helden-Meeuwsen CG, Versnel MA, Kruize AA, Radstake TR, Leavis HL, Hillen MR, van Roon JA. Leflunomide/hydroxychloroquine combination therapy targets type I IFN-associated proteins in patients with Sjögren's syndrome that show potential to predict and monitor clinical response. RMD Open 2023; 9:e002979. [PMID: 37532471 PMCID: PMC10401261 DOI: 10.1136/rmdopen-2023-002979] [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: 01/02/2023] [Accepted: 05/24/2023] [Indexed: 08/04/2023] Open
Abstract
OBJECTIVES To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sjögren's syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment. METHODS In 21 patients treated with LEF/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint. RESULTS IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90). CONCLUSIONS LEF/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF/HCQ.
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Affiliation(s)
- Safae Hamkour
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Eefje Hm van der Heijden
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Ana P Lopes
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Sofie L M Blokland
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Cornelis P J Bekker
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | | | | | - Aike A Kruize
- Department of Rheumatology and Clinical Immunology, Utrecht University, Utrecht, The Netherlands
| | - Timothy Rdj Radstake
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Helen L Leavis
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Maarten R Hillen
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
| | - Joel Ag van Roon
- Department of Rheumatology and Clinical Immunology, Laboratory of Translational Immunology, UMC, Utrecht, The Netherlands
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15
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Ma D, Wu Z, Zhao X, Zhu X, An Q, Wang Y, Zhao J, Su Y, Yang B, Xu K, Zhang L. Immunomodulatory effects of umbilical mesenchymal stem cell-derived exosomes on CD4 + T cells in patients with primary Sjögren's syndrome. Inflammopharmacology 2023:10.1007/s10787-023-01189-x. [PMID: 37012581 DOI: 10.1007/s10787-023-01189-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 03/03/2023] [Indexed: 04/05/2023]
Abstract
BACKGROUND Primary Sjögren's syndrome (pSS) is an autoimmune disease that leads to the destruction of exocrine glands and multisystem lesions. Abnormal proliferation, apoptosis, and differentiation of CD4+ T cells are key factors in the pathogenesis of pSS. Autophagy is one of the important mechanisms to maintain immune homeostasis and function of CD4+ T cells. Human umbilical cord mesenchymal stem cell-derived exosomes (UCMSC-Exos) may simulate the immunoregulation of MSCs while avoiding the risks of MSCs treatment. However, whether UCMSC-Exos can regulate the functions of CD4+ T cells in pSS, and whether the effects via the autophagy pathway remains unclear. METHODS The study analyzed retrospectively the peripheral blood lymphocyte subsets in pSS patients, and explored the relationship between lymphocyte subsets and disease activity. Next, peripheral blood CD4+ T cells were sorted using immunomagnetic beads. The proliferation, apoptosis, differentiation, and inflammatory factors of CD4+ T cells were determined using flow cytometry. Autophagosomes of CD4+ T cells were detected using transmission electron microscopy, autophagy-related proteins and genes were detected using western blotting or RT-qPCR. RESULTS The study demonstrated that the peripheral blood CD4+ T cells decreased in pSS patients, and negatively correlated with disease activity. UCMSC-Exos inhibited excessive proliferation and apoptosis of CD4+ T cells in pSS patients, blocked them in the G0/G1 phase, inhibited them from entering the S phase, reduced the Th17 cell ratio, elevated the Treg ratio, inhibited IFN-γ, TNF-α, IL-6, IL-17A, and IL-17F secretion, and promoted IL-10 and TGF-β secretion. UCMSC-Exos reduced the elevated autophagy levels in the peripheral blood CD4+ T cells of patients with pSS. Furthermore, UCMSC-Exos regulated CD4+ T cell proliferation and early apoptosis, inhibited Th17 cell differentiation, promoted Treg cell differentiation, and restored the Th17/Treg balance in pSS patients through the autophagy pathway. CONCLUSIONS The study indicated that UCMSC-Exos exerts an immunomodulatory effect on the CD4+ T cells, and maybe as a new treatment for pSS.
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Affiliation(s)
- Dan Ma
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Zewen Wu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Xingxing Zhao
- Shanxi University of Chinese Medicine, Jinzhong, 030619, Shanxi, China
| | - Xueqing Zhu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Qi An
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Yajing Wang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Jingwen Zhao
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Yazhen Su
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Baoqi Yang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Ke Xu
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China
| | - Liyun Zhang
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Taiyuan, 030032, Shanxi, China.
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Liu S, Yang Y, Zeng L, Wang L, He C, Chen Z, Sun J, Lyu T, Wang M, Chen H, Zhang F. TOX promotes follicular helper T cell differentiation in patients with primary Sjögren's syndrome. Rheumatology (Oxford) 2023; 62:946-957. [PMID: 35713502 DOI: 10.1093/rheumatology/keac304] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 03/27/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
OBJECTIVES Whether naive CD4+ T cells are dysregulated and associated with the overactivation of CD4+ T cells in primary SS (pSS) remains unclear. We aimed to explore the role and underlying mechanism of naive CD4+ T cells in pSS. METHODS We examined the activation, proliferation and differentiation of naive CD4+ T cells from pSS patients and healthy controls. Differentially expressed genes were identified using RNA sequencing, and were overexpressed or silenced to determine the gene regulating follicular helper T (Tfh) cells. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) with chromatin immunoprecipitation with high-throughput sequencing (ChIP-seq) was performed to explore the epigenetic mechanism. Naive CD4+ T cells were treated with pSS-related cytokines to explore the upstream signalling pathway. RESULTS pSS naive CD4+ T cells had higher potentials of activation, proliferation and differentiation towards Tfh cells. Thymocyte selection-associated high mobility group box protein (TOX) was upregulated in pSS naive CD4+ T cells and promoted T cell activation and Tfh cell polarization. TOX silencing in pSS naive CD4+ T cells downregulated B cell lymphoma 6 (BCL6) expression and altered levels of multiple Tfh-associated genes. ChIP-seq analysis implied that TOX bound to the BCL6 locus, where there were accessible regions found by ATAC-seq. IFN-α induced TOX overexpression, which was attenuated by Janus kinase (JAK) and signal transducer and activator of transcription 1 (STAT1) inhibitors. CONCLUSION Our data suggest that TOX in pSS naive CD4+ T cells is upregulated, which facilitates Tfh cell differentiation. Mechanistically, IFN-α induces TOX overexpression in naive CD4+ T cells through JAK-STAT1 signalling and TOX regulates BCL6 expression. Therefore, IFN-α-JAK-STAT1 signalling and TOX might be potential therapeutic targets in pSS.
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Affiliation(s)
- Suying Liu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Yanlei Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Liuting Zeng
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Li Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Chengmei He
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Zhilei Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Jinlei Sun
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Taibiao Lyu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Mu Wang
- Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Hua Chen
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College.,Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education
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17
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Li J, Wu L, Chen Y, Yan Z, Fu J, Luo Z, Du J, Guo L, Xu J, Liu Y. Anticeramide Improves Sjögren's Syndrome by Blocking BMP6-Induced Th1. J Dent Res 2023; 102:93-102. [PMID: 36281063 DOI: 10.1177/00220345221119710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
T-cell dysfunction has been shown to play an important role in the pathogenesis of Sjögren's syndrome (SS). In recent studies, the increased expression of BMP6 has been reported to be related to SS. However, the roles that BMP6 plays in immune homeostasis in the development of SS as well as the downstream signals activated by BMP6 remain unclear. In this study, we investigated the effects and molecular mechanisms of BMP6 on naive CD4+ T cells, showing that BMP6 could upregulate interferon (IFN)-γ secretion from CD4+ T cells through a ceramide/nuclear factor-κB pathway, with no effect on T-cell activation or proliferation. Moreover, an in vivo study showed that anticeramide treatment (myriocin) for an SS animal model (NOD/LtJ mice) could significantly decrease the IFN-γ expression and Th1 frequency in the salivary glands and suppress the inflammation infiltration in salivary glands and maintain the salivary flow rates, both of which reflect SS-like symptoms. This study identifies a promising target that could effectively attenuate the abnormal state of CD4+ T cells and reverse the progression of SS.
