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Kosmara D, Neofotistou-Themeli E, Semitekolou M, Bertsias G. The molecular underpinnings of female predominance in lupus. Trends Mol Med 2025; 31:438-451. [PMID: 39627079 DOI: 10.1016/j.molmed.2024.11.002] [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: 08/01/2024] [Revised: 11/03/2024] [Accepted: 11/05/2024] [Indexed: 05/17/2025]
Abstract
Most people affected by systemic lupus erythematosus (SLE) are women. Although the role of sex hormones has been appreciated, we discuss emerging evidence that links X-linked genes escaping from dosage compensation to female predisposition to lupus. This is exemplified by TLR7 and CXorf21 whose female-biased expression may converge to enhance interferon responses and promote autoantibody-producing B cells, which are hallmarks of SLE. Notably, autosomal transcription factors with female overexpression may regulate molecular programs in the skin that are sufficient to induce lupus. These findings indicate a multifactorial basis for female vulnerability; however, several areas remain elusive, including the epigenetic landscape of X-chromosome inactivation (XCI) in SLE, the interplay with environmental factors, and the role of male-specific factors such as Y-linked genes.
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Affiliation(s)
- Despoina Kosmara
- Rheumatology and Clinical Immunology, University of Crete Medical School, Heraklion, Greece; Division of Immunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece
| | - Elpida Neofotistou-Themeli
- Rheumatology and Clinical Immunology, University of Crete Medical School, Heraklion, Greece; Division of Immunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece
| | - Maria Semitekolou
- Rheumatology and Clinical Immunology, University of Crete Medical School, Heraklion, Greece; Dendritic cells and Adaptive Immunity Unit, CNRS UMR 3738 Developmental Biology and Stem Cells, Institut Pasteur, Paris, France
| | - George Bertsias
- Rheumatology and Clinical Immunology, University of Crete Medical School, Heraklion, Greece; Division of Immunity, Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas (FORTH), Heraklion, Greece.
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2
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DeBerg HA, Fahning ML, Varkhande SR, Schlenker JD, Schmitt WP, Gupta A, Singh A, Gratz IK, Carlin JS, Campbell DJ, Morawski PA. T Cells Promote Distinct Transcriptional Programs of Cutaneous Inflammatory Disease in Keratinocytes and Dermal Fibroblasts. J Invest Dermatol 2025:S0022-202X(25)00401-4. [PMID: 40216155 DOI: 10.1016/j.jid.2025.03.033] [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: 08/30/2024] [Revised: 03/06/2025] [Accepted: 03/23/2025] [Indexed: 04/25/2025]
Abstract
T cells and structural cells coordinate appropriate inflammatory responses and restoration of barrier integrity following insult. Dysfunctional T cells precipitate skin pathology occurring alongside altered structural cell frequencies and transcriptional states, but to what extent different T cells promote disease-associated changes remains unclear. We show that functionally diverse circulating and skin-resident CD4+CLA+ T-cell populations promote distinct transcriptional outcomes in human keratinocytes and fibroblasts associated with inflamed or healthy tissue. We identify T helper 17 cell-induced genes in keratinocytes that are enriched in psoriasis patient skin and normalized by anti-IL-17 therapy. We also describe a CD103+ skin-resident T-cell-induced transcriptional module enriched in healthy controls that is diminished during psoriasis and scleroderma and show that CD103+ T-cell frequencies are altered during disease. Interrogating clinical data using immune-dependent transcriptional signatures defines the T-cell subsets and genes distinguishing inflamed from healthy skin and allows investigation of heterogeneous patient responses to biologic therapy.
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Affiliation(s)
- Hannah A DeBerg
- Center for Systems Immunology, Benaroya Research Institute, Seattle, Washington, USA
| | - Mitch L Fahning
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA
| | - Suraj R Varkhande
- Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria
| | - James D Schlenker
- Plastic and Reconstructive Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - William P Schmitt
- Plastic and Reconstructive Surgery, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Aayush Gupta
- Department of Dermatology, Leprology, and Venereology, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Pune, India
| | - Archana Singh
- Systems Biology Lab, CSIR - Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Gaziabad, India
| | - Iris K Gratz
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA; Department of Biosciences and Medical Biology, University of Salzburg, Salzburg, Austria; EB House Austria, Department of Dermatology, University Hospital of the Paracelsus Medical University, Salzburg, Austria; Center for Tumor Biology and Immunology, University of Salzburg, Salzburg, Austria
| | - Jeffrey S Carlin
- Center for Translational Immunology, Benaroya Research Institute, Seattle, Washington, USA; Division of Rheumatology, Virginia Mason Medical Center, Seattle, Washington, USA
| | - Daniel J Campbell
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA; Department of Immunology, University of Washington School of Medicine, Seattle, Washington, USA
| | - Peter A Morawski
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, Washington, USA.
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3
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Ahi EP, Verta JP, Kurko J, Ruokolainen A, Debes PV, Primmer CR. Hippo-vgll3 signaling may contribute to sex differences in Atlantic salmon maturation age via contrasting adipose dynamics. Biol Sex Differ 2025; 16:23. [PMID: 40176157 PMCID: PMC11966934 DOI: 10.1186/s13293-025-00705-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Accepted: 03/20/2025] [Indexed: 04/04/2025] Open
Abstract
BACKGROUND Sexual maturation in Atlantic salmon entails a transition in energy utilization, regulated by genes and environmental stimuli in sex-specific manner. Males require less energy, in the form of adiposity, to mature and typically mature younger than females. Maturation age is also influenced in a sex-dependent fashion by the vgll3 genotype (vestigial-like 3), a co-factor in the Hippo pathway. The underlying molecular processes of sex-dependent maturation age, and their interplay with adiposity and vgll3 genotypes, remain unclear. METHODS To elucidate the mechanisms underlying sex- and genotype-specific maturation differences, we investigated the association of early (E) and late (L) maturation vgll3 alleles with the transcription of > 330 genes involved in the regulation of the Hippo pathway and sexual maturation, and related molecular signals in brain, adipose, and gonads. RESULTS The strongest effect of vgll3 genotype was observed in adipose for females and in brain for males, highlighting sex-specific expression differences in association with vgll3 genotype. Genes related to ovarian development showed increased expression in vgll3*EE compared to vgll3*LL females. Moreover, vgll3*EE females compared to vgll3*EE males exhibited reduced markers of pre-adipocyte differentiation and lipolysis yet enhanced expression of genes related to adipocyte maturation and lipid storage. Brain gene expression further showed sex-specific expression signals for genes related to hormones and lipids, as well as tight junction assembly. CONCLUSIONS Overall, these sex-specific patterns point towards a greater lipid storage and slower energy utilization in females compared to males. These results suggest Hippo-dependent mechanisms may be important mediators of sex differences in maturation age in salmon.
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Affiliation(s)
- Ehsan Pashay Ahi
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland.
| | - Jukka-Pekka Verta
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland
- Faculty of Biosciences and Aquaculture, Nord University, Bodø, Norway
| | - Johanna Kurko
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland
| | - Annukka Ruokolainen
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland
| | - Paul Vincent Debes
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland
- Department of Aquaculture and Fish Biology, Hólar University, Hólar, Iceland
| | - Craig R Primmer
- Organismal and Evolutionary Biology Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Viikinkaari 1, 00014, Helsinki, Finland
- Institute of Biotechnology, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland
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Kennicott K, Liang Y. The human-specific noncoding RNA RP11-424G14.1 functions at the intersection of sexually dimorphic pathways in inflammation, senescence, and metabolism. FASEB Bioadv 2025; 7:e1479. [PMID: 39917395 PMCID: PMC11795277 DOI: 10.1096/fba.2024-00101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 10/16/2024] [Accepted: 10/31/2024] [Indexed: 02/09/2025] Open
Abstract
Sexual dimorphism is a fundamental characteristic of various physiological and pathological processes in humans, including immune responses, senescence, and metabolism. Most studies on the sex bias have focused on sex hormones or female-biased genes, whereas male-biased genetic factors remain understudied. Here, we show that the Y-linked noncoding RNA, RP11-424G14.1, is expressed in human male keratinocytes. Microarray study suggests the NF-κB pathway as the top biological pathway affected by RP11-424G14.1 knockdown, consistent with known sex differences in inflammation. Additionally, IGFBP3 is identified as the top gene supported by RP11-424G14.1 in male keratinocytes. Conversely, in female keratinocytes, IGFBP3 is the top gene repressed by the X-linked long noncoding RNA XIST, suggesting a central role of IGFBP3 in mediating sexual dimorphism. Knockdown of RP11-424G14.1 or IGFBP3 in male keratinocytes inhibits cellular senescence, consistent with increased longevity in females. IGFBP3 expression is dependent on insulin, and metabolomics analysis suggests that RP11-424G14.1 and IGFBP3 regulate acrylcarnitine metabolism. Our study identifies the role of the RP11-424G14.1-IGFBP3 pathway in coordinating sex differences in immunity, senescence, and metabolism. With RP11-424G14.1 being a human-specific genetic element, our study suggests the evolving feature of sexual dimorphisms in biological processes.
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Affiliation(s)
- Kameron Kennicott
- Department of Physiology and Pharmacology and ToxicologyMichigan State UniversityEast LansingMichiganUSA
| | - Yun Liang
- Department of Physiology and Pharmacology and ToxicologyMichigan State UniversityEast LansingMichiganUSA
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5
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Jafari AJ, McGee C, Klimas N, Hebert AA. Monoclonal antibodies for the management of cutaneous lupus erythematosus: an update on the current treatment landscape. Clin Exp Dermatol 2025; 50:314-322. [PMID: 39243383 DOI: 10.1093/ced/llae374] [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: 03/05/2024] [Revised: 08/07/2024] [Accepted: 08/27/2024] [Indexed: 09/09/2024]
Abstract
Cutaneous lupus erythematosus (CLE) is a complex autoimmune disease often characterized by a multitude of skin findings. CLE is generally classified into three main categories: acute CLE, subacute CLE and chronic CLE. The current therapeutic guidelines for CLE include counselling patients on general measures and medication regimens. Treatment options include optimized photoprotection, avoidance of environmental triggers, corticosteroids, topical and systemic immunomodulators, and antimalarials. To date, no biologic medications (i.e. monoclonal antibodies, mAbs) are approved for CLE. The first mAb for the treatment of both systemic lupus erythematosus (SLE) and active lupus nephritis was belimumab, and was approved for these diseases in 2011 and 2020, respectively. Belimumab is a specific inhibitor of B-lymphocyte stimulator. Anifrolumab, a type I interferon receptor antagonist, was approved in 2021 for SLE. Other mAbs with different targets, including a novel biologic that inhibits blood dendritic cell antigen 2, are currently under investigation for CLE. This review will describe the general treatment landscape for CLE. Selected studies related to these various mAbs will be discussed, as well as their safety profiles and efficacies demonstrated in clinical trials. Biologic medications can potentially augment the number of treatment options for patients living with CLE.
