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1
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Zhang W, Zhu C, Liao Y, Zhou M, Xu W, Zou Z. Caspase-8 in inflammatory diseases: a potential therapeutic target. Cell Mol Biol Lett 2024; 29:130. [PMID: 39379817 PMCID: PMC11463096 DOI: 10.1186/s11658-024-00646-x] [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: 05/20/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024] Open
Abstract
Caspase-8, a renowned cysteine-aspartic protease within its enzyme family, initially garnered attention for its regulatory role in extrinsic apoptosis. With advancing research, a growing body of evidence has substantiated its involvement in other cell death processes, such as pyroptosis and necroptosis, as well as its modulatory effects on inflammasomes and proinflammatory cytokines. PANoptosis, an emerging concept of cell death, encompasses pyroptosis, apoptosis, and necroptosis, providing insight into the often overlapping cellular mortality observed during disease progression. The activation or deficiency of caspase-8 enzymatic activity is closely linked to PANoptosis, positioning caspase-8 as a key regulator of cell survival or death across various physiological and pathological processes. Aberrant expression of caspase-8 is closely associated with the development and progression of a range of inflammatory diseases, including immune system disorders, neurodegenerative diseases (NDDs), sepsis, and cancer. This paper delves into the regulatory role and impact of caspase-8 in these conditions, aiming to elucidate potential therapeutic strategies for the future intervention.
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Affiliation(s)
- Wangzheqi Zhang
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Chenglong Zhu
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Yan Liao
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China
| | - Miao Zhou
- Department of Anesthesiology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University, Nanjing, 210009, Jiangsu, China.
| | - Wenyun Xu
- Department of Anesthesiology, Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
| | - Zui Zou
- Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, 200433, China.
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Sisto M, Ribatti D, Lisi S. Molecular Mechanisms Linking Inflammation to Autoimmunity in Sjögren's Syndrome: Identification of New Targets. Int J Mol Sci 2022; 23:13229. [PMID: 36362017 PMCID: PMC9658723 DOI: 10.3390/ijms232113229] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 10/15/2023] Open
Abstract
Sjögren's syndrome (SS) is a systemic autoimmune rheumatic disorder characterized by the lymphocytic infiltration of exocrine glands and the production of autoantibodies to self-antigens. The involvement of the exocrine glands drives the pathognomonic manifestations of dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) that define sicca syndrome. To date, the molecular mechanisms mediating pathological salivary gland dysfunction in SS remain to be elucidated, despite extensive studies investigating the underlying cause of this disease, hampering the development of novel therapeutic strategies. Many researchers have identified a multifactorial pathogenesis of SS, including environmental, genetic, neuroendocrine, and immune factors. In this review, we explore the latest developments in understanding the molecular mechanisms involved in the pathogenesis of SS, which have attracted increasing interest in recent years.
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Affiliation(s)
- Margherita Sisto
- Department of Translational Biomedicine and Neuroscience (DiBraiN), Section of Human Anatomy and Histology, University of Bari “Aldo Moro”, Piazza Giulio Cesare 1, I-70124 Bari, Italy
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Sisto M, Ribatti D, Lisi S. Understanding the Complexity of Sjögren's Syndrome: Remarkable Progress in Elucidating NF-κB Mechanisms. J Clin Med 2020; 9:jcm9092821. [PMID: 32878252 PMCID: PMC7563658 DOI: 10.3390/jcm9092821] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 08/26/2020] [Accepted: 08/28/2020] [Indexed: 12/13/2022] Open
Abstract
Sjögren’s syndrome (SS) is a systemic autoimmune inflammatory disease with a poorly defined aetiology, which targets exocrine glands (particularly salivary and lachrymal glands), affecting the secretory function. Patients suffering from SS exhibit persistent xerostomia and keratoconjunctivitis sicca. It is now widely acknowledged that a chronic grade of inflammation plays a central role in the initiation, progression, and development of SS. Consistent with its key role in organizing inflammatory responses, numerous recent studies have shown involvement of the transcription factor nuclear factor κ (kappa)-light-chain-enhancer of activated B cells (NF-κB) in the development of this disease. Therefore, chronic inflammation is considered as a critical factor in the disease aetiology, offering hope for the development of new drugs for treatment. The purpose of this review is to describe the current knowledge about the NF-κB-mediated molecular events implicated in the pathogenesis of SS.
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Yang Y, Hou Y, Li J, Zhang F, Du Q. Characterization of antiapoptotic microRNAs in primary Sjögren's syndrome. Cell Biochem Funct 2020; 38:1111-1118. [PMID: 32575162 DOI: 10.1002/cbf.3569] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 05/23/2020] [Accepted: 05/25/2020] [Indexed: 02/02/2023]
Abstract
During the development of primary Sjögren's syndrome (pSS), aberrant expression of autoantigen is a hallmark event. To explore the regulation of autoantigen tripartite motif containing 21 (Ro/SSA, TRIM21), microRNA profiling was performed in our previous study. In which, two TRIM21-targeting microRNAs were identified, namely miR-1207-5p and miR-4695-3p. To further pursue their roles in the development of pSS, assays were performed with cultured human submandibular gland (HSG) cells, and salivary gland tissues. Results showed that transfection of miR-1207-5p or miR-4695-3p mimics down-regulated not only the expression of TRIM21, but also the levels of pro-apoptotic genes B cell lymphoma 2 associated X (BAX), Caspase 9 (CASP-9) and Caspase 8 (CASP-8). This finally led to antiapoptotic phenotypes in HSG cells. Consistent with the antiapoptotic activity, transfection of microRNA inhibitors up-regulated the expression of TRIM21 and led to a pro-apoptotic phenotype. These therefore propose miR-1207-5p and miR-4695-3p as two antiapoptotic microRNAs functioning through apoptosis pathway. Supporting this speculation, assays performed with salivary gland tissues revealed down-regulation of miR-1207-5p and miR-4695-3p, as well as up-regulation of TRIM21 and pro-apoptotic CASP-8 gene in pSS samples. SIGNIFICANCE OF THE STUDY: For pSS patients, apoptosis of acinar and ductal epithelial cells has been proposed to be a potential mechanism that impairs the secretion of salivary glands. In our study, two autoantigen-targeting microRNAs were characterized as antiapoptotic microRNAs functioning through apoptosis pathway, which may be potential targets for the treatment of pSS.