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Affiliation(s)
- J Li
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China.,Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, P.R. China
| | - L Wu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China.,Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, P.R. China
| | - Y Chen
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - Z Yan
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - J Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - Z Luo
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - J Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - L Guo
- Department of Orthodontics School of Stomatology, Capital Medical University, Beijing, P.R. China
| | - J Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China.,Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, P.R. China
| | - Y Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, P.R. China.,Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, P.R. China
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18
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An Q, Zhao J, Zhu X, Yang B, Wu Z, Su Y, Zhang L, Xu K, Ma D. Exploiting the role of T cells in the pathogenesis of Sjögren's syndrome for therapeutic treatment. Front Immunol 2022; 13:995895. [PMID: 36389806 PMCID: PMC9650646 DOI: 10.3389/fimmu.2022.995895] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Accepted: 10/17/2022] [Indexed: 08/19/2023] Open
Abstract
Sjögrens syndrome (SS) is caused by autoantibodies that attack proprioceptive salivary and lacrimal gland tissues. Damage to the glands leads to dry mouth and eyes and affects multiple systems and organs. In severe cases, SS is life-threatening because it can lead to interstitial lung disease, renal insufficiency, and lymphoma. Histological examination of the labial minor salivary glands of patients with SS reveals focal lymphocyte aggregation of T and B cells. More studies have been conducted on the role of B cells in the pathogenesis of SS, whereas the role of T cells has only recently attracted the attention of researchers. This review focusses on the role of various populations of T cells in the pathogenesis of SS and the progress made in research to therapeutically targeting T cells for the treatment of patients with SS.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Dan Ma
- Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
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19
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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.
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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
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20
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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.
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21
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Tanaka Y, Onozato M, Mikami T, Kohwi-Shigematsu T, Fukushima T, Kondo M. Increased Indoleamine 2,3-Dioxygenase Levels at the Onset of Sjögren's Syndrome in SATB1-Conditional Knockout Mice. Int J Mol Sci 2021; 22:10125. [PMID: 34576286 PMCID: PMC8468825 DOI: 10.3390/ijms221810125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 01/16/2023] Open
Abstract
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dysfunction of salivary and lacrimal glands, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Autoantibodies, such as anti-SSA and anti-SSB antibodies, are hallmarks and important diagnostic factors for SS. In our previous study, we demonstrated that SS-like xerostomia was observed in SATB1 conditional knockout (SATB1cKO) mice, in which the floxed SATB1 gene was specifically deleted in hematopoietic cells as early as 4 weeks of age. In these mice, autoantibodies were not detected until 8 weeks of age in SATB1cKO mice, although exocrine gland function reached its lowest at this age. Therefore, other markers may be necessary for the diagnosis of SS in the early phase. Here, we found that mRNA expression of the interferonγ (IFN-γ) gene and the IFN-responsive indoleamine 2,3-dioxygenase (IDO) gene is upregulated in the salivary glands of SATB1cKO mice after 3 and 4 weeks of age, respectively. We detected l-kynurenine (l-KYN), an intermediate of l-tryptophan (l-Trp) metabolism mediated by IDO, in the serum of SATB1cKO mice after 4 weeks of age. In addition, the upregulation of IDO expression was significantly suppressed by the administration of IFN-γ neutralizing antibodies in SATB1cKO mice. These results suggest that the induction of IFN-dependent IDO expression is an initial event that occurs immediately after the onset of SS in SATB1cKO mice. These results also imply that serum l-KYN could be used as a marker for SS diagnosis in the early phases of the disease before autoantibodies are detectable.
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Grants
- JP24390121 to M.K. and Y.T., JP26670240 to M.K., 18K07075 to Y.T. MEXT/JSPS KAKENHI
- Strategic Research Foundation Grant-aided Project for Private Schools at Heisei 26th (S1411015 ) Ministry of Education, Culture, Sports, Science and Technology
- Research Promotion Grant (14-02) Toho University Graduate School of Medicine
- Project Research Grants (23-4 and 26-22 to Y.T.) Toho University School of Medicine
- N/A Public Foundation of the Vaccination Research Center
- Joint research Fund to M.K., Y.T., M.O. and K.F. Toho University
- Initiative for Realizing Diversity in the Research Environment Japan Science and Technology Agency
- R37CA39681 to T.K.-S. NIH HHS
- Grant-in Aid for Private University Research Branding Project Ministry of Education, Culture, Sports, Science and Technology
- Grant for Research Initiative Program Toho University
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Affiliation(s)
- Yuriko Tanaka
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan;
| | - Mayu Onozato
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan; (M.O.); (T.F.)
| | - Tetuo Mikami
- Department of Pathology, Toho University School of Medicine, Tokyo 143-8540, Japan;
| | - Terumi Kohwi-Shigematsu
- Department of Orofacial Sciences, University of California San Francisco School of Dentistry, San Francisco, CA 94143, USA;
| | - Takeshi Fukushima
- Department of Analytical Chemistry, Faculty of Pharmaceutical Sciences, Toho University, Chiba 274-8510, Japan; (M.O.); (T.F.)
| | - Motonari Kondo
- Department of Molecular Immunology, Toho University School of Medicine, Tokyo 143-8540, Japan;
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22
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Gao S, Wang Y, Li Y, Xiao D, Lin Y, Chen Y, Cai X. Tetrahedral Framework Nucleic Acids Reestablish Immune Tolerance and Restore Saliva Secretion in a Sjögren's Syndrome Mouse Model. ACS APPLIED MATERIALS & INTERFACES 2021; 13:42543-42553. [PMID: 34477358 DOI: 10.1021/acsami.1c14861] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
As one of the most frequent autoimmune diseases, Sjogren's syndrome (SS) is characterized by overactive lymphocytic infiltration in the exocrine glands, with ensuing dry mouth and dry eyes. Unfortunately, so far, there are no appropriate therapies without causing overall immunosuppression. Tetrahedral framework nucleic acids (tFNAs) were regarded as promising nanoscale materials whose immunomodulatory capabilities have already been verified. Herein, we reveal, for the first time, that tFNAs were utilized to treat SS in female nonobese diabetic (NOD) mice, the animal model used for SS. We proved a 250 nM tFNA treatment was successful in suppressing inflammation and stimulating saliva secretion in NOD mice. Specialised proteins for the secretory function and structure of acinar cells in submandibular glands (SMGs) were restored. It has been the permanent goal for SS treatment to establish immune tolerance and stop disease development. Surprisingly, tFNA treatment guided T cells toward regulatory T cells (Tregs), while suppressing T helper (Th) cell responses. Th cells include Th1, Th17, and follicular helper T (Tfh) cells. Tregs are highly significant in immune tolerance. Inducing Tregs is a promising approach to reestablish immune tolerance. Comparable results were also observed in B cell responses. Reductions in the percentage of germinal center (GC) B cells and plasma cells were detected, and a marked increase in the percentage of regulatory B cells (Bregs) was also noticed. The mechanisms of inducing Tregs may associated with cytokine changes. Changes of T cell subsets, especially changes of Tfh, may influence the differentiation of B cells accordingly. Collectively, our results demonstrated the immunomodulatory capacities of tFNAs once again, which may provide a novel, safe, and effective option for the treatment of SS and other autoimmune diseases.