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Affiliation(s)
- Alexander J Jafari
- Department of Dermatology, UTHealth McGovern Medical School, Houston, TX, USA
| | | | - Natasha Klimas
- Department of Dermatology, UTHealth McGovern Medical School, Houston, TX, USA
| | - Adelaide A Hebert
- Department of Dermatology, UTHealth McGovern Medical School, Houston, TX, USA
- Department of Pediatrics, UTHealth McGovern Medical School, Houston, TX, USA
- Department of Dermatology, MD Anderson Cancer Center, Houston, TX, USA
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Perricone C, Bruno L, Cafaro G, Latini A, Ceccarelli F, Borgiani P, Ciccacci C, Bogdanos D, Novelli G, Gerli R, Bartoloni E. Sjogren's syndrome: Everything you always wanted to know about genetic and epigenetic factors. Autoimmun Rev 2024; 23:103673. [PMID: 39490751 DOI: 10.1016/j.autrev.2024.103673] [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: 08/28/2024] [Revised: 10/21/2024] [Accepted: 10/24/2024] [Indexed: 11/05/2024]
Abstract
Primary Sjögren's syndrome (pSS) is a chronic, systemic autoimmune disease characterized by a wide spectrum of glandular and extra-glandular features. Genetic and epigenetic factors play an important role in the disease susceptibility and phenotype. There are a multitude of genes that have been identified as implicated in the pathogenesis of pSS, both in HLA and extra-HLA regions with a strong contribution given by genes in interferon signalling pathways. Among the HLA alleles, the most consistent associations have been found with DR2 and DR3 alleles at the DRB1 locus. Moreover, several gene variants outside the MHC locus are in genes involved in NF-κB signalling, B- and T-cell function and methylation processes possibly responsible for lymphomagenesis. There is still a lack of knowledge on precise genetic patterns and prediction models of diseases, and data on pharmacogenetics is scarce. A comprehensive summary of the common genetic factors and an extensive analysis of novel epigenetic aspects is provided, together with a view on the relationships between novel therapeutic agents for pSS and genetic targets in signalling pathways, aiming at improving tailored treatment strategies in the view of a more personalized medicine.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy.
| | - Lorenza Bruno
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy
| | - Andrea Latini
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Fulvia Ceccarelli
- Division of Rheumatology, Department of Clinical Internal, Anaesthesiologic and Cardiovascular Sciences, Sapienza University, 00133 Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Cinzia Ciccacci
- UniCamillus, Saint Camillus International University of Health Sciences, 00131 Rome, Italy
| | - Dimitrios Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Thessaly, Greece.
| | - Giuseppe Novelli
- Department of Biomedicine and Prevention, Genetics Section, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Roberto Gerli
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy
| | - Elena Bartoloni
- Rheumatology, Department of Medicine, University of Perugia, Piazzale Giorgio Menghini, 1, 06129 Perugia, Italy
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Chizzolini C, Guery JC, Noulet F, Gruaz L, Cenac C, Frasca L, Spoerl D, Arlettaz L, Horisberger A, Ribi C, Hugues S. Extrafollicular CD19 lowCXCR5 -CD11c - double negative 3 (DN3) B cells are significantly associated with disease activity in females with systemic lupus erythematosus. J Transl Autoimmun 2024; 9:100252. [PMID: 39444662 PMCID: PMC11497371 DOI: 10.1016/j.jtauto.2024.100252] [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: 08/21/2024] [Revised: 10/03/2024] [Accepted: 10/03/2024] [Indexed: 10/25/2024] Open
Abstract
Objective B cells play a major role in the development and maintenance of systemic lupus erythematosus (SLE). Double negative (DN) B cells defined by the lack of surface expression of IgD and CD27 have attracted recent interest for their sensitivity to Toll-like receptor 7 (TLR7) ligands and their potential role in the production of autoantibodies. Here we aimed at investigating the possible association of DN B cells and their subsets with SLE disease activity specifically in female patients, in which TLR7 gene has been reported to escape X chromosome inactivation. Methods Peripheral blood mononuclear cells were purified from woman participating to the clinically well-characterized Swiss SLE Cohort Study (SSCS). PBMC from age-matched healthy females were used as controls. PBMC were stained for cell surface markers, intracellular Tbet and analyzed by multicolor cytofluorimetry. Single nucleotide TLR7 polymorphisms were assessed by polymerase chain reaction. Results The median SLE disease activity index of the 86 females was 2, IQR [0-6], all but 8 were under chronic SLE treatment. B cells co-expressing CD11c and Tbet were increased, the mean fluorescence intensity (MFI) of CD19 was considerably reduced and we observed a large increase in CD11c + CXCR5-and CD11c-CXCR5-concomitantly with a reduction of CD11c-CXCR5+ B cells in SLE compared to 40 healthy donors (HD). When focusing on the DN B cell subset, we found a reduction of DN1 (CD11c-CXCR5+) and an increase of DN2 (CD11c + CXCR5-) and most impressively of DN3 (CD11c-CXCR5-) cells. The DN subset, particularly DN3, showed the lowest level of CD19 expression. Both DN1 and DN3 percentages as well as the CD19 MFI of DN cells were associated with SLE disease activity. The use of glucocorticoids, immunosuppressants, and antimalarials impacted differentially on the frequencies of DN B cell subsets. CD19 MFI in B cells and the percentage of DN3 were the strongest biomarkers of disease activity. The TLR7 snp3858384 G allele was associated with increased percentages of B cells and CD19+CD11c-CXCR5+ and decreased CD19+CD11c-CXCR5-. Conclusions DN3 B cells are strongly associated with SLE clinical activity pointing to their potential involvement in disease pathogenesis, and CD19 expression level performs accurately as disease activity biomarker.
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Affiliation(s)
- Carlo Chizzolini
- Department of Pathology and Immunology, Centre Médical Universitaire, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Jean-Charles Guery
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291, CNRS UMR5051, University Paul Sabatier Toulouse, F-31024, Toulouse, France
| | - Fanny Noulet
- Department of Pathology and Immunology, Centre Médical Universitaire, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Lyssia Gruaz
- Department of Pathology and Immunology, Centre Médical Universitaire, School of Medicine, University of Geneva, Geneva, Switzerland
| | - Claire Cenac
- Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) INSERM UMR1291, CNRS UMR5051, University Paul Sabatier Toulouse, F-31024, Toulouse, France
| | - Loredana Frasca
- National Center for Global Health, Istituto Superiore di Sanità, Rome, Italy
| | - David Spoerl
- Clinical Immunology and Allergy, Department of Medicine, University Hospital and Faculty of Medicine, Geneva, Switzerland
| | - Lionel Arlettaz
- Department of Biology, ICH, Valais Hospital, Sion, Switzerland
| | - Alice Horisberger
- Service of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Camillo Ribi
- Service of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - Stéphanie Hugues
- Department of Pathology and Immunology, Centre Médical Universitaire, School of Medicine, University of Geneva, Geneva, Switzerland
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Li Y, Liu Y, Yu XY, Xu Y, Pan X, Sun Y, Wang Y, Song YH, Shen Z. Membraneless organelles in health and disease: exploring the molecular basis, physiological roles and pathological implications. Signal Transduct Target Ther 2024; 9:305. [PMID: 39551864 PMCID: PMC11570651 DOI: 10.1038/s41392-024-02013-w] [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: 05/10/2024] [Revised: 08/22/2024] [Accepted: 10/10/2024] [Indexed: 11/19/2024] Open
Abstract
Once considered unconventional cellular structures, membraneless organelles (MLOs), cellular substructures involved in biological processes or pathways under physiological conditions, have emerged as central players in cellular dynamics and function. MLOs can be formed through liquid-liquid phase separation (LLPS), resulting in the creation of condensates. From neurodegenerative disorders, cardiovascular diseases, aging, and metabolism to cancer, the influence of MLOs on human health and disease extends widely. This review discusses the underlying mechanisms of LLPS, the biophysical properties that drive MLO formation, and their implications for cellular function. We highlight recent advances in understanding how the physicochemical environment, molecular interactions, and post-translational modifications regulate LLPS and MLO dynamics. This review offers an overview of the discovery and current understanding of MLOs and biomolecular condensate in physiological conditions and diseases. This article aims to deliver the latest insights on MLOs and LLPS by analyzing current research, highlighting their critical role in cellular organization. The discussion also covers the role of membrane-associated condensates in cell signaling, including those involving T-cell receptors, stress granules linked to lysosomes, and biomolecular condensates within the Golgi apparatus. Additionally, the potential of targeting LLPS in clinical settings is explored, highlighting promising avenues for future research and therapeutic interventions.
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Affiliation(s)
- Yangxin Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
| | - Yuzhe Liu
- Department of Orthopedics, The Second Hospital of Jilin University, Changchun, Jilin, 130041, P. R. China
| | - Xi-Yong Yu
- NMPA Key Laboratory for Clinical Research and Evaluation of Drug for Thoracic Diseases, Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou, 511436, P. R. China
| | - Yan Xu
- Department of General Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, P. R. China
| | - Xiangbin Pan
- Department of Structural Heart Disease, National Center for Cardiovascular Disease, China & Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, State key laboratory of cardiovascular disease, Beijing, 100037, P. R. China
| | - Yi Sun
- Department of Cardiovascular Surgery, Fuwai Yunnan Cardiovascular Hospital, Kunming, 650102, P. R. China
| | - Yanli Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China
| | - Yao-Hua Song
- Cyrus Tang Hematology Center, Collaborative Innovation Center of Hematology, Soochow University, National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, 215123, P.R. China.
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.