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Affiliation(s)
- Ying Yang
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yingzi Hou
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Jinghui Li
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Fangming Zhang
- Department of Stomatology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Quan Du
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
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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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Apostolou E, Moustardas P, Iwawaki T, Tzioufas AG, Spyrou G. Ablation of the Chaperone Protein ERdj5 Results in a Sjögren's Syndrome-Like Phenotype in Mice, Consistent With an Upregulated Unfolded Protein Response in Human Patients. Front Immunol 2019; 10:506. [PMID: 30967862 PMCID: PMC6438897 DOI: 10.3389/fimmu.2019.00506] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Accepted: 02/25/2019] [Indexed: 12/21/2022] Open
Abstract
Objective: Sjögren's syndrome (SS) is a chronic autoimmune disorder that affects mainly the exocrine glands. Endoplasmic reticulum (ER) stress proteins have been suggested to participate in autoimmune and inflammatory responses, either acting as autoantigens, or by modulating factors of inflammation. The chaperone protein ERdj5 is an ER-resident disulfide reductase, required for the translocation of misfolded proteins during ER-associated protein degradation. In this study we investigated the role of ERdj5 in the salivary glands (SGs), in association with inflammation and autoimmunity. Methods:In situ expression of ERdj5 and XBP1 activation were studied immunohistochemically in minor SG tissues from primary SS patients and non-SS sicca-complaining controls. We used the mouse model of ERdj5 ablation and characterized its features: Histopathological, serological (antinuclear antibodies and cytokine levels), and functional (saliva flow rate). Results: ERdj5 was highly expressed in the minor SGs of SS patients, with stain intensity correlated to inflammatory lesion severity and anti-SSA/Ro positivity. Moreover, SS patients demonstrated higher XBP1 activation within the SGs. Remarkably, ablation of ERdj5 in mice conveyed many of the cardinal features of SS, like spontaneous inflammation in SGs with infiltrating T and B lymphocytes, distinct cytokine signature, excessive cell death, reduced saliva flow, and production of anti-SSA/Ro and anti-SSB/La autoantibodies. Notably, these features were more pronounced in female mice. Conclusions: Our findings suggest a critical connection between the function of the ER chaperone protein ERdj5 and autoimmune inflammatory responses in the SGs and provide evidence for a new, potent animal model of SS.
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Affiliation(s)
- Eirini Apostolou
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Academic Joint Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Petros Moustardas
- Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.,Department of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
| | - Takao Iwawaki
- Division of Cell Medicine, Department of Life Science, Medical Research Institute, Kanazawa Medical University, Uchinada, Japan
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.,Academic Joint Rheumatology Program, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Giannis Spyrou
- Division of Microbiology and Molecular Medicine, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
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Xuan J, Wang Y, Xiong Y, Qian H, He Y, Shi G. Investigation of autoantibodies to SP-1 in Chinese patients with primary Sjögren's syndrome. Clin Immunol 2017; 188:58-63. [PMID: 29292085 DOI: 10.1016/j.clim.2017.12.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2017] [Revised: 12/20/2017] [Accepted: 12/20/2017] [Indexed: 11/28/2022]
Abstract
In order to evaluate autoantibody to SP-1 as an early biomarker in pSS, we investigated autoantibody to SP-1 in Chinese patients with primary Sjögren's syndrome (pSS). Autoantibodies to SP-1 are significantly increased in pSS patients compared to RA patients, SLE patients, and healthy people without secondary SS. The presence of anti SP-1 antibodies was negatively correlated with the focus score (FS), RF, and salivary gland function. It was positively correlated with FS=0, RF≤20, and normal salivary gland function. In further studies, the autoantigen SP-1 was identified in ductal epithelia of salivary glands in il14α TG mice by IIF. SP-1 mRNAs expression increased with growing age in il14α TG mice. SP-1 mRNA was also identified in labial biopsies of patients with pSS. In conclusion, autoantibody to SP-1 is an early marker in pSS. It is useful to diagnose pSS patients who lack RF or antibodies to Ro/La.
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Affiliation(s)
- Jingxiu Xuan
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China
| | - Ying Wang
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China
| | - Yingling Xiong
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China
| | - Hongyan Qian
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China
| | - Yan He
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China
| | - Guixiu Shi
- Department of Rheumatism and Immunology, The First Affiliated Hospital of Xiamen University, 55 Zhenhai Road, Xiamen, Fujian 361003, China.
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8
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X-linked ectodermal dysplasia receptor (XEDAR) gene silencing prevents caspase-3-mediated apoptosis in Sjögren's syndrome. Clin Exp Med 2015; 17:111-119. [PMID: 26659383 DOI: 10.1007/s10238-015-0404-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/25/2015] [Indexed: 01/04/2023]
Abstract
Despite recent advancements in the knowledge of the etiology and pathogenic mechanisms, treatment of the autoimmune disease Sjögren's syndrome (SS) remains mostly empiric and symptom-based, indicating the need for novel therapeutic approaches. Ectodysplasin-A2 (EDA-A2) is a recently isolated member of the tumor necrosis factor superfamily that binds to X-linked ectodermal dysplasia receptor (XEDAR). In this report, we have analyzed the expression and the biological activity of EDA-A2 in human salivary gland epithelial cells (SGEC) from primary Sjögren's syndrome (pSS) patients. We report that EDA-A2 and its receptor XEDAR are overexpressed in pSS SGEC in comparison with healthy individuals and that the EDA-A2/XEDAR system in these cells is involved in the induction of apoptosis via caspases activation. Collectively, our results suggest that EDA-A2/XEDAR system may be a promising agent for the gene therapy of pSS.
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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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10
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Kroese FGM, Baeten D, Huizinga TWJ. Autoimmunity: break-through in the diagnosis and treatment of immune-mediated inflammatory diseases. Immunol Lett 2014; 162:150-62. [PMID: 25455603 DOI: 10.1016/j.imlet.2014.10.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The study of fundamental mechanisms of autoimmunity has been instrumental to clinical progress in the diagnosis and treatment of a range of immune-mediated inflammatory disorders. Dutch immunology has made major contributions to these developments, ranging from fundamental studies on immune cells, antibodies and cytokines to translational and clinical studies with targeted therapies in patients. In this paper we illustrate the progress made in our understanding of autoimmunity and the translational implications for human disease management by focusing on three areas: the autoantibody response in rheumatoid arthritis (RA), T-B cell interactions in Sjögren's syndrome (SS), and cytokine targeting in spondylarthritis (SpA).
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Affiliation(s)
- Frans G M Kroese
- Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
| | - Dominique Baeten
- Department of Clinical Immunology and Rheumatology, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Tom W J Huizinga
- Department of Rheumatology, C1-41 Leiden University Medical Center, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands
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Chronic inflammation enhances NGF-β/TrkA system expression via EGFR/MEK/ERK pathway activation in Sjögren’s syndrome. J Mol Med (Berl) 2014; 92:523-37. [DOI: 10.1007/s00109-014-1130-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 01/27/2014] [Accepted: 01/28/2014] [Indexed: 10/25/2022]
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Misuno K, Tran SD, Khalili S, Huang J, Liu Y, Hu S. Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup. PLoS One 2014; 9:e87158. [PMID: 24489858 PMCID: PMC3906116 DOI: 10.1371/journal.pone.0087158] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 12/18/2013] [Indexed: 01/11/2023] Open
Abstract
Background Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. Methods Whole BM cells were lysed and soluble intracellular contents (“BM Soup”) were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. Results BM Soup restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. Conclusion BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment.