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Affiliation(s)
- Shaojingya Gao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yun Wang
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yanjing Li
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Dexuan Xiao
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yunfeng Lin
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
- College of Biomedical Engineering, Sichuan University, Chengdu 610041, China
| | - Yu Chen
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xiaoxiao Cai
- State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
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23
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Kabeerdoss J, Sandhya P, Kurien BT, Scofield RH, Danda D. In vitro effects of curcumin on proinflammatory cytokines and expression of their genes in minor salivary gland tissue of patients with Sjogren's syndrome. Rheumatol Int 2021; 42:545-551. [PMID: 33861386 DOI: 10.1007/s00296-021-04859-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/05/2021] [Indexed: 11/30/2022]
Abstract
Curcumin reduces disease severity and ameliorates lupus-like/Sjögren's Syndrome-like disease in mice model. The immunological basis of these effects is largely unknown. This study examined the effects of curcumin on pro-inflammatory cytokines secreted by minor salivary glands in patients with primary Sjögren's syndrome (pSS). Minor salivary gland (MSG) tissue samples were collected from patients undergoing biopsy for suspected pSS. The tissues were treated with phytohemagglutinin (PHA) alone as well as PHA with curcumin (30 μM) and cultured in RPMI 1640 medium for 48 h at 37 °C in CO2 incubator. After the incubation period, culture supernatant and tissues were stored in the freezer (-80 °C). IL-6 levels were measured in supernatant by ELISA kit. Gene expressions of pro-inflammatory cytokines, namely IL-6, IL-8, TNF-α, IL-1β, IL-4, IL-10, IL-17, IL-21, and IFN-γ, were measured by qPCR. IL-6 secretion levels and gene expressions were compared statistically between groups by Student's t test. Forty-seven patients were screened. Eight patients satisfied ACR/EULAR criteria for pSS. Seven patients with absent glandular inflammation and negative serology constituted sicca controls. These 15 subjects were included in final analysis. In pSS group, but not in controls, median IL-6 levels in supernatant were less in curcumin-treated as compared to PHA-alone subset [5.5 (0.7-13.34) vs 18.3 (12-32) ng/ml; p = 0.0156]. mRNA expression levels of IL-6 were also lower in curcumin-treated samples as compared to PHA alone, when cases and controls were analyzed together as well as in cases alone (p = 0.0009 and p = 0.0078, respectively); however, mRNA expression of IL-1β was lower in curcumin-treated samples as compared to PHA alone, only when cases and controls were analyzed together (p = 0.0215). There was no difference in other cytokine gene expression levels between the subsets under the in-vitro experimental conditions. In conclusion, curcumin reduced mRNA expression as well as secretion of IL-6 levels by salivary gland tissue of patients with pSS. Curcumin also suppressed PHA-induced mRNA expression levels of IL-6 and IL-1β in MSG tissue of patients with pSS and controls when analyzed together as a combined group.
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Affiliation(s)
- Jayakanthan Kabeerdoss
- Department of Clinical Immunology and Rheumatology, Christian Medical College and Hospital, Vellore, Tamil Nadu, 632004, India
| | - Pulukool Sandhya
- Department of Clinical Immunology and Rheumatology, Christian Medical College and Hospital, Vellore, Tamil Nadu, 632004, India.,Department of Rheumatology, St Stephen's Hospital, Tis Hazari, Delhi, 110054, India
| | - Biji T Kurien
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.,Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Robert Hal Scofield
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.,Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.,Department of Veterans Affairs Medical Center, Oklahoma City, OK, USA
| | - Debashish Danda
- Department of Clinical Immunology and Rheumatology, Christian Medical College and Hospital, Vellore, Tamil Nadu, 632004, India.
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24
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Chatzis L, Vlachoyiannopoulos PG, Tzioufas AG, Goules AV. New frontiers in precision medicine for Sjogren's syndrome. Expert Rev Clin Immunol 2021; 17:127-141. [PMID: 33478279 DOI: 10.1080/1744666x.2021.1879641] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Introduction: Sjögren's syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients' morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients' management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren's syndrome covering several research fields including clinical, translational, and basic research has been reviewed.Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.
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Affiliation(s)
- Loukas Chatzis
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | | | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Andreas V Goules
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
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25
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Traditional Chinese medicine is a useful and promising alternative strategy for treatment of Sjogren's syndrome: A review. JOURNAL OF INTEGRATIVE MEDICINE-JIM 2021; 19:191-202. [PMID: 33509710 DOI: 10.1016/j.joim.2021.01.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 11/11/2020] [Indexed: 01/03/2023]
Abstract
Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease involving exocrine glands. Current studies have found that the occurrence of the disease is closely related to genetic, environmental and neuroendocrine factors, as well as abnormal activation of T and B lymphocytes. The etiology and pathogenesis of pSS is complex, and there is a lack of specific targeted drugs. Traditional Chinese medicines (TCMs) have been comprehensively investigated for their treatment effects on pSS. Through a systematic review of the literature, we summarized the TCMs used to treat pSS, and find that there are four major ways that TCMs are used, including upregulation of aquaporin proteins, suppression of cell apoptosis, suppression of the abnormal activation of B lymphocytes and suppression of the abnormal activation of T lymphocytes (balancing T helper type [Th]1/Th2 & Th17/Treg and suppressing follicular helper T [Tfh] cells). However, there are not enough data about the active constituents, quality control, pharmacokinetics, toxicity and modern preparations of these TCMs; therefore, more investigations are needed. This paper highlights the importance of TCMs for treating pSS and provides guidance for future investigations.
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26
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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: 48] [Impact Index Per Article: 12.0] [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.
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Khalafalla MG, Woods LT, Jasmer KJ, Forti KM, Camden JM, Jensen JL, Limesand KH, Galtung HK, Weisman GA. P2 Receptors as Therapeutic Targets in the Salivary Gland: From Physiology to Dysfunction. Front Pharmacol 2020; 11:222. [PMID: 32231563 PMCID: PMC7082426 DOI: 10.3389/fphar.2020.00222] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2019] [Accepted: 02/18/2020] [Indexed: 12/12/2022] Open
Abstract
Although often overlooked in our daily lives, saliva performs a host of necessary physiological functions, including lubricating and protecting the oral cavity, facilitating taste sensation and digestion and maintaining tooth enamel. Therefore, salivary gland dysfunction and hyposalivation, often resulting from pathogenesis of the autoimmune disease Sjögren's syndrome or from radiotherapy of the head and neck region during cancer treatment, severely reduce the quality of life of afflicted patients and can lead to dental caries, periodontitis, digestive disorders, loss of taste and difficulty speaking. Since their initial discovery in the 1970s, P2 purinergic receptors for extracellular nucleotides, including ATP-gated ion channel P2X and G protein-coupled P2Y receptors, have been shown to mediate physiological processes in numerous tissues, including the salivary glands where P2 receptors represent a link between canonical and non-canonical saliva secretion. Additionally, extracellular nucleotides released during periods of cellular stress and inflammation act as a tissue alarmin to coordinate immunological and tissue repair responses through P2 receptor activation. Accordingly, P2 receptors have gained widespread clinical interest with agonists and antagonists either currently undergoing clinical trials or already approved for human use. Here, we review the contributions of P2 receptors to salivary gland function and describe their role in salivary gland dysfunction. We further consider their potential as therapeutic targets to promote physiological saliva flow, prevent salivary gland inflammation and enhance tissue regeneration.