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Hughes AN, Li X, Lehman JS, Nelson SA, DiCaudo DJ, Mudappathi R, Hwang A, Kechter J, Pittelkow MR, Mangold AR, Sekulic A. Drug Repurposing Using Molecular Network Analysis Identifies Jak as Targetable Driver in Necrobiosis Lipoidica. JID INNOVATIONS 2024; 4:100296. [PMID: 39391813 PMCID: PMC11465178 DOI: 10.1016/j.xjidi.2024.100296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 03/18/2024] [Accepted: 04/08/2024] [Indexed: 10/12/2024] Open
Abstract
Drug repurposing is an attractive strategy for therapy development, particularly in rare diseases where traditional drug development approaches may be challenging owing to high cost and small numbers of patients. In this study, we used a drug identification and repurposing pipeline to identify candidate targetable drivers of disease and corresponding therapies through application of causal reasoning using a combination of open-access resources and transcriptomics data. We optimized our approach on psoriasis as a disease model, demonstrating the ability to identify known and, to date, unrecognized molecular drivers of psoriasis and link them to current and emerging therapies. Application of our approach to a cohort of tissue samples of necrobiosis lipoidica (an unrelated; rare; and, to date, molecularly poorly characterized cutaneous inflammatory disorder) identified a unique set of upstream regulators, particularly highlighting the role of IFNG and the Jak-signal transducer and activator of transcription pathway as a likely driver of disease pathogenesis and linked it to Jak inhibitors as potential therapy. Analysis of an independent cohort of necrobiosis lipoidica samples validated these findings, with the overall agreement of drug-matched upstream regulators above 96%. These data highlight the utility of our approach in rare diseases and offer an opportunity for drug discovery in other rare diseases in dermatology and beyond.
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Affiliation(s)
- Alysia N. Hughes
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Xing Li
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Julia S. Lehman
- Department of Dermatology, Mayo Clinic, Rochester, Minnesota, USA
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Steven A. Nelson
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - David J. DiCaudo
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Rekha Mudappathi
- Department of Quantitative Health Sciences, Mayo Clinic, Scottsdale, Arizona, USA
- Center for Individualized Medicine, Mayo Clinic, Scottsdale, Arizona, USA
- College of Health Solutions, Arizona State University, Phoenix, Arizona, USA
| | - Angelina Hwang
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Jacob Kechter
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | | | - Aaron R. Mangold
- Department of Dermatology, Mayo Clinic, Scottsdale, Arizona, USA
| | - Aleksandar Sekulic
- Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona, USA
- City of Hope, Phoenix, Arizona, USA
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10
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Wu W, Fan Z, Fu H, Ma X, Wang D, Liu H, Zhang C, Zheng H, Yang Y, Wu H, Miao X, An R, Gong Y, Tang TS, Guo C. VGLL3 modulates chemosensitivity through promoting DNA double-strand break repair. SCIENCE ADVANCES 2024; 10:eadr2643. [PMID: 39383226 PMCID: PMC11463272 DOI: 10.1126/sciadv.adr2643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 09/04/2024] [Indexed: 10/11/2024]
Abstract
Transcription cofactor vestigial-like 3 (VGLL3), as a master regulator of female-biased autoimmunity, also functions in tumor development, while the underlying mechanisms remain largely elusive. Here, we report that VGLL3 plays an important role in DNA damage response (DDR). VGLL3 can be recruited to damage sites in a PARylation-dependent manner. VGLL3 depletion impairs the accumulation of RNF8 and RAD51 at sites of DNA damage, leading to reduced homologous recombination efficiency and increased cellular sensitivity to chemotherapeutic drugs. Mechanistically, VGLL3 can prevent CtIP from KLHL15-mediated ubiquitination and degradation through competitive binding with KLHL15 and, meanwhile, stabilize MDC1 by limiting TRIP12-MDC1 but promoting USP7-MDC1 associations for optimal RNF8 signaling initiation. Consistently, VGLL3 depletion delays tumor development and sensitizes the xenografts to etoposide treatment. Overall, our results reveal an unexpected role of VGLL3 in DDR, which is distinct from its transcriptional cofactor function and not conserved among VGLL family members.
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Affiliation(s)
- Wei Wu
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Zhenzhen Fan
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hui Fu
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Xiaolu Ma
- Key Laboratory of Organ Regeneration and Reconstruction’State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Dongzhou Wang
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hongmei Liu
- Key Laboratory of Organ Regeneration and Reconstruction’State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Chuanchao Zhang
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Hui Zheng
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Yeran Yang
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
| | - Honglin Wu
- University of Chinese Academy of Sciences, Beijing 100049, China
- Key Laboratory of Organ Regeneration and Reconstruction’State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Xiuxiu Miao
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ruiyuan An
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yifei Gong
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Tie-Shan Tang
- University of Chinese Academy of Sciences, Beijing 100049, China
- Key Laboratory of Organ Regeneration and Reconstruction’State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing 100101, China
| | - Caixia Guo
- China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
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11
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Schell SL, Nelson AM. Setting the Stage for Standardized Reporting of Clinical and Demographic Information in Laboratory-Based Studies of Hidradenitis Suppurativa. J Invest Dermatol 2024; 144:1689-1695. [PMID: 38888525 DOI: 10.1016/j.jid.2024.04.014] [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: 11/17/2023] [Revised: 04/12/2024] [Accepted: 04/25/2024] [Indexed: 06/20/2024]
Abstract
Hidradenitis suppurativa (HS) is a complex inflammatory skin condition affecting 0.1-4% of the population that leads to permanent scarring in the axilla, inframammary region, groin, and buttocks. Its complex pathogenesis involves genetics, innate and adaptive immunity, microbiota, and environmental stimuli. Specific populations have a higher incidence of HS, including females and Black individuals and those with associated comorbidities. HS registries and biobanks have set standards for the documentation of clinical data in the context of clinical trials and outcomes research, but collection, documentation, and reporting of these important clinical and demographic variables are uncommon in HS laboratory research studies. Standardization in the laboratory setting is needed because it helps to elucidate the factors that contribute mechanistically to HS symptoms and pathophysiology. The purpose of this article is to begin to set the stage for standardized reporting in the laboratory setting. We discuss how clinical guidelines can inform laboratory research studies, and we highlight what additional information is necessary for the use of samples in the wet laboratory and interpretation of associated mechanistic data. Through standardized data collection and reporting, data harmonization between research studies will transform our understanding of HS and lead to novel discoveries that will positively impact patient care.
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Affiliation(s)
- Stephanie L Schell
- Department of Dermatology, Penn State College of Medicine, Hershey, Pennsylvania, USA
| | - Amanda M Nelson
- Department of Dermatology, Penn State College of Medicine, Hershey, Pennsylvania, USA.
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12
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Yao Y, Zuo X, Shao F, Yu K, Liang Q. Jaceosidin attenuates the progression of hepatic fibrosis by inhibiting the VGLL3/HMGB1/TLR4 signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155502. [PMID: 38489889 DOI: 10.1016/j.phymed.2024.155502] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 02/19/2024] [Accepted: 02/27/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND Jaceosidin (JA) is a natural flavone extracted from Artemisia that is used as a food and traditional medicinal herb. It has been reported to possess numerous biological activities. However, the regulatory mechanisms underlying amelioration of hepatic fibrosis remain unclear. HYPOTHESIS/PURPOSE We hypothesized that jaceosidin acid (JA) modulates hepatic fibrosis and inflammation. METHODS Thioacetamide (TAA) was used to establish an HF mouse model. In vitro, mouse primary hepatocytes and HSC-T6 cells were induced by TGF-β, whereas mouse peritoneal macrophages received a treatment lipopolysaccharide (LPS)/ATP. RESULTS JA decreased serum transaminase levels and improved hepatic histological pathology in TAA-treated mice stimulated by TAA. Moreover, the expression of pro-fibrogenic biomarkers associated with the activation of liver stellate cells was downregulated by JA. Likewise, JA down-regulated the expression of vestigial-like family member 3 (VGLL3), high mobility group protein B1 (HMGB1), toll-like receptors 4 (TLR4), and nucleotide-binding domain-(NOD-) like receptor protein 3 (NLRP3), thereby inhibiting the inflammatory response and inhibiting the release of mature-IL-1β in TAA-stimulated mice. Additionally, JA suppressed HMGB1 release and NLRP3/ASC inflammasome activation in LPS/ATP-stimulated murine peritoneal macrophages. JA decreases the expression of pro-fibrogenic biomarkers related to liver stellate cell activation and inhibits inflammasome activation in mouse primary hepatocytes. It also down-regulated α-SMA and VGLL3 expressions and also suppressed inflammasome activation in HSC-T6 cells. VGLL3 and α-SMA expression levels were decreased in TGF-β-stimulated HSC-T6 cells following Vgll3 knockdown. In addition, the expression levels of NLRP3 and cleaved-caspase-1 were decreased in Vgll3-silenced HSC-T6 cells. JA enhanced the inhibitory effects on Vgll3-silenced HSC-T6 cells. Finally, Vgll3 overexpression in HSC-T6 cells affected the expression levels of α-SMA, NLRP3, and cleaved-caspase-1. CONCLUSION JA effectively modulates hepatic fibrosis by suppressing fibrogenesis and inflammation via the VGLL3/HMGB1/TLR4 axis. Therefore, JA may be a candidate therapeutic agent for the management of hepatic fibrosis. Understanding the mechanism of action of JA is a novel approach to hepatic fibrosis therapy.
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Affiliation(s)
- Youli Yao
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Xiaoling Zuo
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Feng Shao
- Qingdao Jinmotang Biotechnology Co., Ltd, Qingdao, Shandong Province 266000, China
| | - Kexin Yu
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China
| | - Quanquan Liang
- College of Electronic and Information Engineering, Shandong University of Science and Technology, Qingdao, Shandong Province 266000, China.