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Affiliation(s)
- Kaori Misuno
- School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America
| | - Simon D. Tran
- Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
- * E-mail: (SH); (SH)
| | - Saeed Khalili
- Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
| | - Junwei Huang
- School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America
| | - Younan Liu
- Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, Quebec, Canada
| | - Shen Hu
- School of Dentistry, University of California Los Angeles, Los Angeles, California, United States of America
- * E-mail: (SH); (SH)
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Saito K, Mori S, Date F, Ono M. Epigallocatechin gallate inhibits oxidative stress-induced DNA damage and apoptosis in MRL-Faslprmice with autoimmune sialadenitis via upregulation of heme oxygenase-1 and Bcl-2. Autoimmunity 2014; 47:13-22. [DOI: 10.3109/08916934.2013.850079] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Altered IκBα expression promotes NF-κB activation in monocytes from primary Sjögren's syndrome patients. Pathology 2013; 44:557-61. [PMID: 22935973 DOI: 10.1097/pat.0b013e3283580388] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
AIMS To study the importance of IκBα in NF-κB signal transduction, we analysed the IκBα expression in monocytes from Sjögren's syndrome (SS) patients versus healthy controls. METHODS Monocytes were obtained from the peripheral blood of 30 SS patients and 23 healthy subjects. IκBα expression was studied by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR), real-time PCR, immunoblotting, flow cytometry and enzyme linked immunosorbent assay (ELISA). RESULTS Analysis of the gene and protein expression profiles of SS monocytes revealed a down-regulation of IκBα, and in all the Sjögren's syndrome cases examined, serum IκBα levels were significantly decreased in comparison with controls. CONCLUSIONS Our findings clearly demonstrate changes in the levels of IκBα in SS monocytes, suggesting that the attenuated expression of IκBα could contribute to the deregulation of NF-κB pathways in the SS pathogenesis. Decreased expression of IκBα may specifically amplify cytokines production and inflammatory response linked to Sjögren's syndrome.
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15
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Sisto M, Lisi S, Lofrumento DD, Ingravallo G, De Lucro R, D'Amore M. Salivary gland expression level of IκBα regulatory protein in Sjögren's syndrome. J Mol Histol 2013; 44:447-54. [PMID: 23377923 DOI: 10.1007/s10735-013-9487-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2012] [Accepted: 01/28/2013] [Indexed: 12/22/2022]
Abstract
Diagnosis and therapeutic strategies in Sjögren's syndrome (SS) might greatly benefit of the present multidisciplinary approach to studying the molecular pathogenesis of the disease. A deregulated inflammatory response has been described in the SS. The research in the last years sheds light on the importance of the NF-κB pathway regulating the pro-inflammatory cytokine production and leukocyte recruitment. These are important contributors to the inflammatory response during the development of SS. In this study we examine the expression of the NF-κB inhibitory protein termed IκBα in salivary glands epithelial cells (SGEC) comparing it with SGEC from healthy controls, to test the hypothesis that an altered expression of IκBα occurs in SGEC from SS biopsies. Real-Time PCR, western blot and immunohistochemistry demonstrated that the expression level of IκBα was significantly lower in SS with respect to healthy controls leading to an increased NF-κB activity. Our results suggest that the analysis of IκBα expression at salivary gland epithelial cell level could be a potential new hallmark of SS progression and sustain a rationale to more deeply investigate the therapeutic potential of specific NF-κB inhibitors in SS.
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Affiliation(s)
- Margherita Sisto
- Laboratory of Cell Biology, Section of Human Anatomy and Histology, Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Medical School, piazza Giulio Cesare 1, 70124, Bari, Italy.
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Emerging avenues linking inflammation, angiogenesis and Sjögren's syndrome. Cytokine 2013; 61:693-703. [PMID: 23340181 DOI: 10.1016/j.cyto.2012.12.021] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2012] [Revised: 12/10/2012] [Accepted: 12/19/2012] [Indexed: 12/28/2022]
Abstract
Sjögren's syndrome (SS) is an autoimmune disease characterized by an inflammatory mononuclear infiltration and the destruction of epithelial cells of the lachrymal and salivary glands. The aetiology is unknown. The expression "autoimmune epithelitis" has been proposed as an alternative to SS, in view of the emerging central role of the epithelial cells in the disease pathogenesis. At the biomolecular level, the epithelial cells play an important role in triggering the autoimmune condition via antigen presentation, apoptosis, and chemokine and cytokines release. Inflammation and angiogenesis are frequently coupled in the pathological conditions associated to autoimmune diseases, and an angiogenic imbalance contributes to the pathogenesis of a number of inflammatory disorders. This work reviews the current knowledge of the molecular and cellular mechanisms underlying the pathogenesis of the inflammatory reactions that characterize SS. The literature and our data on the role of angiogenesis in the pathophysiology of the disease are discussed.
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Polysaccharides of Dendrobium officinale inhibit TNF-α-induced apoptosis in A-253 cell line. Inflamm Res 2012; 62:313-24. [DOI: 10.1007/s00011-012-0584-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 12/05/2012] [Accepted: 12/10/2012] [Indexed: 01/10/2023] Open
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Gheita TA, El Sisi RW, Raafat HA, Khalil HM. Anti-annexin V antibodies in primary fibromyalgia syndrome: relation to associated Sjögren's syndrome. J Clin Immunol 2012; 33:311-2. [PMID: 23097039 DOI: 10.1007/s10875-012-9826-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2012] [Accepted: 10/16/2012] [Indexed: 10/27/2022]
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19
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Sisto M, Lisi S, D'Amore M, De Lucro R, Carati D, Castellana D, La Pesa V, Zuccarello V, Lofrumento DD. Saponins from Tribulus terrestris L. protect human keratinocytes from UVB-induced damage. JOURNAL OF PHOTOCHEMISTRY AND PHOTOBIOLOGY B-BIOLOGY 2012; 117:193-201. [PMID: 23142932 DOI: 10.1016/j.jphotobiol.2012.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 09/21/2012] [Accepted: 10/06/2012] [Indexed: 12/24/2022]
Abstract
Chronic exposure to solar UVB radiation damages skin, increasing the risk to develop cancer. Hence the identification of compounds with a photoprotective efficacy is essential. This study examined the role of saponins derived from Tribulus terrestris L. (TT) on the modulation of apoptosis in normal human keratinocytes (NHEK) exposed to physiological doses of UVB and to evaluate their antitumoral properties. In NHEK, TT saponins attenuate UVB-induced programmed cell death through inhibition of intrinsic apoptotic pathway. In squamous cell carcinomas (SCC) TT saponins do not make the malignant keratinocytes more resistant to UVB and determine an enhanced apoptotic response. The photoprotective effect of TT saponins is tightly correlated to the enhancement of NER genes expression and the block of UVB-mediated NF-κB activation. Collectively, our study shows experimental evidence that TT has a preventive efficacy against UVB-induced carcinogenesis and the molecular knowledge on the mechanisms through which TT saponins regulate cell death suggests great potential for TT to be developed into a new medicine for cancer patients.
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Affiliation(s)
- Margherita Sisto
- Department of Basic Medical Sciences, Section of Human Anatomy and Histology, University of Bari, Bari, Italy.