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Affiliation(s)
- Mahmoud G. Khalafalla
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, United States
| | - Lucas T. Woods
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
| | - Kimberly J. Jasmer
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
| | - Kevin Muñoz Forti
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
| | - Jean M. Camden
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
| | - Janicke L. Jensen
- Institute of Clinical Dentistry, Section of Oral Surgery and Oral Medicine, University of Oslo, Oslo, Norway
| | - Kirsten H. Limesand
- Department of Nutritional Sciences, University of Arizona, Tucson, AZ, United States
| | - Hilde K. Galtung
- Institute of Oral Biology, Faculty of Dentistry, University of Oslo, Oslo, Norway
| | - Gary A. Weisman
- Department of Biochemistry, University of Missouri, Columbia, MO, United States
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO, United States
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Klinngam W, Janga SR, Lee C, Ju Y, Yarber F, Shah M, Guo H, Wang D, MacKay JA, Edman MC, Hamm-Alvarez SF. Inhibition of Cathepsin S Reduces Lacrimal Gland Inflammation and Increases Tear Flow in a Mouse Model of Sjögren's Syndrome. Sci Rep 2019; 9:9559. [PMID: 31267034 PMCID: PMC6606642 DOI: 10.1038/s41598-019-45966-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 06/17/2019] [Indexed: 12/16/2022] Open
Abstract
Cathepsin S (CTSS) is highly increased in Sjögren's syndrome (SS) patients tears and in tears and lacrimal glands (LG) of male non-obese diabetic (NOD) mice, a murine model of SS. To explore CTSS's utility as a therapeutic target for mitigating ocular manifestations of SS in sites where CTSS is increased in disease, the tears and the LG (systemically), the peptide-based inhibitor, Z-FL-COCHO (Z-FL), was administered to 14-15 week male NOD mice. Systemic intraperitoneal (i.p.) injection for 2 weeks significantly reduced CTSS activity in tears, LG and spleen, significantly reduced total lymphocytic infiltration into LG, reduced CD3+ and CD68+ cell abundance within lymphocytic infiltrates, and significantly increased stimulated tear secretion. Topical administration of Z-FL to a different cohort of 14-15 week male NOD mice for 6 weeks significantly reduced only tear CTSS while not affecting LG and spleen CTSS and attenuated the disease-progression related reduction of basal tear secretion, while not significantly impacting lymphocytic infiltration of the LG. These findings suggest that CTSS inhibitors administered either topically or systemically can mitigate aspects of the ocular manifestations of SS.
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Affiliation(s)
- Wannita Klinngam
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Srikanth R Janga
- Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Changrim Lee
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Yaping Ju
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Frances Yarber
- Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Mihir Shah
- Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Hao Guo
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA
| | - Dandan Wang
- Anatomic and Clinical Pathology, Los Angeles County + University of Southern California Medical Center, Los Angeles, CA, 90033, USA
| | - J Andrew MacKay
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA.,Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.,Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, CA, 90089, USA
| | - Maria C Edman
- Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA
| | - Sarah F Hamm-Alvarez
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, 90033, USA. .,Department of Ophthalmology, Roski Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
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van der Heijden EHM, Hartgring SAY, Kruize AA, Radstake TRDJ, van Roon JAG. Additive immunosuppressive effect of leflunomide and hydroxychloroquine supports rationale for combination therapy for Sjögren’s syndrome. Expert Rev Clin Immunol 2019; 15:801-808. [DOI: 10.1080/1744666x.2019.1624527] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Eefje HM van der Heijden
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Sarita AY Hartgring
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Aike A Kruize
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Timothy RDJ Radstake
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
| | - Joel AG van Roon
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
- Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
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Kim JW, Kim SM, Park JS, Hwang SH, Choi J, Jung KA, Ryu JG, Lee SY, Kwok SK, Cho ML, Park SH. Metformin improves salivary gland inflammation and hypofunction in murine Sjögren's syndrome. Arthritis Res Ther 2019; 21:136. [PMID: 31164166 PMCID: PMC6549273 DOI: 10.1186/s13075-019-1904-0] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2018] [Accepted: 04/28/2019] [Indexed: 12/22/2022] Open
Abstract
Background Activated T and B cells participate in the development and progression of Sjögren’s syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS. Methods Metformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4+ T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay. Results Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells. Conclusion Metformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS. Electronic supplementary material The online version of this article (10.1186/s13075-019-1904-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Ji-Won Kim
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Division of Rheumatology, Department of Internal Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea
| | - Sung-Min Kim
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jin-Sil Park
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sun-Hee Hwang
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - JeongWon Choi
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Kyung-Ah Jung
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jun-Geol Ryu
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seon-Yeong Lee
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Ki Kwok
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Mi-La Cho
- Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
| | - Sung-Hwan Park
- Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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Du ZH, Ding C, Zhang Q, Zhang Y, Ge XY, Li SL, Yu GY. Stem cells from exfoliated deciduous teeth alleviate hyposalivation caused by Sjögren syndrome. Oral Dis 2019; 25:1530-1544. [PMID: 31046162 DOI: 10.1111/odi.13113] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2018] [Revised: 04/08/2019] [Accepted: 04/22/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVES To evaluate the effect of stem cells from exfoliated deciduous teeth on the hyposalivation caused by Sjögren syndrome (SS) and investigate the mechanism. METHODS Stem cells were injected into the tail veins of non-obese diabetic mice, the animal model of SS. The saliva flow was measured after pilocarpine intraperitoneal injection. Apoptosis and autophagy were evaluated by TUNEL and Western blot. Lymphocyte proportions were detected by flow cytometer. RESULTS Fluid secretion was decreased in 21-week-old mice. Stem cell treatment increased fluid secretion, alleviated inflammation in the submandibular glands and reduced inflammatory cytokine levels in the serum, submandibular glands and saliva. Stem cells decreased the apoptotic cell number and the expressions of ATG5 and Beclin-1 in the submandibular glands. Stem cells have no effect on other organs. Furthermore, the infused stem cells migrated to the spleen and liver, not the submandibular gland. Stem cells directed T cells towards Treg cells and suppressed Th1 and Tfh cells in spleen lymphocytes. CONCLUSION Stem cells from exfoliated deciduous teeth alleviate the hyposalivation caused by SS via decreasing the inflammatory cytokines, regulating the inflammatory microenvironment and decreasing the apoptosis and autophagy. The stem cells regulated in T-cell differentiation are involved in the immunomodulatory effects.
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Affiliation(s)
- Zhi-Hao Du
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
| | - Chong Ding
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Qian Zhang
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Yan Zhang
- Department of Physiology and Pathophysiology, Peking University School of Basic Medical Sciences, Beijing, China
| | - Xi-Yuan Ge
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Sheng-Lin Li
- Center Laboratory, Peking University School and Hospital of Stomatology, Beijing, China
| | - Guang-Yan Yu
- Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology, Beijing, China
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Blokland SLM, Flessa CM, van Roon JAG, Mavragani CP. Emerging roles for chemokines and cytokines as orchestrators of immunopathology in Sjögren's syndrome. Rheumatology (Oxford) 2019; 60:3072-3087. [PMID: 30838419 DOI: 10.1093/rheumatology/key438] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 12/03/2018] [Indexed: 12/14/2022] Open
Abstract
In primary SS (pSS), chemokines and cytokines orchestrate immunopathology driven by a complex network of interacting inflammatory cells. In recent years, the importance of chemotactic and non-chemotactic cytokines that control function, movement and placing of all cells within the inflamed exocrine glands and directing immunopathology has become increasingly clear. This paper reviews the current knowledge on chemokines and focuses on the emerging roles of novel chemotactic and non-chemotactic mediators in pSS. It highlights their contribution to pathogenic processes such as B cell hyperactivity and the formation of ectopic lymphoid structures. To this end, the role of acquired (CXCR5/CCR9 Th-cell-mediated) and innate (inflammasome/IL-1/IL-18-mediated) pathways in steering immunopathology is discussed.