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13
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Jie J, Gong Y, Luo S, Yang X, Guo K. Genetically predicted associations between circulating cytokines and autoimmune diseases: a bidirectional two-sample Mendelian randomization. Front Immunol 2024; 15:1404260. [PMID: 38860028 PMCID: PMC11163916 DOI: 10.3389/fimmu.2024.1404260] [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: 03/20/2024] [Accepted: 05/13/2024] [Indexed: 06/12/2024] Open
Abstract
Objectives Previous studies have indicated a correlation between cytokines and autoimmune diseases. yet the causality remains uncertain. Through Mendelian Randomization (MR) analysis, we aimed to investigate the causal relationships between genetically predicted levels of 91 cytokines and three autoimmune diseases: Multiple Sclerosis (MS), Systemic Lupus Erythematosus (SLE), and Hashimoto's Thyroiditis (HT). Methods A bidirectional two-sample MR approach was utilized to assess the causal relationships between cytokines and MS, SLE, and HT. The datasets included 47,429 MS cases and 68,374 controls, 5,201 SLE cases and 9,066 controls, and 16,191 HT cases with 210,612 controls. Data on 91 cytokines comprised 14,824 participants. Causal analyses primarily employed inverse variance weighted, weighted median, and MR-Egger methods, with sensitivity analyses including heterogeneity and pleiotropy assessment. Results Genetically predicted levels of IL-18 (OR = 0.706; 95% C.I. 0.538-0.925), ADA (OR = 0.808; 95% C.I. 0.673-0.970), and SCF (OR = 0.898; 95% C.I. 0.816-0.987) were associated with a decreased risk of MS. IL-4 (OR = 1.384; 95% C.I. 1.081-1.771), IL-7 (OR = 1.401; 95% C.I. 1.010-1.943), IL-10RA (OR = 1.266; 95% C.I. 1.004-1.596), CXCL5 (OR = 1.170; 95% C.I. 1.021-1.341), NTN (OR = 1.225; 95% C.I. 1.004-1.496), FGF23 (OR = 0.644; 95% C.I. 0.460-0.902), and MCP4 (OR = 0.665; 95% C.I. 0.476-0.929) were associated with SLE risk. CDCP1 (OR = 1.127; 95% C.I. 1.008-1.261), IL-33 (OR = 0.852; 95% C.I. 0.727-0.999), and TRAIL (OR = 0.884; 95% C.I. 0.799-0.979) were associated with HT risk. Bidirectional MR results suggest the involvement of CCL19, IL-13, SLAM, ARTN, Eotaxin, IL-22RA1, ADA, and MMP10 in the downstream development of these diseases. Conclusions Our findings support causal relationships between certain cytokines and the risks of MS, SLE, and HT, identifying potential biomarkers for diagnosis and prevention. Additionally, several cytokines previously unexplored in these autoimmune disease contexts were discovered, laying new groundwork for the study of disease mechanisms and therapeutic potentials.
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Affiliation(s)
- Jie Jie
- Changde Hospital, Xiangya School of Medicine, Central South University (The First People’s Hospital of Changde City), Changde, China
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14
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Sun D, Ma R, Wang J, Wang Y, Ye Q. The causal relationship between sarcoidosis and autoimmune diseases: a bidirectional Mendelian randomization study in FinnGen. Front Immunol 2024; 15:1325127. [PMID: 38711527 PMCID: PMC11070530 DOI: 10.3389/fimmu.2024.1325127] [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: 10/20/2023] [Accepted: 04/09/2024] [Indexed: 05/08/2024] Open
Abstract
Background Sarcoidosis has been considered to be associated with many autoimmune diseases (ADs), but the cause-and-effect relationship between these two diseases has not been fully explored. Therefore, the objective of this study is to explore the possible genetic association between sarcoidosis and ADs. Methods We conducted a bidirectional Mendelian randomization (MR) study using genetic variants associated with ADs and sarcoidosis (4,041 cases and 371,255 controls) from the FinnGen study. The ADs dataset comprised 96,150 cases and 281,127 controls, encompassing 44 distinct types of autoimmune-related diseases. Subsequently, we identified seven diseases within the ADs dataset with a case size exceeding 3,500 and performed subgroup analyses on these specific diseases. Results The MR evidence supported the causal association of genetic predictors of ADs with an increased risk of sarcoidosis (OR = 1.79, 95% CI = 1.59 to 2.02, P IVW-FE = 1.01 × 10-21), and no reverse causation (OR = 1.05, 95% CI 0.99 to 1.12, P IVW-MRE = 9.88 × 10-2). Furthermore, subgroup analyses indicated that genetic predictors of type 1 diabetes mellitus (T1DM), celiac disease, and inflammatory bowel disease (IBD) were causally linked to an elevated risk of sarcoidosis (All P < 6.25 × 10-3). Conversely, genetic predictors of sarcoidosis showed causal associations with a higher risk of type 1 diabetes mellitus (P < 6.25 × 10-3). Conclusion The present study established a positive causal relationship between genetic predictors of ADs (e.g. T1DM, celiac disease, and IBD) and the risk of sarcoidosis, with no evidence of reverse causation.
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Affiliation(s)
| | | | | | | | - Qiao Ye
- Department of Occupational Medicine and Toxicology, Clinical Center for Interstitial Lung Diseases, Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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15
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Kennicott K, Liang Y. The immunometabolic function of VGLL3 and female-biased autoimmunity. IMMUNOMETABOLISM (COBHAM, SURREY) 2024; 6:e00041. [PMID: 38726338 PMCID: PMC11078290 DOI: 10.1097/in9.0000000000000041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/15/2024] [Indexed: 05/12/2024]
Abstract
Autoimmune diseases exhibit a pronounced yet unexplained prevalence among women. Vestigial-like family member 3 (VGLL3), a female-biased factor that promotes autoimmunity, has recently been discovered to assist cells in sensing and adapting to nutritional stress. This role of VGLL3 may confer a selective advantage during the evolution of placental mammals. However, the excessive activation of the VGLL3-mediated energy-sensing pathway can trigger inflammatory cell death and the exposure of self-antigens, leading to the onset of autoimmunity. These observations have raised the intriguing perspective that nutrient sensing serves as a double-edged sword in immune regulation. Mechanistically, VGLL3 intersects with Hippo signaling and activates multiple downstream, immune-associated genes that play roles in metabolic regulation. Understanding the multifaceted roles of VGLL3 in nutrient sensing and immune modulation provides insight into the fundamental question of sexual dimorphism in immunometabolism and sheds light on potential therapeutic targets for autoimmune diseases.
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Affiliation(s)
- Kameron Kennicott
- Department of Physiology, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
| | - Yun Liang
- Department of Physiology, Michigan State University, East Lansing, MI, USA
- Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA
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16
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Uppala R, Sarkar MK, Young KZ, Ma F, Vemulapalli P, Wasikowski R, Plazyo O, Swindell WR, Maverakis E, Gharaee-Kermani M, Billi AC, Tsoi LC, Kahlenberg JM, Gudjonsson JE. HERC6 regulates STING activity in a sex-biased manner through modulation of LATS2/VGLL3 Hippo signaling. iScience 2024; 27:108986. [PMID: 38327798 PMCID: PMC10847730 DOI: 10.1016/j.isci.2024.108986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Revised: 11/10/2023] [Accepted: 01/17/2024] [Indexed: 02/09/2024] Open
Abstract
Interferon (IFN) activity exhibits a gender bias in human skin, skewed toward females. We show that HERC6, an IFN-induced E3 ubiquitin ligase, is induced in human keratinocytes through the epidermal type I IFN; IFN-κ. HERC6 knockdown in human keratinocytes results in enhanced induction of interferon-stimulated genes (ISGs) upon treatment with a double-stranded (ds) DNA STING activator cGAMP but not in response to the RNA-sensing TLR3 agonist. Keratinocytes lacking HERC6 exhibit sustained STING-TBK1 signaling following cGAMP stimulation through modulation of LATS2 and TBK1 activity, unmasking more robust ISG responses in female keratinocytes. This enhanced female-biased immune response with loss of HERC6 depends on VGLL3, a regulator of type I IFN signature. These data identify HERC6 as a previously unrecognized negative regulator of ISG expression specific to dsDNA sensing and establish it as a regulator of female-biased immune responses through modulation of STING signaling.
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Affiliation(s)
- Ranjitha Uppala
- Graduate Program in Immunology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Mrinal K. Sarkar
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Kelly Z. Young
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Feiyang Ma
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | | | - Rachael Wasikowski
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Olesya Plazyo
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - William R. Swindell
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Emanual Maverakis
- Department of Dermatology, University of California, Davis, Davis, CA 95616, USA
| | - Mehrnaz Gharaee-Kermani
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
| | - Allison C. Billi
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - Lam C. Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
| | - J. Michelle Kahlenberg
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA
| | - Johann E. Gudjonsson
- Department of Dermatology, University of Michigan, Ann Arbor, MI 48109, USA
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA
- A. Alfred Taubman Medical Research Institute, Ann Arbor, MI 48109, USA
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17
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Ma F, Tsou PS, Gharaee-Kermani M, Plazyo O, Xing X, Kirma J, Wasikowski R, Hile GA, Harms PW, Jiang Y, Xing E, Nakamura M, Ochocki D, Brodie WD, Pillai S, Maverakis E, Pellegrini M, Modlin RL, Varga J, Tsoi LC, Lafyatis R, Kahlenberg JM, Billi AC, Khanna D, Gudjonsson JE. Systems-based identification of the Hippo pathway for promoting fibrotic mesenchymal differentiation in systemic sclerosis. Nat Commun 2024; 15:210. [PMID: 38172207 PMCID: PMC10764940 DOI: 10.1038/s41467-023-44645-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 12/23/2023] [Indexed: 01/05/2024] Open
Abstract
Systemic sclerosis (SSc) is a devastating autoimmune disease characterized by excessive production and accumulation of extracellular matrix, leading to fibrosis of skin and other internal organs. However, the main cellular participants in SSc skin fibrosis remain incompletely understood. Here using differentiation trajectories at a single cell level, we demonstrate a dual source of extracellular matrix deposition in SSc skin from both myofibroblasts and endothelial-to-mesenchymal-transitioning cells (EndoMT). We further define a central role of Hippo pathway effectors in differentiation and homeostasis of myofibroblast and EndoMT, respectively, and show that myofibroblasts and EndoMTs function as central communication hubs that drive key pro-fibrotic signaling pathways in SSc. Together, our data help characterize myofibroblast differentiation and EndoMT phenotypes in SSc skin, and hint that modulation of the Hippo pathway may contribute in reversing the pro-fibrotic phenotypes in myofibroblasts and EndoMTs.
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Affiliation(s)
- Feiyang Ma
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Pei-Suen Tsou
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Mehrnaz Gharaee-Kermani
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Olesya Plazyo
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Xianying Xing
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Joseph Kirma
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Rachael Wasikowski
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Grace A Hile
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Paul W Harms
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
- Department of Pathology, University of Michigan, Ann Arbor, MI, USA
| | - Yanyun Jiang
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Enze Xing
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Mio Nakamura
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Danielle Ochocki
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - William D Brodie
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Shiv Pillai
- Ragon Institute, Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, USA
| | - Emanual Maverakis
- Department of Dermatology, University of California, Davis, Sacramento, CA, USA
| | - Matteo Pellegrini
- Dept of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
| | - Robert L Modlin
- Dept of Molecular, Cell, and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA
- Division of Dermatology, Department of Medicine, University of California, Los Angeles, CA, 90095, USA
| | - John Varga
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA
| | - Lam C Tsoi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Robert Lafyatis
- Division of Rheumatology, University of Pittsburgh, Pittsburgh, PA, USA
| | - J Michelle Kahlenberg
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Allison C Billi
- Department of Dermatology, University of Michigan, Ann Arbor, MI, USA
| | - Dinesh Khanna
- Division of Rheumatology, Dept of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
- University of Michigan Scleroderma Program, Ann Arbor, MI, USA.