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Sjögren's syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-κB. Genes Immun 2012; 13:411-20. [PMID: 22513453 DOI: 10.1038/gene.2012.9] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
We explore the involvement of tumor necrosis factor α (TNF-α)-converting enzyme (TACE) in vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR2) (VEGF-A/VEGFR2)-mediated angiogenesis in Sjögren's syndrome (SS), one of the most common autoimmune rheumatic diseases. To test the hypothesis that SS autoantibodies (Abs) regulate VEGF-A/VEGFR2 expression by a TACE-dependent nuclear factor-κB (NF-κB) activation pathway, their effects on the expression and activation of the VEGF-A/TACE/VEGFR2/NF-κB pathway were determined in human salivary gland epithelial cells (SGEC). An enhanced angiogenesis in SS salivary gland biopsies was observed, associated with an increased VEGF-A expression and activation of VEGF-A/VEGFR2 signaling. Human cytokine array analysis of the pro-inflammatory and pro-angiogenic protein response in SGEC treated with SS Abs revealed an overexpression of multiple pro-angiogenic factors. TACE RNA knockdown, the use of anti-VEGF-A monoclonal antibody and the inhibition of NF-κB activity significantly abrogated the release of pro-angiogenic factors, demonstrating that VEGF-A/TACE/VEGFR2/NF-κB axis dysfunction may be contributory to pathogenesis and exacerbation of this autoimmune condition.
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Reina S, Sterin-Borda L, Borda E. Anti-M(3) peptide IgG from Sjögren's syndrome triggers apoptosis in A253 cells. Cell Immunol 2012; 275:33-41. [PMID: 22513175 DOI: 10.1016/j.cellimm.2012.03.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2011] [Revised: 03/06/2012] [Accepted: 03/26/2012] [Indexed: 01/16/2023]
Abstract
Primary Sjögren's syndrome (pSS) is an autoimmune disease that targets salivary and lachrymal glands, characterized by anti-cholinergic autoantibodies directed against the M(3) muscarinic acetylcholine receptor (mAChR). The aim of this work was to evaluate if cholinergic autoantibodies contained in IgG purified from Sjögren sera could trigger apoptosis of A253 cell line. We also determined if caspase-3 and matrix metalloproteinase-3 (MMP-3) are involved in the induction of A253 cell death. Our results demonstrated that anti-cholinergic autoantibodies stimulate apoptosis and inositol phosphate (InsP) accumulation accompanied by caspase-3 activation and MMP-3 production. All of these effects were blunted by atropine and J104794, indicating that M(3) mAChRs are impacted by the anti-cholinergic autoantibodies. The intracellular pathway leading to autoantibody-induced biological effects involves phospholipase C (PLC), calcium/calmodulin (CaM) and extracellular calcium as demonstrated by treatment with U-73122, W-7, verapamil, BAPTA and BAPTA-AM, all of which blocked the effects of the anti-cholinergic autoantibodies. In conclusion, anti-cholinergic autoantibodies in IgG purified from pSS patient's sera mediates apoptosis of the A253 cell line in an InsP, caspase-3 and MMP-3 dependent manner.
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Affiliation(s)
- Silvia Reina
- Pharmacology Unit, School of Dentistry, Buenos Aires University and Argentine National Research Council (CONICET), Ciudad Autónoma de Buenos Aires, Argentina.
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Lisi S, Sisto M, Lofrumento DD, D'Amore M. Sjögren's syndrome autoantibodies provoke changes in gene expression profiles of inflammatory cytokines triggering a pathway involving TACE/NF-κB. J Transl Med 2012; 92:615-24. [PMID: 22157716 DOI: 10.1038/labinvest.2011.190] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
We explore the association of the inflammatory gene expression profile observed in the chronic inflammatory autoimmune disorder Sjögren's syndrome (SS) with changes in TNF-α converting enzyme (TACE), tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB levels showing that pathways that include TNF-α signaling converge on NF-κB contributing to exacerbate the diseases. The treatment of human salivary gland epithelial cells (SGECs) with SS anti-Ro/SSA autoantibodies (Abs) result in a progressive increase in NF-κB-DNA binding, that includes a marked enhancement in NF-κB subunit p65 protein-DNA binding. A human cytokine multi-analyte array demonstrated that the NF-κB proinflammatory target genes, increased by anti-Ro/SSA Abs treatment, includes CXC chemokines (CXCL1, CXCL6 and CXCL9), CC chemokines (CCL2, CCL13 and CCL20), interleukins (IL-1α, IL-1β, IL-1F8, IL-6, IL-8, IL-9, IL-13, IL-17 and IL-22) and their receptors (IL-1RN, IL-10Rα, IL-13Rα, CCR1, CCR2, CCR3, CCR4 and CXCR1). Blockade of TACE through the use of the specific inhibitor TAPI-1 regulates proinflammatory cytokines production in SGEC treated with anti-Ro/SSA Abs inhibiting NF-κB nuclear translocation and activation. To further investigate the role of NF-κB on anti-Ro/SSA Abs-determined proinflammatory gene expression, we used the inhibitory protein IκB-α dominant negative super-repressor as inhibitor of NF-κB-DNA binding, demonstrating that transfection with dominant-negative IκB-α in anti-Ro/SSA-treated SGEC determined a marked reduction of proinflammatory cytokines gene expression. Although further studies are needed to clarify the mechanisms underlying SS, our results demonstrate that SS Abs exert their pathogenic effects via triggering the TACE/TNF-α/NF-κB axis.
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Affiliation(s)
- Sabrina Lisi
- Department of Human Anatomy and Histology, Laboratory of Cell Biology, University of Bari Medical School, Bari, Italy.
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Lin X, Song JX, Shaw PC, Ng TB, Wong RNS, Sze SCW, Tong Y, Lee KF, Zhang KY. An autoimmunized mouse model recapitulates key features in the pathogenesis of Sjögren's syndrome. Int Immunol 2011; 23:613-24. [PMID: 21846814 DOI: 10.1093/intimm/dxr066] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The pathogenesis of Sjögren's syndrome (SS) is poorly understood. To evaluate an autoimmunization-induced experimental SS model, we firstly observed the phenotype of lymphocyte infiltration in the enlarged submandibular gland (SG). Furthermore, significant activation of caspase-3 and a high ratio of Bax-to-Bcl-2 were detected, indicating the inflammatory apoptosis associated with developmental foci. Meanwhile, the dysregulated cytokines, such as tumor necrosis factor α, IL-1β and IL-6 mRNA expression, were found to be over-expressed. A progressive decrease of aquaporin 5 and its subcellular translocation from apical to basal membrane in SG was found to be associated with the abnormally expressed M3 muscarinic acetylcholine receptor. This pattern was found to be similar to that seen in human SS and possibly contributed to the saliva secretion deficiency. Thus, this autoimmunization-induced model recapitulates the key features of human SS and may have potential for studying the pathogenesis of human SS.