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Affiliation(s)
- Sofie L M Blokland
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, The Netherlands.,Laboratory of Translational Immunology, Department of Immunology, Utrecht University, Utrecht, The Netherlands
| | - Christina-Maria Flessa
- Department of Physiology, National and Kapodistrian University of Athens, Athens, Greece
| | - Joel A G van Roon
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, The Netherlands.,Laboratory of Translational Immunology, Department of Immunology, Utrecht University, Utrecht, The Netherlands
| | - Clio P Mavragani
- Department of Physiology, National and Kapodistrian University of Athens, Athens, Greece.,Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Joint Academic Rheumatology Program, National and Kapodistrian University of Athens, Athens, Greece
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Verstappen GM, Kroese FGM, Bootsma H. T cells in primary Sjögren's syndrome: targets for early intervention. Rheumatology (Oxford) 2019; 60:3088-3098. [PMID: 30770920 PMCID: PMC8516500 DOI: 10.1093/rheumatology/kez004] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 12/30/2018] [Indexed: 01/27/2023] Open
Abstract
A histologic hallmark of primary SS (pSS) is lymphocytic infiltration of the salivary and lacrimal glands, in particular by CD4+ T and B cells. In the early stages of the disease, infiltrates are dominated by CD4+ T cells, while B cell accumulation occurs at later stages. Activated T cells contribute to pathogenesis by producing pro-inflammatory cytokines and by inducing B cell activation, which results in the establishment of a positive feedback loop. In the inflamed glandular tissues, many different CD4+ effector subsets are present, including IFN-γ-producing Th1 cells, IL-17-producing Th17 cells and IL-21-producing T follicular helper cells. In blood from pSS patients, frequently observed abnormalities of the T cell compartment are CD4+ T cell lymphopenia and enrichment of circulating follicular helper T (Tfh) cells. Tfh cells are critical mediators of T cell–dependent B cell hyperactivity and these cells can be targeted by immunotherapy. Inhibition of T cell activation, preferably early in the disease process, can mitigate B cell activity and may be a promising treatment approach in this disease.
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Affiliation(s)
- Gwenny M Verstappen
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Frans G M Kroese
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Hendrika Bootsma
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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34
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The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic autoimmune rheumatic disease. Arthritis Res Ther 2018; 20:264. [PMID: 30486869 PMCID: PMC6263058 DOI: 10.1186/s13075-018-1752-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/24/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. METHODS Healthy ANA- controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. RESULTS A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA- healthy controls. CONCLUSIONS ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD.
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Gu F, Xu S, Zhang P, Chen X, Wu Y, Wang C, Gao M, Si M, Wang X, Heinrich K, Wu H, Wei W. CP-25 Alleviates Experimental Sjögren's Syndrome Features in NOD/Ltj Mice and Modulates T Lymphocyte Subsets. Basic Clin Pharmacol Toxicol 2018; 123:423-434. [PMID: 29665238 DOI: 10.1111/bcpt.13025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2018] [Accepted: 04/03/2018] [Indexed: 01/19/2023]
Abstract
Primary Sjögren's syndrome (pSS) is a chronic inflammatory autoimmune illness of the moisture-producing glands such as salivary glands that is characterized by various immune abnormalities. The aetiology of pSS remains unclear and there is no curative agent. In this study, we investigated the putative therapeutic effects on a NOD/Ltj mouse model of Sjögren's syndrome-like disorders of an ester derivative of paeoniflorin, paeoniflorin-6'O-benzene (termed CP-25). Our study showed that CP-25 alleviated effectively clinical manifestations in NOD/Ltj mice resulting, for example, in increased salivary flow and reduced histopathological scores. Furthermore, CP-25 decreased lymphocyte viability in NOD/Ltj mice and attenuated the infiltration of Th1 cells and Th2 cells into the salivary glands of NOD/Ltj mice. In the spleen on NOD/Ltj mice, CP-25 skewed the ratio of Th17 and regulatory T cells towards regulatory T cells. After treatment, concentrations of anti-La/SSB and IgG antibodies were reduced and the titre of the inflammatory cytokines IFN-γ, IL-4, IL-6 and IL-17A in the serum on NOD/Ltj mice was alleviated. Thus, we define CP-25 as a novel compound that is a potent therapeutic agent for pSS by modulating T lymphocyte subsets. Future studies will validate the use of CP-25 as a therapeutic strategy for the treatment of pSS.
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Affiliation(s)
- Fang Gu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Shixia Xu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Pengying Zhang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Xiaoyun Chen
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Yujing Wu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Chun Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Mei Gao
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Min Si
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Xinming Wang
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Korner Heinrich
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Huaxun Wu
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
| | - Wei Wei
- Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China.,Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Hefei, Anhui, China.,Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei, Anhui, China
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Janga SR, Shah M, Ju Y, Meng Z, Edman MC, Hamm-Alvarez SF. Longitudinal analysis of tear cathepsin S activity levels in male non-obese diabetic mice suggests its potential as an early stage biomarker of Sjögren's Syndrome. Biomarkers 2018; 24:91-102. [PMID: 30126300 DOI: 10.1080/1354750x.2018.1514656] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
CONTEXT Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. OBJECTIVE To evaluate longitudinal expression of tear and tissue CTSS activity relative to other disease indicators in Non-Obese Diabetic (NOD) mice. METHODS CTSS activity was measured in tears and lacrimal glands (LG) from male 1-6 month (M) NOD and 1 and 6 M BALB/c mice. Lymphocytic infiltration was quantified by histopathology, while disease-related proteins (Rab3D, CTSS, collagen 1) were quantified using q-PCR and immunofluorescence. RESULTS In NOD LG, lymphocytic infiltration was noted by 2 M and established by 3 M (p < 0.01). IFN-ɣ, TNF-α, and MHC II expression were increased by 2 M (p < 0.01). Tear CTSS activity was significantly elevated at 2 M (p < 0.001) to a maximum of 10.1-fold by 6 M (p < 0.001). CTSS activity in LG lysates was significantly elevated by 2 M (p < 0.001) to a maximum of 14-fold by 3 M (p < 0.001). CTSS and Rab3D immunofluorescence were significantly increased and decreased maximally in LG acini by 3 M and 2 M, respectively. Comparable changes were not detected between 1 and 6 M BALB/c mouse LG, although Collagen 1 was decreased by 6 M in LG of both strains. CONCLUSION Tear CTSS activity is elevated with other early disease indicators, suggesting potential as an early stage biomarker for SS.