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Pandey SP, Bhaskar R, Han SS, Narayanan KB. Autoimmune Responses and Therapeutic Interventions for Systemic Lupus Erythematosus: A Comprehensive Review. Endocr Metab Immune Disord Drug Targets 2024; 24:499-518. [PMID: 37718519 DOI: 10.2174/1871530323666230915112642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 06/05/2023] [Accepted: 07/22/2023] [Indexed: 09/19/2023]
Abstract
Systemic Lupus Erythematosus (SLE) or Lupus is a multifactorial autoimmune disease of multiorgan malfunctioning of extremely heterogeneous and unclear etiology that affects multiple organs and physiological systems. Some racial groups and women of childbearing age are more susceptible to SLE pathogenesis. Impressive progress has been made towards a better understanding of different immune components contributing to SLE pathogenesis. Recent investigations have uncovered the detailed mechanisms of inflammatory responses and organ damage. Various environmental factors, pathogens, and toxicants, including ultraviolet light, drugs, viral pathogens, gut microbiome metabolites, and sex hormones trigger the onset of SLE pathogenesis in genetically susceptible individuals and result in the disruption of immune homeostasis of cytokines, macrophages, T cells, and B cells. Diagnosis and clinical investigations of SLE remain challenging due to its clinical heterogeneity and hitherto only a few approved antimalarials, glucocorticoids, immunosuppressants, and some nonsteroidal anti-inflammatory drugs (NSAIDs) are available for treatment. However, the adverse effects of renal and neuropsychiatric lupus and late diagnosis make therapy challenging. Additionally, SLE is also linked to an increased risk of cardiovascular diseases due to inflammatory responses and the risk of infection from immunosuppressive treatment. Due to the diversity of symptoms and treatment-resistant diseases, SLE management remains a challenging issue. Nevertheless, the use of next-generation therapeutics with stem cell and gene therapy may bring better outcomes to SLE treatment in the future. This review highlights the autoimmune responses as well as potential therapeutic interventions for SLE particularly focusing on the recent therapeutic advancements and challenges.
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Affiliation(s)
- Surya Prakash Pandey
- Aarogya Institute of Healthcare and Research, Jaipur, Rajasthan, 302033, India
- Department of Zoology, School of Science, IFTM University, Moradabad, Uttar Pradesh, 244102, India
| | - Rakesh Bhaskar
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, South Korea
| | - Sung Soo Han
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, South Korea
| | - Kannan Badri Narayanan
- School of Chemical Engineering, Yeungnam University, Gyeongsan, 38541, South Korea
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, South Korea
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19
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Phongpreecha T, Godrich D, Berson E, Espinosa C, Kim Y, Cholerton B, Chang AL, Mataraso S, Bukhari SA, Perna A, Yakabi K, Montine KS, Poston KL, Mormino E, White L, Beecham G, Aghaeepour N, Montine TJ. Quantitative estimate of cognitive resilience and its medical and genetic associations. Alzheimers Res Ther 2023; 15:192. [PMID: 37926851 PMCID: PMC10626669 DOI: 10.1186/s13195-023-01329-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Accepted: 10/09/2023] [Indexed: 11/07/2023]
Abstract
BACKGROUND We have proposed that cognitive resilience (CR) counteracts brain damage from Alzheimer's disease (AD) or AD-related dementias such that older individuals who harbor neurodegenerative disease burden sufficient to cause dementia remain cognitively normal. However, CR traditionally is considered a binary trait, capturing only the most extreme examples, and is often inconsistently defined. METHODS This study addressed existing discrepancies and shortcomings of the current CR definition by proposing a framework for defining CR as a continuous variable for each neuropsychological test. The linear equations clarified CR's relationship to closely related terms, including cognitive function, reserve, compensation, and damage. Primarily, resilience is defined as a function of cognitive performance and damage from neuropathologic damage. As such, the study utilized data from 844 individuals (age = 79 ± 12, 44% female) in the National Alzheimer's Coordinating Center cohort that met our inclusion criteria of comprehensive lesion rankings for 17 neuropathologic features and complete neuropsychological test results. Machine learning models and GWAS then were used to identify medical and genetic factors that are associated with CR. RESULTS CR varied across five cognitive assessments and was greater in female participants, associated with longer survival, and weakly associated with educational attainment or APOE ε4 allele. In contrast, damage was strongly associated with APOE ε4 allele (P value < 0.0001). Major predictors of CR were cardiovascular health and social interactions, as well as the absence of behavioral symptoms. CONCLUSIONS Our framework explicitly decoupled the effects of CR from neuropathologic damage. Characterizations and genetic association study of these two components suggest that the underlying CR mechanism has minimal overlap with the disease mechanism. Moreover, the identified medical features associated with CR suggest modifiable features to counteract clinical expression of damage and maintain cognitive function in older individuals.
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Affiliation(s)
- Thanaphong Phongpreecha
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
| | - Dana Godrich
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
| | - Eloise Berson
- Department of Pathology, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Camilo Espinosa
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Yeasul Kim
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | | | - Alan L Chang
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Samson Mataraso
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Syed A Bukhari
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Amalia Perna
- Department of Pathology, Stanford University, Stanford, CA, USA
| | - Koya Yakabi
- Department of Pathology, Stanford University, Stanford, CA, USA
| | | | - Kathleen L Poston
- Department of Neurology Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Elizabeth Mormino
- Department of Neurology Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Lon White
- Pacific Health Research and Education Institute, Honolulu, HI, USA
| | - Gary Beecham
- Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, FL, USA
| | - Nima Aghaeepour
- Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA
- Department of Biomedical Data Science, Stanford University, 300 Pasteur Dr Rm L216, Stanford, CA, 94305, USA
- Department of Pediatrics, Stanford University, Stanford, CA, USA
| | - Thomas J Montine
- Department of Pathology, Stanford University, Stanford, CA, USA.
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20
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Romhányi D, Szabó K, Kemény L, Groma G. Histone and Histone Acetylation-Related Alterations of Gene Expression in Uninvolved Psoriatic Skin and Their Effects on Cell Proliferation, Differentiation, and Immune Responses. Int J Mol Sci 2023; 24:14551. [PMID: 37833997 PMCID: PMC10572426 DOI: 10.3390/ijms241914551] [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: 08/24/2023] [Revised: 09/11/2023] [Accepted: 09/21/2023] [Indexed: 10/15/2023] Open
Abstract
Psoriasis is a chronic immune-mediated skin disease in which the symptom-free, uninvolved skin carries alterations in gene expression, serving as a basis for lesion formation. Histones and histone acetylation-related processes are key regulators of gene expression, controlling cell proliferation and immune responses. Dysregulation of these processes is likely to play an important role in the pathogenesis of psoriasis. To gain a complete overview of these potential alterations, we performed a meta-analysis of a psoriatic uninvolved skin dataset containing differentially expressed transcripts from nearly 300 individuals and screened for histones and histone acetylation-related molecules. We identified altered expression of the replication-dependent histones HIST2H2AA3 and HIST2H4A and the replication-independent histones H2AFY, H2AFZ, and H3F3A/B. Eight histone chaperones were also identified. Among the histone acetyltransferases, ELP3 and KAT5 and members of the ATAC, NSL, and SAGA acetyltransferase complexes are affected in uninvolved skin. Histone deacetylation-related alterations were found to affect eight HDACs and members of the NCOR/SMRT, NURD, SIN3, and SHIP HDAC complexes. In this article, we discuss how histone and histone acetylation-related expression changes may affect proliferation and differentiation, as well as innate, macrophage-mediated, and T cell-mediated pro- and anti-inflammatory responses, which are known to play a central role in the development of psoriasis.
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Affiliation(s)
- Dóra Romhányi
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
| | - Kornélia Szabó
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- Hungarian Centre of Excellence for Molecular Medicine-University of Szeged Skin Research Group (HCEMM-USZ Skin Research Group), H-6720 Szeged, Hungary
- HUN-REN-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
| | - Lajos Kemény
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- Hungarian Centre of Excellence for Molecular Medicine-University of Szeged Skin Research Group (HCEMM-USZ Skin Research Group), H-6720 Szeged, Hungary
- HUN-REN-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
| | - Gergely Groma
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- HUN-REN-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
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21
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Londe AC, Fernandez-Ruiz R, Julio PR, Appenzeller S, Niewold TB. Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response. J Rheumatol 2023; 50:1103-1113. [PMID: 37399470 DOI: 10.3899/jrheum.2022-0827] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2023] [Indexed: 07/05/2023]
Abstract
Type I interferon (IFN-I) is thought to play a role in many systemic autoimmune diseases. IFN-I pathway activation is associated with pathogenic features, including the presence of autoantibodies and clinical phenotypes such as more severe disease with increased disease activity and damage. We will review the role and potential drivers of IFN-I dysregulation in 5 prototypic autoimmune diseases: systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, primary Sjögren syndrome, and systemic sclerosis. We will also discuss current therapeutic strategies that directly or indirectly target the IFN-I system.
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Affiliation(s)
- Ana Carolina Londe
- A.C. Londe, MSc, Autoimmunity Lab, and Graduate Program in Physiopathology, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Ruth Fernandez-Ruiz
- R. Fernandez-Ruiz, MD, Department of Medicine, Hospital for Special Surgery, New York, New York, USA
| | - Paulo Rogério Julio
- P. Rogério Julio, MSc, Autoimmunity Lab, and Graduate Program of Child and Adolescent Health, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Simone Appenzeller
- S. Appenzeller, MD, PhD, Autoimmunity Lab, and Rheumatology Unit, Department of Medicine, School of Medical Science, State University of Campinas, Campinas, São Paulo, Brazil
| | - Timothy B Niewold
- T.B. Niewold, MD, Department of Medicine, Hospital for Special Surgery, New York, New York, USA.
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22
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Al Rudaisat M, Chen X, Chen S, Amanullah M, Wang X, Liang Q, Hua C, Zhou C, Song Y, van der Veen S, Cheng H. RNA sequencing and metabolic analysis of imiquimod-induced psoriasis-like mice with chronic restrain stress. Life Sci 2023:121788. [PMID: 37230377 DOI: 10.1016/j.lfs.2023.121788] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/25/2023] [Accepted: 05/15/2023] [Indexed: 05/27/2023]
Abstract
AIM Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective. MAIN METHOD We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis. KEY FINDING We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets. SIGNIFICANCE Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.