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Affiliation(s)
- Xiang Lin
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, University of Hong Kong, 10 Sassoon Road, Hong Kong, China
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Sisto M, Lisi S, Lofrumento DD, Caprio S, Mitolo V, D’Amore M. TNF blocker drugs modulate human TNF-α-converting enzyme pro-domain shedding induced by autoantibodies. Immunobiology 2010; 215:874-83. [DOI: 10.1016/j.imbio.2009.11.005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2009] [Revised: 11/27/2009] [Accepted: 11/28/2009] [Indexed: 02/04/2023]
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Sisto M, Lisi S, Lofrumento DD, Cucci L, Mitolo V, D'Amore M. RETRACTED: Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies. J Transl Med 2010:labinvest2010168. [PMID: 20856228 DOI: 10.1038/labinvest.2010.168] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
The aim of this study was to analyze the Furin-TNF-α-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-α-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-α blockade on AREG expression and TNF-α-AREG-mediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-α produced after anti-Ro/SSA Abs uptake via Fcγ receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-α blocking and TNF-α gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-α-induced IL-6 and IL-8 secretion in SGEC treated with anti-Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-α and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-α as stimulant, clarified that TNF-α induces IL-6 and IL-8 secretion through AREG.Laboratory Investigation advance online publication, 20 September 2010; doi:10.1038/labinvest.2010.168.
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Affiliation(s)
- Margherita Sisto
- Laboratory of Cell Biology, Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy
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Lisi S, Sisto M, Lofrumento DD, Cucci L, Frassanito MA, Mitolo V, D’Amore M. Pro-inflammatory role of Anti-Ro/SSA autoantibodies through the activation of Furin–TACE–amphiregulin axis. J Autoimmun 2010; 35:160-70. [DOI: 10.1016/j.jaut.2010.06.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2010] [Revised: 06/29/2010] [Accepted: 06/30/2010] [Indexed: 11/29/2022]
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27
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Regulation of mRNA caspase-8 levels by anti-nuclear autoantibodies. Clin Exp Med 2009; 10:199-203. [DOI: 10.1007/s10238-009-0087-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2009] [Accepted: 12/04/2009] [Indexed: 11/24/2022]
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28
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Effects of biological drug adalimumab on tumour necrosis factor‐α‐converting enzyme activation. Immunol Cell Biol 2009; 88:297-304. [DOI: 10.1038/icb.2009.97] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
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29
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Sisto M, Lisi S, Lofrumento DD, Frassanito MA, Cucci L, D'Amore S, Mitolo V, D'Amore M. Induction of TNF-alpha-converting enzyme-ectodomain shedding by pathogenic autoantibodies. Int Immunol 2009; 21:1341-1349. [DOI: 10.1093/intimm/dxp103] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Hwang SM, Li J, Koo NY, Choi SY, Lee SJ, Oh SB, Castro R, Kim JS, Park K. Role of purinergic receptor in alpha fodrin degradation in Par C5 cells. J Dent Res 2009; 88:927-32. [PMID: 19783801 DOI: 10.1177/0022034509342227] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Autoantibodies specific for alpha-fodrin fragments are found in the tissues of persons afflicted with Sjögren's syndrome (SS). However, the mechanism for alpha-fodrin degradation remains elusive. The following experiments utilized Par C5 cells to examine the role of P2X7 receptor (P2X7R) in apoptosis, particularly in the cleavage and release of alpha-fodrin, an apparent SS autoantigen. Five mM ATP stimulation induced apoptotic cell death with a sustained Ca2+ influx, which was mimicked in HEK cells transfected with P2X7R. ATP also induced cleavage of alpha-fodrin mediated by caspase-3 and calpain, releasing alpha-fodrin fragments through membrane blebs. However, both apoptotic cell death and alpha-fodrin cleavage were inhibited in the presence of 300 microM oxidized-ATP (ox-ATP), an irreversible blocker of P2X7R, or in Ca(2+)-free solution. We concluded that P2X7R plays an important role in apoptosis and alpha-fodrin degradation in salivary epithelial cells, providing an important clue elucidating the presence of alpha-fodrin fragments in SS tissues.
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Affiliation(s)
- S-M Hwang
- Department of Physiology, School of Dentistry, Seoul National University and Dental Research Institute, Yeongeon Dong 28, Chongno Ku, Seoul 110-749, Korea
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Pérez P, Anaya JM, Aguilera S, Urzúa U, Munroe D, Molina C, Hermoso MA, Cherry JM, Alliende C, Olea N, Ruiz-Narváez E, González MJ. Gene expression and chromosomal location for susceptibility to Sjögren's syndrome. J Autoimmun 2009; 33:99-108. [DOI: 10.1016/j.jaut.2009.05.001] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2009] [Revised: 05/11/2009] [Accepted: 05/19/2009] [Indexed: 01/18/2023]
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Sisto M, D'Amore M, Caprio S, Mitolo V, Scagliusi P, Lisi S. Tumor Necrosis Factor Inhibitors Block Apoptosis of Human Epithelial Cells of the Salivary Glands. Ann N Y Acad Sci 2009; 1171:407-14. [PMID: 19723083 DOI: 10.1111/j.1749-6632.2009.04688.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
MESH Headings
- Adalimumab
- Anti-Inflammatory Agents/pharmacology
- Antibodies, Antinuclear/pharmacology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal, Humanized
- Apoptosis/drug effects
- Cells, Cultured
- DNA Fragmentation/drug effects
- Enzyme-Linked Immunosorbent Assay
- Epithelial Cells/cytology
- Epithelial Cells/drug effects
- Epithelial Cells/metabolism
- Etanercept
- Flow Cytometry
- Gene Expression/drug effects
- Humans
- Immunoglobulin G/pharmacology
- Receptors, Tumor Necrosis Factor
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Receptors, Tumor Necrosis Factor, Type II/genetics
- Reverse Transcriptase Polymerase Chain Reaction
- Salivary Glands/cytology
- Tumor Necrosis Factor-alpha/antagonists & inhibitors
- Tumor Necrosis Factor-alpha/genetics
- Tumor Necrosis Factor-alpha/metabolism
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Affiliation(s)
- Margherita Sisto
- Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
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Autoantibody against caspase-3, an executioner of apoptosis, in patients with systemic sclerosis. Rheumatol Int 2009; 30:871-8. [DOI: 10.1007/s00296-009-1068-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2009] [Accepted: 07/12/2009] [Indexed: 01/21/2023]
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Hwang SM, Koo NY, Choi SY, Chun GS, Kim JS, Park K. P2X7 Receptor-mediated Membrane Blebbing in Salivary Epithelial Cells. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY : OFFICIAL JOURNAL OF THE KOREAN PHYSIOLOGICAL SOCIETY AND THE KOREAN SOCIETY OF PHARMACOLOGY 2009; 13:175-9. [PMID: 19885034 DOI: 10.4196/kjpp.2009.13.3.175] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2009] [Revised: 05/06/2009] [Accepted: 05/18/2009] [Indexed: 11/15/2022]
Abstract
High concentrations of ATP induce membrane blebbing. However, the underlying mechanism involved in epithelial cells remains unclear. In this study, we investigated the role of the P2X7 receptor (P2X7R) in membrane blebbing using Par C5 cells. We stimulated the cells with 5 mM of ATP for 1~2 hrs and found the characteristics of membrane blebbing, a hallmark of apoptotic cell death. In addition, 500 microM Bz-ATP, a specific P2X7R agonist, induced membrane blebbing. However, 300 microM of Ox-ATP, a P2X7R antagonist, inhibited ATP-induced membrane blebbing, suggesting that ATP-induced membrane blebbing is mediated by P2X7R. We found that ATP-induced membrane blebbing was mediated by ROCK I activation and MLC phosphorylation, but not by caspase-3. Five mM of ATP evoked a biphasic [Ca(2+)](i) response; a transient [Ca(2+)](i) peak and sustained [Ca(2+)](i) increase secondary to ATP-stimulated Ca(2+) influx. These results suggest that P2X7R plays a role in membrane blebbing of the salivary gland epithelial cells.