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Affiliation(s)
- Srikanth R Janga
- a Department of Ophthalmology, USC Keck School of Medicine , Roski Eye Institute , Los Angeles , CA , USA
| | - Mihir Shah
- a Department of Ophthalmology, USC Keck School of Medicine , Roski Eye Institute , Los Angeles , CA , USA
| | - Yaping Ju
- b Department of Pharmacology and Pharmaceutical Sciences , USC School of Pharmacy , Los Angeles , CA , USA
| | - Zhen Meng
- b Department of Pharmacology and Pharmaceutical Sciences , USC School of Pharmacy , Los Angeles , CA , USA
| | - Maria C Edman
- a Department of Ophthalmology, USC Keck School of Medicine , Roski Eye Institute , Los Angeles , CA , USA
| | - Sarah F Hamm-Alvarez
- a Department of Ophthalmology, USC Keck School of Medicine , Roski Eye Institute , Los Angeles , CA , USA.,b Department of Pharmacology and Pharmaceutical Sciences , USC School of Pharmacy , Los Angeles , CA , USA
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Bone Morphogenetic Protein 6 Inhibits the Immunomodulatory Property of BMMSCs via Id1 in Sjögren's Syndrome. Stem Cells Int 2018; 2018:9837035. [PMID: 30174696 PMCID: PMC6098892 DOI: 10.1155/2018/9837035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 06/19/2018] [Indexed: 12/29/2022] Open
Abstract
Mesenchymal stem cells (MSCs) treatment has emerged as a promising approach for treating Sjögren's syndrome (SS). Impaired immunoregulatory activities of bone marrow mesenchymal stem cells (BMMSCs) are found in both SS patients and animal models, and the underlying mechanism is poorly understood. Increased expression of BMP6 is reported to be related to SS. The aim herein was to determine the effects of BMP6 on BMMSCs function. BMMSCs were isolated from SS patients and NOD mice and showed a high level of BMP6 expression. The effects of BMP6 on BMMSCs function were investigated using in vitro BMMSCs differentiation and in vitro and in vivo T cell proliferation and polarization assays. BMP6 increased osteogenic differentiation of BMMSCs and inhibited the immunomodulatory properties of BMMSCs. BMP6 enhanced T cell proliferation and Th1/Th17 differentiation in a T cell-BMMSC coculture system. Mechanistically, BMP6 downregulated PGE2 and upregulated IFN-gamma via Id1 (inhibitor of DNA-binding protein 1). Neutralizing BMP6 and knockdown of Id1 could restore the BMMSCs immunosuppressive function both in vitro and in vivo. The present results suggest a novel role of Id1 in BMP-mediated MSCs function, which may contribute to a better understanding of the mechanism of action of MSCs in treating autoimmune diseases.
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Unique glandular ex-vivo Th1 and Th17 receptor motifs in Sjögren's syndrome patients using single-cell analysis. Clin Immunol 2018; 192:58-67. [PMID: 29679709 DOI: 10.1016/j.clim.2018.04.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 03/28/2018] [Accepted: 04/17/2018] [Indexed: 02/06/2023]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease in which the underlying cause has yet to be elucidated. The main objective of this study was to determine the T cell receptor (TCR) repertoires of individual infiltrating T helper (Th)-1 and 17 cells of pSS patients using single-cell analysis. Single-cell analysis of ex-vivo infiltrating T cells demonstrated that pSS patients had higher frequencies of activated Th17 cells. Single-cell TCR sequencing revealed that TCRβ variable (TRBV)3-1/joint (J)1-2 (CLFLSMSACVW) and TRBV20-1/J1-1 (SVGSTAIPP*T) were expressed by activated Th1 and Th17 cells in both cohorts. Uniquely, TCRα variable (TRAV)8-2/J5 (VVSDTVLETAGE) was expressed by Th1 cells present only in patients and complementarity-determining region (CDR)3α-specific motif (LSTD*E) present in both Th1/Th17 cells. The study demonstrates that both activated Th1 and Th17 cells of pSS patients showed restricted clonal diversities of which two CDR3 motifs were present in controls and patients, with another two motifs unique to pSS.
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Inhibition of lysophosphatidic acid receptor ameliorates Sjögren's syndrome in NOD mice. Oncotarget 2018; 8:27240-27251. [PMID: 28460477 PMCID: PMC5432331 DOI: 10.18632/oncotarget.15916] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 02/20/2017] [Indexed: 01/05/2023] Open
Abstract
Lysophosphatidic acid (LPA), a bioactive lysophospholipid, is involved in the pathogenesis of chronic inflammatory and autoimmune diseases. In this study, we investigated the role of LPA/LPA receptor (LPAR) signaling in the pathogenesis of Sjögren's syndrome (SS). We found that autotaxin, an LPA producing enzyme, and LPAR1 and LPAR3 mRNA, and IL-17 mRNA were highly expressed in the exocrine glands of 20-week-old nonobese diabetic (NOD) mice, which show SS symptoms at this age, as compared with non-symptomatic 8-week-old NOD mice. In an adoptive transfer model using NOD lymphocytes, treatment with Ki16425, an LPAR1/3 antagonist, restored tear and saliva secretion and decreased symptoms of SS compared with the vehicle-treated group. IL-17 levels in serum and lacrimal glands were also significantly reduced by Ki16425 in recipient mice. In addition, Ki16425 treatment of 20-week-old NOD mice, which spontaneously developed SS, restored saliva volume. Treatment of NOD splenocytes with LPA induced the expression of IL-17 in a dose-dependent manner, and Ki16425 inhibited this increase. LPA stimulated the activation of ROCK2 and p38 MAPK; and inhibition of ROCK2 or p38 MAPK suppressed LPA-induced IL-17 expression. Our data suggest that LPAR signaling stimulates SS development by induction of IL-17 production via ROCK and p38 MAPK pathways. Thus, LPAR inhibition could be a possible therapeutic strategy for SS.
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Meng Z, Klinngam W, Edman MC, Hamm-Alvarez SF. Interferon-γ treatment in vitro elicits some of the changes in cathepsin S and antigen presentation characteristic of lacrimal glands and corneas from the NOD mouse model of Sjögren's Syndrome. PLoS One 2017; 12:e0184781. [PMID: 28902875 PMCID: PMC5597228 DOI: 10.1371/journal.pone.0184781] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Accepted: 08/30/2017] [Indexed: 12/19/2022] Open
Abstract
Inflammation and impaired secretion by lacrimal and salivary glands are hallmarks of the autoimmune disease, Sjögren’s Syndrome. These changes in the lacrimal gland promote dryness and inflammation of the ocular surface, causing pain, irritation and corneal damage. The changes that initiate and sustain autoimmune inflammation in the lacrimal gland are not well-established. Here we demonstrate that interferon-γ (IFN-γ) is significantly elevated in lacrimal gland and tears of the male NOD mouse, a model of autoimmune dacryoadenitis which exhibits many ocular characteristics of Sjögren’s Syndrome, by 12 weeks of age early in lacrimal gland inflammation. Working either with primary cultured lacrimal gland acinar cells from BALB/c mice and/or rabbits, in vitro IFN-γ treatment for 48 hr decreased expression of Rab3D concurrent with increased expression of cathepsin S. Although total cellular cathepsin S activity was not commensurately increased, IFN-γ treated lacrimal gland acinar cells showed a significant increase in carbachol-stimulated secretion of cathepsin S similar to the lacrimal gland in disease. In vitro IFN-γ treatment did not increase the expression of most components of major histocompatibility complex (MHC) class II-mediated antigen presentation although antigen presentation was slightly but significantly stimulated in primary cultured lacrimal gland acinar cells. However, exposure of cultured human corneal epithelial cells to IFN-γ more robustly increased expression and activity of cathepsin S in parallel with increased expression and function of MHC class II-mediated antigen presentation. We propose that early elevations in IFN-γ contribute to specific features of ocular disease pathology in Sjögren’s Syndrome.
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Affiliation(s)
- Zhen Meng
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America
| | - Wannita Klinngam
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America
| | - Maria C. Edman
- Department of Ophthalmology, USC Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
| | - Sarah F. Hamm-Alvarez
- Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, California, United States of America
- Department of Ophthalmology, USC Roski Eye Institute and Keck School of Medicine, University of Southern California, Los Angeles, California, United States of America
- * E-mail:
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Matta B, Song S, Li D, Barnes BJ. Interferon regulatory factor signaling in autoimmune disease. Cytokine 2017; 98:15-26. [PMID: 28283223 DOI: 10.1016/j.cyto.2017.02.006] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2017] [Accepted: 02/06/2017] [Indexed: 12/14/2022]
Abstract
Interferon regulatory factors (IRFs) play critical roles in pathogen-induced innate immune responses and the subsequent induction of adaptive immune response. Dysregulation of IRF signaling is therefore thought to contribute to autoimmune disease pathogenesis. Indeed, numerous murine in vivo studies have documented protection from or enhanced susceptibility to particular autoimmune diseases in Irf-deficient mice. What has been lacking, however, is replication of these in vivo observations in primary immune cells from patients with autoimmune disease. These types of studies are essential as the majority of in vivo data support a protective role for IRFs in Irf-deficient mice, yet IRFs are often found to be overexpressed in patient immune cells. A significant body of work is beginning to emerge from both of these areas of study - mouse and human.