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Affiliation(s)
- Mus'ab Al Rudaisat
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Xianzhen Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Siji Chen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Md Amanullah
- Institute of Translational Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Xuewen Wang
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Qichang Liang
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Chunting Hua
- Institute of Translational Medicine, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Can Zhou
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Yinjing Song
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China
| | - Stijn van der Veen
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China; Department of Microbiology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, School of Medicine, Zhejiang University, Hangzhou 310000, China.
| | - Hao Cheng
- Department of Dermatology and Venereology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310000, China.
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23
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Punnanitinont A, Kramer JM. Sex-specific differences in primary Sjögren's disease. FRONTIERS IN DENTAL MEDICINE 2023; 4:1168645. [PMID: 39916928 PMCID: PMC11797869 DOI: 10.3389/fdmed.2023.1168645] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 04/28/2023] [Indexed: 02/09/2025] Open
Abstract
Many autoimmune diseases show a striking female sex predilection, including primary Sjögren's disease (pSD). Patients with pSD display exocrine gland pathology, such as salivary hypofunction and salivary and lacrimal gland inflammation. Moreover, many serious systemic disease manifestations are well-documented, including interstitial nephritis, hypergammaglobulinemia and neuropathies. Of note, women and men with pSD display distinct clinical phenotypes. While the underlying reasons for these clinical observations were poorly understood for many years, recent studies provide mechanistic insights into the specific regulatory landscapes that mediate female susceptibility to autoimmunity. We will review factors that contribute to the female sex bias, with an emphasis on those that are most relevant to pSD pathogenesis. Specifically, we will focus on sex hormones in disease, genetic alterations that likely contribute to the significant disease prevalence in females, and studies that provide evidence for the role of the gut microbiota in disease. Lastly, we will discuss therapeutics that are in clinical trials for pSD that may be particularly efficacious in targeting signaling networks that mediate inflammation in a sex-specific manner.
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Affiliation(s)
| | - Jill M. Kramer
- Department of Oral Biology, School of Dental Medicine, The University at Buffalo, State University of New York, Buffalo, NY, United States
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24
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Young KZ, Dimitrion P, Zhou L, Adrianto I, Mi QS. Sex-biased immunological processes drive hidradenitis suppurativa. Front Immunol 2023; 14:1167021. [PMID: 37215102 PMCID: PMC10192729 DOI: 10.3389/fimmu.2023.1167021] [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: 02/15/2023] [Accepted: 04/13/2023] [Indexed: 05/24/2023] Open
Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition that can manifest with abscesses, sinus tracts, and scarring in the intertriginous areas of the body. HS is characterized by immune dysregulation, featuring elevated levels of myeloid cells, T helper (Th) cells, and pro-inflammatory cytokines, particularly those involved in Th1- and Th17-mediated immunity. In most epidemiological studies, HS shows a strong female sex bias, with reported female-to-male ratios estimated at roughly 3:1, suggesting that sex-related factors contribute to HS pathophysiology. In this article, we review the role of intrinsic and extrinsic factors that contribute to immunological differences between the sexes and postulate their role in the female sex bias observed in HS. We discuss the effects of hormones, X chromosome dosage, genetics, the microbiome, and smoking on sex-related differences in immunity to postulate potential immunological mechanisms in HS pathophysiology. Future studies are required to better characterize sex-biased factors that contribute to HS disease presentations.
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Affiliation(s)
- Kelly Z. Young
- Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, United States
- University of Michigan Medical School, Ann Arbor, MI, United States
| | - Peter Dimitrion
- Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, United States
- Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, United States
- Cancer Biology Graduate Program, School of Medicine, Wayne State University, Detroit, MI, United States
| | - Li Zhou
- Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, United States
- Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, United States
- Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, United States
| | - Indra Adrianto
- Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, United States
- Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, United States
- Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, United States
- Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, United States
| | - Qing-Sheng Mi
- Center for Cutaneous Biology and Immunology Research, Department of Dermatology, Henry Ford Health, Detroit, MI, United States
- Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, United States
- Cancer Biology Graduate Program, School of Medicine, Wayne State University, Detroit, MI, United States
- Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, United States
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25
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Herrera E, Pérez-Sánchez MDC, San Miguel-Abella R, Barrenechea A, Blanco C, Solares L, González L, Iza C, Castro I, Nicolás E, Sierra D, Suárez P, González-Nosti M. Cognitive impairment in young adults with post COVID-19 syndrome. Sci Rep 2023; 13:6378. [PMID: 37076533 PMCID: PMC10113715 DOI: 10.1038/s41598-023-32939-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 04/05/2023] [Indexed: 04/21/2023] Open
Abstract
In this study, we aimed to examine different cognitive domains in a large sample of patients with post COVID-19 syndrome. Two hundred and fourteen patients, 85.04% women, ranged 26 to 64 years (mean = 47.48 years) took part in this investigation. Patients' processing speed, attention, executive functions and various language modalities were examined online using a comprehensive task protocol designed for this research. Alteration in some of the tasks was observed in 85% of the participants, being the attention and executive functions tests the ones that show the highest percentage of patients with severe impairment. Positive correlations were observed between the age of the participants in almost all the tasks assessed, implying better performance and milder impairment with increasing age. In the comparisons of patients according to age, the oldest patients were found to maintain their cognitive functions relatively preserved, with only a mild impairment in attention and speed processing, while the youngest showed the most marked and heterogeneous cognitive impairment. These results confirm the subjective complaints in patients with post COVID-19 syndrome and, thanks to the large sample size, allow us to observe the effect of patient age on performance, an effect never reported before in patients with these characteristics.
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Affiliation(s)
- Elena Herrera
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | | | | | | | - Claudia Blanco
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Lucía Solares
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Lucía González
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Clara Iza
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Isabel Castro
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Elena Nicolás
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Damián Sierra
- Department of Psychology, University of Oviedo, Oviedo, Spain
| | - Paula Suárez
- Department of Psychology, University of Oviedo, Oviedo, Spain
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26
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Tartar T, Akdeniz I, Onalan E, Bakal U, Sarac M, Genc E, Kaymaz T, Kazez A. Investigation of VGLL3 and sub-target genes in the aetiology of paediatric acute appendicitis: a prospective case-control study. Pediatr Surg Int 2023; 39:169. [PMID: 37029824 DOI: 10.1007/s00383-023-05462-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/03/2023] [Indexed: 04/09/2023]
Abstract
PURPOSE Vestigial like family member 3 (VGLL3) and its sub-target genes show considerable transcriptomic overlap in terms of several autoimmune and inflammatory diseases. Herein, we investigated the role of VGLL3 rs13074432 polymorphism and its sub-target genes in the aetiology of acute appendicitis (AA). METHODS In this prospective case-control study, we included 250 patients (age, 0-18 years) who underwent appendectomy with the diagnosis of AA (patient group; blood and appendix tissue samples) and 200 healthy children (control group; only blood samples) without appendectomy. ELISA method was used for protein-level detection of VGLL3 and sub-target genes expression change in obtained tissue samples, and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used for mRNA level detection. Genotyping analyses were performed on DNA samples isolated from blood using TaqMan SNP genotyping test. RESULTS The frequency of TT variant genotype (p < 0.001) and T allele (p = 0.002) showed a significant decrease in the patient group compared with the control group. No significant correlation was observed between the expression of VGLL3 in the appendiceal tissue and patient clinical and demographic data (p > 0.050). CONCLUSION This study revealed that the VGLL3 gene and its sub-target genes are associated with AA aetiology.
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Affiliation(s)
- Tugay Tartar
- Department of Pediatric Surgery, Firat University Faculty of Medicine, 23119, Elazig, Turkey.
| | - Ibrahim Akdeniz
- Department of Pediatric Surgery, Fethi Sekin City Hospital, 23280, Elazig, Turkey
| | - Ebru Onalan
- Department of Medical Biology and Genetics, Firat University Faculty of Medicine, 23119, Elazig, Turkey
| | - Unal Bakal
- Department of Pediatric Surgery, Firat University Faculty of Medicine, 23119, Elazig, Turkey
| | - Mehmet Sarac
- Department of Pediatric Surgery, Adiyaman University Faculty of Medicine, 02200, Elazig, Turkey
| | - Ercan Genc
- Department of Pediatric Surgery, Firat University Faculty of Medicine, 23119, Elazig, Turkey
| | - Tugce Kaymaz
- Department of Medical Biology and Genetics, Firat University Faculty of Medicine, 23119, Elazig, Turkey
| | - Ahmet Kazez
- Department of Pediatric Surgery, Firat University Faculty of Medicine, 23119, Elazig, Turkey
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27
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Infectious mononucleosis is associated with an increased incidence of Crohn's disease: results from a cohort study of 31 862 outpatients in Germany. Eur J Gastroenterol Hepatol 2023; 35:255-260. [PMID: 36708295 DOI: 10.1097/meg.0000000000002505] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE The pathogenesis of inflammatory bowel disease (IBD) has not been fully uncovered to date. Epstein-Barr-Virus (EBV) infection has recently been associated with the pathogenesis of multiple sclerosis, suggesting a general link between EBV and autoimmune diseases. However, data on an association between EBV and IBD have remained inconclusive. This study aims at evaluating an association between EBV and the development of IBD. METHODS This retrospective cohort study included 15 931 patients with and 15 931 matched patients without infectious mononucleosis from the Disease Analyzer database (IQVIA) between 2000 and 2018. Incidences of Crohn's disease and ulcerative colitis were evaluated using Cox regression models. RESULTS Within 5 years of the index date, the cumulative incidence of IBD was 124 and 90 cases per 100 000 person-years among patients with and without infectious mononucleosis, respectively (P = 0.040). In regression analyses, infectious mononucleosis was significantly associated with IBD [hazard ratios (HR), 1.35; 95% confidence interval (CI), 1.01-1.81]. Subgroup analyses revealed an association between infectious mononucleosis and Crohn's disease (HR, 1.93; 95% CI, 1.22-3.05) but not ulcerative colitis (HR, 1.03; 95% CI, 0.70-1.51). This association was strongest in patients between 14 and 20 years (HR, 4.50; 95% CI, 1.55-13.13) and was only observed in females (HR, 2.51; 95% CI, 1.39-4.53). CONCLUSION Infectious mononucleosis is significantly associated with an increased incidence of Crohn's disease but not ulcerative colitis, especially in young female patients. Our data support the hypothesis of a pathophysiological involvement of EBV in the development of Crohn's disease and should trigger molecular research to further dissect the pathophysiology of IBD.