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Affiliation(s)
- Sung-Min Hwang
- Department of Physiology, School of Dentistry, Seoul National University and Dental Research Institute, Seoul 110-749, Korea
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Lisi S, D'Amore M, Scagliusi P, Mitolo V, Sisto M. Anti-Ro/SSA autoantibody-mediated regulation of extracellular matrix fibulins in human epithelial cells of the salivary gland. Scand J Rheumatol 2009; 38:198-206. [PMID: 19229767 DOI: 10.1080/03009740802520722] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
OBJECTIVES The fibulins are a family of extracellular matrix (ECM) molecules that regulate the organ shape along with other growth factors and stromal cells and have recently been shown to be involved in a variety of cellular functions including proliferation, migration, differentiation, and survival. Important changes in acinar and ductal morphology and function, together with pronounced ECM remodelling, are detectable in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS). Here we report the in vitro expression of the recently identified ECM proteins fibulin-6 and fibulin-7 by human salivary gland epithelial cells (SGECs). The ability of anti-Ro/SSA autoantibodies (Abs) to modulate fibulin-6 and fibulin-7 expression was investigated. METHODS Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR were used to analyse fibulin-6 and fibulin-7 mRNA expression. Confocal microscopy and fluorescence-activated cell sorting (FACS) were used to study expression of the proteins in primary human SGEC cultures, established from biopsies of minor LSGs, in both untreated control cells and anti-Ro/SSA Abs-treated cells. RESULTS The methods used show the expression of fibulin-6 and fibulin-7 in SGECs. Treatment of cells with anti-Ro/SSA Abs results in a down-regulation of fibulin-6 mRNA expression whereas no significant differences were observed in fibulin-7 expression between untreated and treated cells. CONCLUSION Dysregulation of fibulin expression in SGECs by anti-Ro/SSA Abs may contribute to disorganization of the ECM environment and thus cause injury to the salivary gland architecture and functionality observed in SS.
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Affiliation(s)
- S Lisi
- Department of Human Anatomy and Histology, University of Bari, Bari, Italy
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36
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Van den Bergh K, Hooijkaas H, Blockmans D, Westhovens R, Op De Beéck K, Verschueren P, Dufour D, van de Merwe JP, Fijak M, Klug J, Michiels G, Devogelaere B, De Smedt H, Derua R, Waelkens E, Blanckaert N, Bossuyt X. Heterogeneous Nuclear Ribonucleoprotein H1, a Novel Nuclear Autoantigen. Clin Chem 2009; 55:946-54. [DOI: 10.1373/clinchem.2008.115626] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Abstract
Background: Serum samples from patients with autoimmune connective tissue diseases that show a finely speckled antinuclear antibody (ANA) on indirect immune-fluorescence often have antibodies against unknown nuclear target antigens. To search for such autoantigens we applied a proteomic approach using sera from patients with a high ANA titer (≥640) and finely speckled fluorescence but in whom no antibodies to extractable nuclear antigens (ENA) could be identified.
Methods: Using an immunoproteomics approach we identified heterogeneous nuclear ribonucleoprotein H1 (hnRNP H1) as a novel nuclear target of autoantibody response.
Results: Recombinant rat hnRNP H1 reacted in Western blot analyses with 48% of 93 sera from patients with primary Sjögren syndrome and with 5.2% of 153 sera from patients with other connective tissue diseases (diseased controls). For comparison, the diagnostic sensitivity and specificity of anti–Sjögren syndrome A (SSA) antibodies for primary Sjögren syndrome in the same patient cohort were 88.2% and 76.3%, respectively. Interestingly, 5 of 11 primary Sjögren syndrome patients with no anti-SSA or anti-SSB antibodies had anti–hnRNP H1 antibodies. Anti–hnRNP H1 antibodies were preabsorbed by hnRNP H1, as demonstrated by indirect immunofluorescence. In an evaluation of the presence of anti–hnRNP H1 antibodies in 188 consecutive samples submitted to the clinical laboratory with positive ANA (titer ≥160), anti–hnRNP H1 antibodies were found in 3 of 7 (2 primary and 5 secondary) Sjögren syndrome patients and in 8.3% of the diseased controls.
Conclusions: HnRNP H1 is a newly discovered autoantigen that could become an additional diagnostic marker.
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Affiliation(s)
| | - Herbert Hooijkaas
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | | | | | | | | | - Diana Dufour
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, the Netherlands
| | - Joop P van de Merwe
- Department of Immunology and Department of Internal Medicine, Erasmus Medical Center Rotterdam, the Netherlands
| | - Monika Fijak
- Department of Anatomy and Cell Biology, Justus-Liebig-University of Giessen, Germany
| | - Jörg Klug
- Department of Anatomy and Cell Biology, Justus-Liebig-University of Giessen, Germany
| | - Georges Michiels
- Laboratory Medicine, Immunology, University Hospitals Leuven, Belgium
| | - Benoit Devogelaere
- Department of Molecular Cell Biology (Laboratory of Molecular and Cellular Signalling), Catholic University of Leuven, Belgium
| | - Humbert De Smedt
- Department of Molecular Cell Biology (Laboratory of Molecular and Cellular Signalling), Catholic University of Leuven, Belgium
| | - Rita Derua
- Department of Molecular Cell Biology (Laboratory of Protein Phosphorylation and Proteomics) and Biomacs, Catholic University of Leuven, Belgium
| | - Etienne Waelkens
- Department of Molecular Cell Biology (Laboratory of Protein Phosphorylation and Proteomics) and Biomacs, Catholic University of Leuven, Belgium
| | | | - Xavier Bossuyt
- Laboratory Medicine, Immunology, University Hospitals Leuven, Belgium
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Sisto M, D'Amore M, Lofrumento DD, Scagliusi P, D'Amore S, Mitolo V, Lisi S. Fibulin-6 expression and anoikis in human salivary gland epithelial cells: implications in Sjogren's syndrome. Int Immunol 2009; 21:303-11. [PMID: 19190085 DOI: 10.1093/intimm/dxp001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Important changes in acinar and ductal morphology and function, together with pronounced extracellular matrix (ECM) remodelling, are detectable in the labial salivary glands of Sjögren's syndrome (SS) patients. The objective of this work was to determine the effect of treatment with the anti-Ro/SSA auto-antibodies, characterizing SS, on the expression of fibulin-6, a member of the fibulins family of the ECM, in primary human salivary gland epithelial cell (SGEC) cultures established from biopsies of labial minor salivary glands obtained from healthy donors. The induction of cell detachment and anoikis in SGECs treated with anti-Ro/SSA auto-antibodies were also investigated. Changes in fibulin-6 mRNA expression were measured by semi-quantitative reverse transcriptase-PCR and real-time PCR. Fibulin-6 expression in cells treated with anti-Ro/SSA auto-antibodies was evaluated by flow cytometric analysis and confocal laser scanning microscopy. SGECs undergoing death by anoikis were identified and quantified using Calcein blue/YOPRO-1 dyes. Herein, we present the first evidence of fibulin-6 expression in SGEC that results distributed in the cytoplasm surrounding the inner side of the plasma membrane. Fibulin-6 was down-regulated in SGECs treated with anti-Ro/SSA auto-antibodies in which a marked cell detachment and a reduction of cell viability were observed. Notably, a reduction of fibulin-6 expression in SGECs treated with anti-Ro/SSA auto-antibodies corresponds to an increase of anoikis cell death. Our observations demonstrate a dysregulation of fibulin-6 in the pathological processes observed in SS and provide new evidence that disorganization of the ECM environment could damage the architecture and function of the salivary glands.