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Affiliation(s)
- Bharati Matta
- Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States
| | - Su Song
- Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States
| | - Dan Li
- Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States
| | - Betsy J Barnes
- Center for Autoimmune and Musculoskeletal Diseases, The Feinstein Institute for Medical Research, Manhasset, NY 11030, United States.
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Is it Sjögren's syndrome or burning mouth syndrome? Distinct pathoses with similar oral symptoms. Oral Surg Oral Med Oral Pathol Oral Radiol 2017; 123:482-495. [PMID: 28283095 DOI: 10.1016/j.oooo.2017.01.005] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2016] [Revised: 01/10/2017] [Accepted: 01/12/2017] [Indexed: 12/17/2022]
Abstract
Sjögren's syndrome (SS) and burning mouth syndrome (BMS) typically occur in postmenopausal women. Although these conditions have significantly different etiopathogeneses, patients with SS or BMS often present with analogous oral complaints. The similarities between the two conditions have led to considerable confusion on the part of medical and dental practitioners, and those with BMS or SS often wait years to receive a diagnosis. Therefore, it is imperative for clinicians to understand the characteristic subjective and objective features of each disease and how these can be used to distinguish them. This review will discuss the proposed etiology, clinical manifestations, histopathology, diagnostic criteria, and patient management of SS and BMS. We also identify key differences between the two pathoses that aid in establishing the correct diagnosis. Recognition of the defining features of each condition will lead to reduced time to diagnosis and improved patient management for these poorly understood conditions.
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Zhou J, Jin JO, Kawai T, Yu Q. Endogenous programmed death ligand-1 restrains the development and onset of Sjӧgren's syndrome in non-obese diabetic mice. Sci Rep 2016; 6:39105. [PMID: 27966604 PMCID: PMC5155421 DOI: 10.1038/srep39105] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 11/17/2016] [Indexed: 01/09/2023] Open
Abstract
Programmed death-ligand 1 (PD-L1) down-modulates various immune responses by engaging the co-inhibitory receptor programmed death-1. Expression of PD-L1 and programmed death-1 is elevated in the salivary glands of patients with Sjögren’s syndrome (SS). The objective of this study is to define the role of endogenous PD-L1 in SS pathogenesis in non-obese diabetic (NOD) mouse model of this disease. We inhibited endogenous PD-L1 function by intraperitoneal administration of a blocking antibody to 6 week-old female NOD/ShiLtJ mice repeatedly during a 9-day period. PD-L1 blockade accelerated leukocyte infiltration and caspase-3 activation in the submandibular gland (SMG), production of antinuclear and anti-M3 muscarinic acetylcholine receptor (M3R) autoantibodies and impairment of saliva secretion, indicative of accelerated development and onset of SS. The effect of PD-L1 blockade was associated with increased T- and B cells and T helper 1 cytokine IFN-γ in the SMG. Local administration of exogenous IFN-γ to the SMG led to impaired salivary secretion accompanied by down-regulation of aquaporin 5 and an increase in anti-M3R autoantibodies. Conversely, neutralization of IFN-γ markedly improved salivary secretion and aquaporin 5 expression in anti-PD-L1-treated NOD/ShiLtJ mice. Hence, endogenous PD-L1 hinders the development and onset of SS in NOD mice, in part by suppressing IFN-γ production.
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Affiliation(s)
- Jing Zhou
- Department of Immunology and Infectious Diseases, 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
| | - Jun-O Jin
- Department of Immunology and Infectious Diseases, the Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA
| | - Toshihisa Kawai
- Department of Immunology and Infectious Diseases, 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
- Department of Immunology and Infectious Diseases, 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
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Abstract
Primary Sjögren syndrome (pSS) can be considered a systemic autoimmune disease with a strong organ bias. The involvement of the exocrine glands is prevalent and drives the pathognomonic manifestations of dryness that define the sicca syndrome. The salivary glands also represent the hub of pSS pathology. Elements belonging to both innate and acquired immune responses have been described at this site that contribute to disease establishment and progression. The interaction between those elements and their relative contributions to the clinical manifestations and lymphoma progression largely remain to be addressed.
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Affiliation(s)
- Joana Campos
- Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, ARUK Center for the Pathogenesis of Rheumatoid Arthritis, University of Birmingham, Queen Elizabeth Hospital, Mindelsohn Way, Birmingham B15 2WB, UK
| | - Maarten R Hillen
- Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, ARUK Center for the Pathogenesis of Rheumatoid Arthritis, University of Birmingham, Queen Elizabeth Hospital, Mindelsohn Way, Birmingham B15 2WB, UK; Laboratory of Translational Immunology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht 3584CX, The Netherlands
| | - Francesca Barone
- Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, ARUK Center for the Pathogenesis of Rheumatoid Arthritis, University of Birmingham, Queen Elizabeth Hospital, Mindelsohn Way, Birmingham B15 2WB, UK.
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Abstract
The genes associated with Sjögren syndrome (SS) can be assigned to the NF-kB pathway, the IFN signaling pathway, lymphocyte signaling, and antigen presentation. The frequencies of risk variants show they are common with modest genetic effects. The strongest genetic association outside the human leukocyte antigen region is in IRF5, a gene relevant in the IFN signaling pathway and for B cell differentiation. Although no association has been found with the NF-kB gene itself, associations in TNFAIP3 and TNIP1 (both genome-wide significant), VCAM1 and IRAK1BP (both suggestive), point to genetic explanations for dysregulation of the NF-kB pathway in SS.
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Affiliation(s)
- Tove Ragna Reksten
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, USA; Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, The Laboratory Building, Haukeland University Hospital, Jonas Lies vei 87, N-5021 Bergen, Norway
| | - Christopher J Lessard
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, MBSB 451, Oklahoma City, OK 73104, USA
| | - Kathy L Sivils
- Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, 825 Northeast 13th Street, Oklahoma City, OK 73104, USA; Department of Pathology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Boulevard, MBSB 451, Oklahoma City, OK 73104, USA.
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Zhou J, Jin JO, Patel ES, Yu Q. Interleukin-6 inhibits apoptosis of exocrine gland tissues under inflammatory conditions. Cytokine 2015; 76:244-252. [PMID: 26255211 PMCID: PMC4605873 DOI: 10.1016/j.cyto.2015.07.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 07/27/2015] [Accepted: 07/29/2015] [Indexed: 01/12/2023]
Abstract
Interleukin (IL)-6 is a multi-functional cytokine that can either promote or suppress tissue inflammation depending on the specific disease context. IL-6 is elevated in the exocrine glands and serum of patients with Sjögren's syndrome (SS), but the specific role of IL-6 in the pathogenesis of this disease has not been defined. In this study, we showed that IL-6 expression levels were increased with age in C56BL/6.NOD-Aec1Aec2 mice, a primary SS model, and higher than the control C57BL/6 mice. To assess the role of IL-6 during the immunological phase of SS development, a neutralizing anti-IL-6 antibody was administered into 16 week-old female C56BL/6.NOD-Aec1Aec2 mice, 3 times weekly for a consecutive 8 weeks. Neutralization of endogenous IL-6 throughout the immunological phase of SS development led to increased apoptosis, caspase-3 activation, leukocytic infiltration, and IFN-γ- and TNF-α production in the salivary gland. To further determine the effect of IL-6 on the apoptosis of exocrine gland cells, recombinant human IL-6 or the neutralizing anti-IL-6 antibody was injected into female C57BL/6 mice that received concurrent injection of anti-CD3 antibody to induce the apoptosis of exocrine gland tissues. Neutralization of IL-6 enhanced, whereas administration of IL-6 inhibited apoptosis and caspase-3 activation in salivary and lacrimal glands in this model. The apoptosis-suppressing effect of IL-6 was associated with up-regulation of Bcl-xL and Mcl-1 in both glands. Moreover, IL-6 treatment induced activation of STAT3 and up-regulated Bcl-xL and Mcl-1 gene expression in a human salivary gland epithelial cell line. In conclusion, IL-6 inhibits the apoptosis of exocrine gland tissues and exerts a tissue-protective effect under inflammatory conditions including SS. These findings suggest the possibility of using this property of IL-6 to preserve exocrine gland tissue integrity and function under autoimmune and inflammatory conditions.