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28
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Horii Y, Matsuda S, Toyota C, Morinaga T, Nakaya T, Tsuchiya S, Ohmuraya M, Hironaka T, Yoshiki R, Kasai K, Yamauchi Y, Takizawa N, Nagasaka A, Tanaka A, Kosako H, Nakaya M. VGLL3 is a mechanosensitive protein that promotes cardiac fibrosis through liquid-liquid phase separation. Nat Commun 2023; 14:550. [PMID: 36754961 PMCID: PMC9908974 DOI: 10.1038/s41467-023-36189-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 01/17/2023] [Indexed: 02/10/2023] Open
Abstract
Myofibroblasts cause tissue fibrosis by producing extracellular matrix proteins, such as collagens. Humoral factors like TGF-β, and matrix stiffness are important for collagen production by myofibroblasts. However, the molecular mechanisms regulating their ability to produce collagen remain poorly characterised. Here, we show that vestigial-like family member 3 (VGLL3) is specifically expressed in myofibroblasts from mouse and human fibrotic hearts and promotes collagen production. Further, substrate stiffness triggers VGLL3 translocation into the nucleus through the integrin β1-Rho-actin pathway. In the nucleus, VGLL3 undergoes liquid-liquid phase separation via its low-complexity domain and is incorporated into non-paraspeckle NONO condensates containing EWS RNA-binding protein 1 (EWSR1). VGLL3 binds EWSR1 and suppresses miR-29b, which targets collagen mRNA. Consistently, cardiac fibrosis after myocardial infarction is significantly attenuated in Vgll3-deficient mice, with increased miR-29b expression. Overall, our results reveal an unrecognised VGLL3-mediated pathway that controls myofibroblasts' collagen production, representing a novel therapeutic target for tissue fibrosis.
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Affiliation(s)
- Yuma Horii
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Shoichi Matsuda
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Chikashi Toyota
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takumi Morinaga
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Takeo Nakaya
- Department of Pathology, Jichi Medical University, Tochigi, Japan
| | - Soken Tsuchiya
- Department of Pharmaceutical Biochemistry, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
| | - Masaki Ohmuraya
- Department of Genetics, Hyogo College of Medicine, Hyogo, Japan
| | - Takanori Hironaka
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Ryo Yoshiki
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Kotaro Kasai
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuto Yamauchi
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Noburo Takizawa
- Department of Disease Control, Kyushu University, Fukuoka, Japan.,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akiomi Nagasaka
- Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
| | - Akira Tanaka
- Department of Pathology, Jichi Medical University, Tochigi, Japan
| | - Hidetaka Kosako
- Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima, Japan
| | - Michio Nakaya
- Department of Disease Control, Kyushu University, Fukuoka, Japan. .,Department of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan. .,AMED-PRIME, Japan Agency for Medical Research and Development, Tokyo, Japan.
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29
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Singh G. Is Chronic Pain as an Autoimmune Disease? Can J Pain 2023. [DOI: 10.1080/24740527.2023.2175205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Affiliation(s)
- Gurmit Singh
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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30
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Miyagawa F. Current Knowledge of the Molecular Pathogenesis of Cutaneous Lupus Erythematosus. J Clin Med 2023; 12:987. [PMID: 36769633 PMCID: PMC9918007 DOI: 10.3390/jcm12030987] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 01/23/2023] [Accepted: 01/24/2023] [Indexed: 02/01/2023] Open
Abstract
Cutaneous lupus erythematosus (CLE) is an autoimmune disease, which can be limited to the skin or associated with systemic lupus erythematosus (SLE). Gene expression analysis has revealed that both the innate and adaptive immune pathways are activated in CLE. Ultraviolet (UV) light, the predominant environmental factor associated with CLE, induces apoptosis in keratinocytes, and the endogenous nucleic acids released from the apoptotic cells are recognized via pattern recognition receptors, including Toll-like receptors. This leads to the production of type I interferon, a major contributor to the pathogenesis of CLE, by plasmacytoid dendritic cells. UV irradiation can also induce the externalization of autoantigens, such as SS-A/Ro, exposing them to circulating autoantibodies. T-helper 1 cells have been reported to play important roles in the adaptive immune response to CLE. Other environmental factors associated with CLE include drugs and cigarette smoke. Genetic factors also confer a predisposition to the development of CLE, and many susceptibility genes have been identified. Monogenetic forms of CLE also exist. This article aims to review current knowledge about the pathogenesis of CLE. A better understanding of the environmental, genetic, and immunoregulatory factors that drive CLE may provide important insights for the treatment of CLE.
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Affiliation(s)
- Fumi Miyagawa
- Department of Dermatology, Nara Medical University School of Medicine, 840 Shijo, Kashihara, Nara 634-8522, Japan
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31
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Kerick M, Acosta-Herrera M, Simeón-Aznar CP, Callejas JL, Assassi S, Proudman SM, Nikpour M, Hunzelmann N, Moroncini G, de Vries-Bouwstra JK, Orozco G, Barton A, Herrick AL, Terao C, Allanore Y, Fonseca C, Alarcón-Riquelme ME, Radstake TRDJ, Beretta L, Denton CP, Mayes MD, Martin J. Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis. NPJ Genom Med 2022; 7:57. [PMID: 36198672 PMCID: PMC9534873 DOI: 10.1038/s41525-022-00327-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 09/22/2022] [Indexed: 11/16/2022] Open
Abstract
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals.
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Affiliation(s)
- Martin Kerick
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
| | - Marialbert Acosta-Herrera
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
- Systemic Autoimmune Disease Unit, Hospital Clínico San Cecilio, Instituto de Investigación Biosanitaria Ibs. GRANADA, Granada, Spain.
| | | | | | - Shervin Assassi
- Department of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Susanna M Proudman
- Rheumatology Unit, Royal Adelaide Hospital and University of Adelaide, Adelaide, SA, Australia
| | - Mandana Nikpour
- The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia
| | | | - Gianluca Moroncini
- Department of Clinical and Molecular Science, Università Politecnica delle Marche e Ospedali Riuniti, Ancona, Italy
| | | | - Gisela Orozco
- Center for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Center, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Anne Barton
- Center for Genetics and Genomics Versus Arthritis, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Center, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Ariane L Herrick
- Division of Musculoskeletal and Dermatological Sciences, The University of Manchester, Northern care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Chikashi Terao
- Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan
| | - Yannick Allanore
- Department of Rheumatology A, Hospital Cochin, Paris, Île-de-France, France
| | - Carmen Fonseca
- Center for Rheumatology, Royal Free and University College Medical School, London, UK
| | - Marta Eugenia Alarcón-Riquelme
- Center for Genomics and Oncological Research (GENYO), Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain
| | - Timothy R D J Radstake
- Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lorenzo Beretta
- Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy
| | - Christopher P Denton
- Center for Rheumatology, Royal Free and University College Medical School, London, UK
| | - Maureen D Mayes
- Department of Rheumatology, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Javier Martin
- Department of Cell Biology and Immunology, Institute of Parasitology and Biomedicine López-Neyra, CSIC, Granada, Spain.
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32
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Wijdeven RH, Cabukusta B, Behr FM, Qiu X, Amiri D, Borras DM, Arens R, Liang Y, Neefjes J. CRISPR Activation Screening Identifies VGLL3–TEAD1–RUNX1/3 as a Transcriptional Complex for PD-L1 Expression. THE JOURNAL OF IMMUNOLOGY 2022; 209:907-915. [DOI: 10.4049/jimmunol.2100917] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 06/24/2022] [Indexed: 11/06/2022]
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Yuan H, Ikegame M, Fukuhara Y, Takemoto F, Yu Y, Teramachi J, Weng Y, Guo J, Yamada D, Takarada T, Li Y, Okamura H, Zhang B. Vestigial-Like 3 Plays an Important Role in Osteoblast Differentiation by Regulating the Expression of Osteogenic Transcription Factors and BMP Signaling. Calcif Tissue Int 2022; 111:331-344. [PMID: 35750933 DOI: 10.1007/s00223-022-00997-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 06/01/2022] [Indexed: 11/02/2022]
Abstract
Our previous gene profiling analysis showed that the transcription cofactor vestigial-like 3 (VGLL3) gene expression was upregulated by mechanical tension in the mouse cranial suture, coinciding with accelerated osteoblast differentiation. Therefore, we hypothesized that VGLL3 plays a significant role in osteogenic differentiation. To clarify the function of VGLL3 in osteoblasts, we examined its expression characteristics in mouse bone tissue and the osteoblastic cell line MC3T3-E1. We further examined the effects of Vgll3 knockdown on osteoblast differentiation and bone morphogenetic protein (BMP) signaling. In the mouse cranial suture, where membranous ossification occurs, VGLL3 was immunohistochemically detected mostly in the nucleus of osteoblasts, preosteoblasts, and fibroblastic cells. VGLL3 expression in MC3T3-E1 cells was transient and peaked at a relatively early stage of differentiation. RNA sequencing revealed that downregulated genes in Vgll3-knockdown cells were enriched in gene ontology terms associated with osteoblast differentiation. Interestingly, most of the upregulated genes were related to cell division. Targeted Vgll3 knockdown markedly suppressed the expression of major osteogenic transcription factors (Runx2, Sp7/osterix, and Dlx5) and osteoblast differentiation. It also attenuated BMP signaling; moreover, exogenous BMP2 partially restore osteogenic transcription factors' expression in Vgll3-knockdown cells. Furthermore, overexpression of Vgll3 increased the expression of osteogenic transcription factors. These results suggest that VGLL3 plays a critical role in promoting osteoblast differentiation and that part of the process is mediated by BMP signaling. Further elucidation of VGLL3 function will increase our understanding of osteogenesis and skeletal disease etiology.
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Affiliation(s)
- Haoze Yuan
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Hard Tissue Development and Regeneration, 246 Xuefu Road, Nangang, Harbin, 150001, Heilongjiang, People's Republic of China
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Mika Ikegame
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan.
| | - Yoko Fukuhara
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Fumiko Takemoto
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
- Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yaqiong Yu
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
- Department of Endodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, P.R. China
| | - Jumpei Teramachi
- Department of Oral Function & Anatomy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yao Weng
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Jiajie Guo
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
- Department of Endodontics, School and Hospital of Stomatology, China Medical University, Liaoning Provincial Key Laboratory of Oral Diseases, Shenyang, P.R. China
| | - Daisuke Yamada
- Department of Regenerative Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University , Okayama, Japan
| | - Takeshi Takarada
- Department of Regenerative Science, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University , Okayama, Japan
| | - Ying Li
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Hard Tissue Development and Regeneration, 246 Xuefu Road, Nangang, Harbin, 150001, Heilongjiang, People's Republic of China
| | - Hirohiko Okamura
- Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8525, Japan
| | - Bin Zhang
- Institute of Hard Tissue Development and Regeneration, The Second Affiliated Hospital of Harbin Medical University, Heilongjiang Provincial Key Laboratory of Hard Tissue Development and Regeneration, 246 Xuefu Road, Nangang, Harbin, 150001, Heilongjiang, People's Republic of China.