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Affiliation(s)
- Margherita Sisto
- Department of Human Anatomy and Histology, University of Bari Medical School, Bari, Italy.
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Sisto M, D'Amore M, Scagliusi P, Mitolo V, Lisi S. Selective TNF-ALPHA Gene Silencing Attenuates Apoptosis in Human Salivary Gland Epithelial Cells. Int J Immunopathol Pharmacol 2008; 21:1045-7. [DOI: 10.1177/039463200802100432] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
RNA interference (RNAi) was used in this study for selective knockdown of TNF-alpha gene expression in anti-Ro/SSA autoantibodies (Abs)-treated human salivary gland epithelial cells. Our findings reveal that selective TNF-alpha gene silencing resulted in the subsequent attenuation of the pro-apoptotic effects of anti-Ro/SSA Abs; this could have therapeutic effects in autoimmune diseases.
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Affiliation(s)
| | - M. D'Amore
- Department of Internal Medicine and Public Medicine, Section of Rheumatology, University of Bari, Bari, Italy
| | - P. Scagliusi
- Department of Internal Medicine and Public Medicine, Section of Rheumatology, University of Bari, Bari, Italy
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Lisi S, D'Amore M, Lofrumento D, Mitolo V, Frassanito MA, Dammacco F, Scagliusi P, Sisto M. Modulation of the Fcgamma receptors induced by anti-Ro and anti-La autoantibodies: observations in salivary gland cells. Rheumatol Int 2008; 28:943-8. [PMID: 18264709 DOI: 10.1007/s00296-008-0536-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2007] [Accepted: 01/14/2008] [Indexed: 01/17/2023]
Abstract
Only few reports have shown protein expression of the Fcgamma receptors (FcgammaRs) molecules on human salivary gland cells. In this study we investigate a possible upregulation of FcgammaRs following anti-Ro and anti-La autoantibodies treatment. Anti-Ro and anti-La autoantibodies were purified from IgG fractions obtained from 14 patients with primary Sjögren's syndrome (SS), using Sepharose 4B-Ro and Sepharose 4B-La affinity columns. Flow cytometry and RT-PCR were used to study the FCgammaRI, FCgammaRII and FCgammaRIII receptors expression and upregulation by anti-Ro and anti-La on a salivary gland cell line. The present data document that the anti-Ro and anti-La autoantibodies determine an increase of the FcgammaRs expression on salivary gland cells, and provide evidence that both the high affinity FcgammaRI and the low affinity FcgammaRII and FcgammaRIII are overexpressed. Treatment with IgG isolated from healthy donors had no effect on the basal FCgammaRs expression.
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Affiliation(s)
- Sabrina Lisi
- Department of Human Anatomy and Histology, University of Bari, p.zza G. Cesare 1, 70124, Bari, Italy.
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Ardesjö B, Hansson CM, Bruder CEG, Rorsman F, Betterle C, Dumanski JP, Kämpe O, Ekwall O. Autoantibodies to glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases. J Autoimmun 2008; 30:273-82. [PMID: 18242955 DOI: 10.1016/j.jaut.2007.11.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2007] [Revised: 11/13/2007] [Accepted: 11/14/2007] [Indexed: 01/06/2023]
Abstract
Primary sclerosing cholangitis (PSC) is an enigmatic disorder with a suggested autoimmune basis. A variety of autoantigens have been suggested but no specific or highly directed epitope has been identified. To address this issue, we constructed a cDNA library from normal human choledochus and screened expressing clones with serum from a patient with PSC and inflammatory bowel disease (IBD). Based on this screening, glutathione S-transferase theta 1 (GSTT1) was identified as a potential autoantigenic target. To study the specificity of GSTT1, we determined immunoreactivity using a panel of 58 patients with PSC, with and without IBD, 57 patients with IBD, 31 patients with Hashimoto's thyroiditis, 30 patients with primary biliary cirrhosis (PBC), 20 patients with insulin dependent diabetes mellitus, 22 patients with autoimmune polyendocrine syndrome type I, 10 patients with systemic lupus erythematosus (SLE), 20 patients with Sjögren's syndrome, 12 patients with autoimmune pancreatitis, 28 patients with Addison's disease, 27 patients with Grave's disease, 17 with myasthenia gravis, and 118 healthy controls. Reactivity against GSTT1 was found with PSC and IBD as well as some patients with other autoimmune pathology, indicating that this population of antibodies is neither specific nor a sensitive serologic marker for PSC, but the frequency was clearly higher in autoimmune patients than controls. GSTT1-antibodies have been described in persons with GSTT1-null genotype and are suggested to develop as an alloimmune response to blood transfusions from GSTT1-positive donors or pregnancies with GSTT1-positive children. Therefore, two IBD patients with and 15 PSC patients without GSTT1-antibodies were genotyped for GSTT1 to investigate if the presence of GSTT1-antibodies was associated with the GSTT1-null genotype and possibly caused by an alloimmune response. Both IBD patients and three of the PSC patients were of the GSTT1-null genotype. We note that the frequency of GSTT1-antibodies in this study is more than 100-fold higher than the frequency described earlier in patients with autoimmune diseases. We also observe an increased frequency of GSTT1-antibodies in patients with autoimmune diseases compared to healthy controls. This increased frequency can be explained by an autoimmune phenotype which increases susceptibility to such autoantibodies, or by a high frequency of the GSTT1-null genotype in autoimmune disease.
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Affiliation(s)
- Brita Ardesjö
- Department of Medical Sciences University Hospital, Research Department 2, Lab 21, Entrance 70, 3rd Floor, Uppsala University, SE-75185 Uppsala, Sweden.