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Affiliation(s)
- Jing Zhou
- Department of Immunology and Infectious Diseases, 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.
| | - Jun-O Jin
- Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, MA 02142, USA.
| | - Ekta S Patel
- Department of Immunology and Infectious Diseases, 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
- Department of Immunology and Infectious Diseases, 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.
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Crispín JC, Rosetti F, Hernández-Molina G. Lessons from Sjögren’s syndrome etiopathogenesis: Novel cellular and molecular targets. World J Immunol 2015; 5:152-159. [DOI: 10.5411/wji.v5.i3.152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 09/22/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
Sjögren’s syndrome (SS) is a systemic autoimmune disease that affects primarily the lacrimal and salivary glands. In addition to a systemic autoimmune response directed against ubiquitous antigens (such as Ro and La antigens), patients with SS mount a localized response that affects the epithelial component of exocrine glands leading to the establishment of a destructive inflammatory infiltrate comprised of activated T and B cells. Local chemokine and cytokine production drive the recruitment and local activation of immune cells that cause injury to acinar cells. CD4 T cells with different functional differentiation programs including Th1 (IFN-γ), Th2 (IL-13, IL-4) and Th17 (IL-17, IL-21, IL-22) as well as diverse cytokine signaling pathways, are involved at the initiation, perpetuation, and progression of the disease. Which factors initiate this response and allow it to become chronic are unknown. Proposed mechanisms include viral infections and acinar cell apoptosis. Moreover risk-conferring genetic variants, probably through the facilitation of innate and adaptive immune activation, most certainly contribute to the creation of an underlying environment that fosters tolerance loss and facilitates perpetuation of the autoimmune response. In this review, we describe the mechanisms through which the immune response causes SS and emphasize the pathways that are amenable of being targeted with therapeutic purposes.
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Hillen MR, Kruize AA, Bikker A, Wenting-van Wijk M, Radstake TRDJ, Hack CE, Lafeber FPJG, van Roon JAG. Decreased expression of thymic stromal lymphopoietin in salivary glands of patients with primary Sjögren’s syndrome is associated with increased disease activity. Mod Rheumatol 2015; 26:105-9. [DOI: 10.3109/14397595.2015.1054089] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Furuzawa-Carballeda J, Sánchez-Guerrero J, Betanzos JL, Enriquez AB, Avila-Casado C, Llorente L, Hernández-Molina G. Differential cytokine expression and regulatory cells in patients with primary and secondary Sjögren's syndrome. Scand J Immunol 2015; 80:432-40. [PMID: 25346207 DOI: 10.1111/sji.12224] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2014] [Accepted: 08/12/2014] [Indexed: 12/11/2022]
Abstract
Sjögren's syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration of the salivary and lacrimal glands. The aim of the study was to characterize and compare the presence of diverse cytokines and regulatory T and B cells in lip minor salivary gland (MSG) biopsies from patients with primary Sjögren's syndrome (pSS), secondary SS (sSS), and patients with connective tissue disease (CTD) without (w/o) SS. We included samples of MSG from 15 pSS, 24 sSS (six scleroderma, nine rheumatoid arthritis and nine lupus patients) and 15 patients with CTD w/o SS. Tissues were examined by an indirect immunoperoxidase technique (goat polyclonal anti-human IL-19, goat polyclonal anti-human IL-22 or mouse monoclonal anti-human IL-24). To determine the subpopulation of CD4(+)/IL-17A(+)-, CD4(+)/IL-4(+)-, CD4(+)/IFN-ɣ(+)-expressing T cells, CD25(+)/Foxp3(+) Treg cells and CD20(+)/IL-10(+)-producing B cell subset, a double-staining procedure was performed. We estimated the mean percentage of positively staining cells in two fields per sample. CD4(+)/IFN-ɣ(+), CD4(+)/IL-4(+) and IL-22(+) cell percentages were elevated in both SS varieties; however, the cells were more prevalent in pSS. Patients with pSS had a high number of CD4(+)/IL-17A(+) and IL-19(+) T cells and a lower percentage of IL-24(+) cells (P < 0.05). The Treg and IL-10-producing B cells were increased in pSS (P < 0.05). Concluding, in our patients, a pro-inflammatory and regulatory balance coexists in SS, being both responses more intense in pSS. The explanation of these differences may be related to disease activity, disease duration and treatment.
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Affiliation(s)
- J Furuzawa-Carballeda
- Department of Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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Li CY, Wu SL, Sun LX, Yan TT, Wang Y. Protective Effect of Zengye Decoction () on Submandibular Glands in Nonobese Diabetic Mice. Chin J Integr Med 2014; 25:45-50. [PMID: 25253552 DOI: 10.1007/s11655-014-1981-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/12/2014] [Indexed: 12/21/2022]
Abstract
OBJECTIVE To investigate the protective effect of Zengye Decoction (, ZYD) on the submandibular glands (SMGs) in nonobese diabetic (NOD) mice. METHODS Twenty-seven female NOD mice were randomly equally divided into 3 groups: the model group, the hydroxychloroquine (HCQ) group, and the ZYD group. Nine C57/B6 mice served as the normal group. After 1-week acclimation, the HCQ and ZYD groups were intragastrically administered with HCQ and ZYD, respectively, and the normal and model groups were administered with normal saline. Changes in the salivary flow rate were observed. Mice from all 4 groups were sacrificed at the age of 20 weeks. The serum and SMGs were collected. Serum cytokines gamma-interferon (IFN-γ), interleukin-10 (IL-10) were detected by enzyme-linked immunosorbent assay. Histological changes in the submandibular glands were examined by hematoxylin and eosin staining. The mRNA expression of IFN-γ, IL-10 and vasoactive intestinal peptide (VIP) in the submandibular glands were measured by real-time polymerase chain reaction. RESULTS Compared with the model group, the salivary flow of the ZYD group significantly increased (P<0.05), the extent of the histological changes was ameliorated (P<0.05), and the Th1/Th2 cytokine imbalance was remedied (P<0.05). In the ZYD-treated mice, the VIP mRNA was up-regulated (P<0.05). CONCLUSIONS ZYD is beneficial in protecting structure and function of SMGs in NOD mice. The mechanism may be associated with the correction of the Th1/Th2 cytokine imbalance, and with the prevention of a progressive decline of the VIP level.
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Affiliation(s)
- Cheng-Yin Li
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
- Department of Rheumatology, Chongqing Hospital of Traditional Chinese Medicine, Chongqing, 400021, China
| | - Su-Ling Wu
- Nanjing Hospital of Traditional Chinese Medicine, Nanjing, 210001, China
| | - Li-Xia Sun
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Ting-Ting Yan
- Institute for Ancient Texts of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Yue Wang
- The First College of Clinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
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