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Abstract
In April 2007, an international Colloquium bridging scientific and clinical disciplines was held to discuss the role of cellular and tissue damage in the initiation, development and persistence of autoimmune disease. Five potential etiologic and pathophysiologic processes fundamental to autoimmune disease (i.e. inflammation, infection, apoptosis, environmental exposure and genetics) were the focus of the presentations and integrative discussions at the Colloquium. The information presented on these topics is condensed in this review. Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Further application of well-designed, long-term epidemiologic and population-based studies is urgently needed to relate antecedent exposures with later occurring stigmata of autoimmunity with a goal of discerning potentially susceptible individuals or subpopulations. Suspect infections requiring closer interrogation include EB virus (SLE and other diseases), HCV (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis) and Helicobacter pylori (autoimmune gastritis) among others. And even if a micro-organism was to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Plausible mechanisms include potentiation and diversion of innate immunity; exposure or spillage of intracellular autoantigens; or provision of autoantigenic mimics. Integrity of apoptosis as a critical safeguard against autoimmunity was discussed in the contexts of over-reactivity causing autoantigens to gain enhanced exposure to the immune system, or under-reactivity producing insufficient elimination of autoreactive clones of lymphocytes. Although environmental agents are widely believed to serve as necessary "triggers" of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified and their mechanism of action defined. Finally an essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. They may be predictive of future or impending disease.
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Affiliation(s)
- Ian R Mackay
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria 3800, Australia
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Sisto M, Lisi S, Lofrumento D, D'Amore M, Scagliusi P, Mitolo V. Autoantibodies from Sjögren's syndrome trigger apoptosis in salivary gland cell line. Ann N Y Acad Sci 2007; 1108:418-25. [PMID: 17894006 DOI: 10.1196/annals.1422.044] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The presence of serum autoantibodies has been associated with Sjögren's syndrome (SS), an autoimmune rheumatic disease that targets salivary and lachrymal glands. The association of apoptosis with autoantibodies production seems to play a role in the pathogenesis of glandular damage. The best-defined antibodies in SS are those reacting with the ribonucleoprotein antigens SS-A (Ro) and SS-B (La). Anti-Ro antibodies are found in about 70-90%, and anti-La in approximately the same frequency, of patients with primary SS. The objective of this work was to explore whether anti-Ro and anti-La autoantibodies purified from Sjögren IgG fractions are able to trigger apoptotic process in the human salivary gland cell line A-253. Anti-Ro and anti-La autoantibodies were purified on protein G Sepharose affinity column and used for the A-253 cell treatment. Apoptosis induced by autoantibodies was revealed by FACS analysis, and the active caspase-3 and the cleaved caspase-3 substrate poly (ADP-ribose) polymerase (PARP) was demonstrated by colorimetric assay and Western blot. This report shows that anti-Ro and anti-La autoantibodies, but not healthy IgG, activate the caspase-3 and determine the cleavage of PARP in A-253 cells. Apoptosis triggered by Sjögren autoantibodies could be responsible for the impairment of the secretory function in the salivary glands.
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Affiliation(s)
- Margherita Sisto
- Department of Human Anatomy and Histology, University of Bari, I-70124 Bari, Italy.
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Lisi S, Sisto M, Soleti R, Saponaro C, Scagliusi P, D'Amore M, Saccia M, Maffione AB, Mitolo V. Fcgamma receptors mediate internalization of anti-Ro and anti-La autoantibodies from Sjögren's syndrome and apoptosis in human salivary gland cell line A-253. J Oral Pathol Med 2007; 36:511-23. [PMID: 17850433 DOI: 10.1111/j.1600-0714.2007.00563.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND The presence of serum anti-Ro and anti-La autoantibodies directed against the ribonucleoproteins Ro and La has been associated with Sjögren's syndrome (SS), an autoimmune rheumatic disease that targets salivary and lachrymal glands. There is increasing evidence of the direct involvement of autoantibodies in the pathogenesis of tissue injury and correlation of their presence with clinical manifestations in SS. The focus of this work was to explore the cellular apoptotic pathway triggered by binding and penetration of anti-Ro and anti-La autoantibodies in human salivary gland cell line A-253 and to identify the membrane receptors through which anti-Ro and anti-La could exert their effect. METHODS Anti-Ro and anti-La autoantibodies were purified from IgG fractions, obtained from eleven healthy volunteers and patients with primary Sjögren's syndrome, using Sepharose 4B-Ro and Sepharose 4B-La affinity columns. Flow cytometry, RT-PCR, western blot and confocal microscopy analysis were used to visualize the FCgammaRI, FCgammaRII and FCgammaRIII receptors on the A-253 cell membrane. DNA laddering and western blot analysis of caspases activation were studied to evaluate in A-253 cells treated with anti-Ro and anti-La autoantibodies. RESULTS The results yeilded the evidence of the presence of members of the Fcgamma receptors (FcgammaRs) family on the cell membrane of the human salivary gland cell line A-253. Furthermore, we demonstrated that, in the A-253 cell line, anti-Ro and anti-La autoantibodies can access the cells probably through Fcgamma receptors, and trigger apoptotis. CONCLUSIONS We conclude that anti-Ro and anti-La autoantibodies have pathogenic effects that could depend on binding to Fcgamma receptors.
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Affiliation(s)
- Sabrina Lisi
- Department of Human Anatomy and Histology, University of Bari, Bari, Italy.
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Wills S, Cabanlit M, Bennett J, Ashwood P, Amaral D, Van de Water J. Autoantibodies in autism spectrum disorders (ASD). Ann N Y Acad Sci 2007; 1107:79-91. [PMID: 17804535 DOI: 10.1196/annals.1381.009] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders defined behaviorally by abnormalities in social, verbal, and nonverbal communication. The etiologies of ASD are unknown, likely to be the result of a variety of numerous genetic, neurological, environmental, and immunological interactions that lead to a general behavioral phenotype defined as ASD. This review will focus on the various immune system anomalies, in particular, autoantibodies, which have been reported in subjects with ASD. In addition, we will discuss recent studies performed by our group concerning the presence of autoantibodies directed against neural antigens, which are observed in patients with ASD.
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Affiliation(s)
- Sharifia Wills
- Division of Rheumatology, Allergy and Clinical Immunology, UC Davis, Davis, CA 95616, USA
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Shoenfeld Y, Gershwin ME. Foreword. Ann N Y Acad Sci 2007. [DOI: 10.1196/annals.1422.000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
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Nesslinger NJ, Sahota RA, Stone B, Johnson K, Chima N, King C, Rasmussen D, Bishop D, Rennie PS, Gleave M, Blood P, Pai H, Ludgate C, Nelson BH. Standard treatments induce antigen-specific immune responses in prostate cancer. Clin Cancer Res 2007; 13:1493-502. [PMID: 17332294 DOI: 10.1158/1078-0432.ccr-06-1772] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immune-stimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. EXPERIMENTAL DESIGN Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. RESULTS Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumor-associated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatment-associated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. CONCLUSION We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.
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Affiliation(s)
- Nancy J Nesslinger
- Trev and Joyce Deeley Research Centre, BC Cancer Agency-Vancouver Island Centre, Victoria, British Columbia, Canada
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