- Heilongjiang Academy of Medical Sciences, Harbin, 150001, Heilongjiang, P.R. China.
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Du Y, Cui R, Tian N, Chen M, Zhang XL, Dai SM. Regulation of type I interferon signature by VGLL3 in the fibroblast-like synoviocytes of rheumatoid arthritis patients via targeting the Hippo pathway. Arthritis Res Ther 2022; 24:188. [PMID: 35941675 PMCID: PMC9358906 DOI: 10.1186/s13075-022-02880-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 07/23/2022] [Indexed: 11/28/2022] Open
Abstract
Background The upregulation of interferon (IFN)-stimulated genes induced by type I IFNs (namely type I IFN signature) in rheumatoid arthritis (RA) patients had implications in early diagnosis and prediction of therapy responses. However, factors that modulate the type I IFN signature in RA are largely unknown. In this study, we aim to explore the involvement of VGLL3, a homologue of the vestigial-like gene in Drosophila and a putative regulator of the Hippo pathway, in the modulation of type I IFN signature in the fibroblast-like synoviocytes (FLS) of RA patients. Methods FLS were isolated from RA and osteoarthritis (OA) patients. Expression of VGLL3 in the synovial tissues and FLS was analyzed by immunohistochemistry and PCR. RNA sequencing was performed in RA-FLS upon VGLL3 overexpression. The expression of IFN-stimulated genes was examined by PCR and Western blotting. Results VGLL3 was upregulated in the RA synovium and RA-FLS compared to OA. Overexpression of VGLL3 promoted the expression of IFN-stimulated genes in RA-FLS. The expression of STAT1 and MX1 was also upregulated in RA synovium compared to OA and was associated with the expression of VGLL3 in RA and OA patients. VGLL3 promoted the IRF3 activation and IFN-β1 expression in RA-FLS. Increased IFN-β1 induced the expression of IFN-stimulated genes in RA-FLS in an autocrine manner. VGLL3 also modulated the expression of the Hippo pathway molecules WWTR1 and AMOTL2, which mediated the regulation of IRF3 activation and IFN-β1 production by VGLL3 in RA-FLS. Conclusions VGLL3 drives the IRF3-induced IFN-β1 expression in RA-FLS by inhibiting WWTR1 expression and subsequently promotes the type I IFN signature expression in RA-FLS through autocrine IFN-β1 signaling.
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Affiliation(s)
- Yu Du
- Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Ran Cui
- Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Na Tian
- Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Miao Chen
- Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China
| | - Xian-Long Zhang
- Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Sheng-Ming Dai
- Department of Rheumatology and Immunology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, Shanghai, 200233, China.
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35
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Jiwrajka N, Anguera MC. The X in seX-biased immunity and autoimmune rheumatic disease. J Exp Med 2022; 219:e20211487. [PMID: 35510951 PMCID: PMC9075790 DOI: 10.1084/jem.20211487] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/04/2022] [Accepted: 03/31/2022] [Indexed: 01/07/2023] Open
Abstract
Sexual dimorphism in the composition and function of the human immune system has important clinical implications, as males and females differ in their susceptibility to infectious diseases, cancers, and especially systemic autoimmune rheumatic diseases. Both sex hormones and the X chromosome, which bears a number of immune-related genes, play critical roles in establishing the molecular basis for the observed sex differences in immune function and dysfunction. Here, we review our current understanding of sex differences in immune composition and function in health and disease, with a specific focus on the contribution of the X chromosome to the striking female bias of three autoimmune rheumatic diseases.
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Affiliation(s)
- Nikhil Jiwrajka
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
- Division of Rheumatology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | - Montserrat C. Anguera
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA
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36
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Concepts in lupus pathophysiology: Lessons learned from disease across the spectrum. Clin Immunol 2022; 238:109021. [DOI: 10.1016/j.clim.2022.109021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 11/22/2022]
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Fernandez-Ruiz R, Niewold TB. Type I Interferons in Autoimmunity. J Invest Dermatol 2022; 142:793-803. [PMID: 35016780 PMCID: PMC8860872 DOI: 10.1016/j.jid.2021.11.031] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 11/08/2021] [Accepted: 11/10/2021] [Indexed: 12/30/2022]
Abstract
Dysregulated IFN-1 responses play crucial roles in the development of multiple forms of autoimmunity. Many patients with lupus, systemic sclerosis, Sjogren's syndrome, and dermatomyositis demonstrate enhanced IFN-1 signaling. IFN-1 excess is associated with disease severity and autoantibodies and could potentially predict response to newer therapies targeting IFN-1 pathways. In this review, we provide an overview of the signaling pathway and immune functions of IFN-1s in health and disease. We also review the systemic autoimmune diseases classically associated with IFN-1 upregulation and current therapeutic strategies targeting the IFN-1 system.
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Affiliation(s)
- Ruth Fernandez-Ruiz
- Division of Rheumatology, Department of Medicine, NYU Grossman School of Medicine, New York, New York, USA
| | - Timothy B Niewold
- Judith & Stewart Colton Center for Autoimmunity, Department of Medicine Research, NYU Grossman School of Medicine, New York, New York, USA.
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ErbB4 Is a Potential Key Regulator of the Pathways Activated by NTRK-Fusions in Thyroid Cancer. APPLIED SCIENCES-BASEL 2022. [DOI: 10.3390/app12052506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
NTRK gene fusions are drivers of tumorigenesis events that specific Trk-inhibitors can target. Current knowledge of the downstream pathways activated has been previously limited to the pathways of regulator proteins phosphorylated directly by Trk receptors. Here, we aimed to detect genes whose expression is increased in response to the activation of these pathways. We identified and analyzed differentially expressed genes in thyroid cancer samples with NTRK1 or NTRK3 gene fusions, and without any NTRK fusions, versus normal thyroid gland tissues, using data from the Cancer Genome Atlas, the DESeq2 tool, and the Genome Enhancer and geneXplain platforms. Searching for the genes activated only in samples with an NTRK fusion as opposed to those without NTRK fusions, we identified 29 genes involved in nervous system development, including AUTS2, DTNA, ERBB4, FLRT2, FLRT3, RPH3A, and SCN4A. We found that genes regulating the expression of the upregulated genes (i.e., upstream regulators) were enriched in the “signaling by ERBB4” pathway. ERBB4 was also one of three genes encoding master regulators whose expression was increased only in samples with an NTRK fusion. Moreover, the algorithm searching for positive feedback loops for gene promoters and transcription factors (a so-called “walking pathways” algorithm) identified the ErbB4 protein as the key master regulator. ERBB4 upregulation (p-value = 0.004) was confirmed in an independent sample of ETV6-NTRK3-positive FFPE specimens. Thus, ErbB4 is the potential key regulator of the pathways activated by NTRK gene fusions in thyroid cancer. These results are preliminary and require additional biochemical validation.
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Abstract
Despite numerous studies of immune sexual dimorphism, sexual differences are not rigorously mapped and dimorphic mechanisms are incompletely understood. Current immune research typically studies sex differences in specific cells, tissues, or diseases but without providing an integrated picture. To connect the dots, we suggest comprehensive research approaches to better our understanding of immune sexual dimorphism and its mechanisms.
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Affiliation(s)
- Shani Talia Gal-Oz
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Tal Shay
- Department of Life Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
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40
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Berzosa M, Nemeskalova A, Zúñiga-Ripa A, Salvador-Bescós M, Larrañeta E, Donnelly RF, Gamazo C, Irache JM. Immune Response after Skin Delivery of a Recombinant Heat-Labile Enterotoxin B Subunit of Enterotoxigenic Escherichia coli in Mice. Pharmaceutics 2022; 14:pharmaceutics14020239. [PMID: 35213971 PMCID: PMC8875158 DOI: 10.3390/pharmaceutics14020239] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/18/2022] [Accepted: 01/18/2022] [Indexed: 02/07/2023] Open
Abstract
Enterotoxigenic Escherichia coli (ETEC) infections have been identified as a major cause of acute diarrhoea in children in developing countries, associated with substantial morbidity and mortality rates. Additionally, ETEC remains the most common cause of acute diarrhea of international travellers to endemic areas. The heat-labile toxin (LT) is a major virulence factor of ETEC, with a significant correlation between the presence of antibodies against LT and protection in infected patients. In the present work, we constructed a recombinant LTB unit (rLTB) and studied the capacity of this toxoid incorporated in microneedles (rLTB-MN) to induce a specific immune response in mice. MN were prepared from aqueous blends of the polymer Gantrez AN® [poly (methyl vinyl ether-co-maleic anhydride)], which is not cytotoxic and has been shown to possess immunoadjuvant properties. The mechanical and dissolution properties of rLTB-MNs were evaluated in an in vitro Parafilm M® model and in mice and pig skin ex vivo models. The needle insertion ranged between 378 µm and 504 µm in Parafilm layers, and MNs fully dissolved within 15 min of application inside porcine skin. Moreover, female and male BALB/c mice were immunized through ear skin with one single dose of 5 μg·rLTB in MNs, eliciting significant fecal anti-LT IgA antibodies, higher in female than in male mice. Moreover, we observed an enhanced production of IL-17A by spleen cells in the immunized female mice, indicating a mucosal non-inflammatory and neutralizing mediated response. Further experiments will now be required to validate the protective capacity of this new rLTB-MN formulation against this deadly non-vaccine-preventable disease.
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Affiliation(s)
- Melibea Berzosa
- Department of Microbiology and Parasitology, Institute of Tropical Health, IDISNA, University of Navarra, 31008 Pamplona, Spain; (M.B.); (A.N.); (A.Z.-R.); (M.S.-B.)
| | - Alzbeta Nemeskalova
- Department of Microbiology and Parasitology, Institute of Tropical Health, IDISNA, University of Navarra, 31008 Pamplona, Spain; (M.B.); (A.N.); (A.Z.-R.); (M.S.-B.)
- Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague, Czech Republic
| | - Amaia Zúñiga-Ripa
- Department of Microbiology and Parasitology, Institute of Tropical Health, IDISNA, University of Navarra, 31008 Pamplona, Spain; (M.B.); (A.N.); (A.Z.-R.); (M.S.-B.)
| | - Miriam Salvador-Bescós
- Department of Microbiology and Parasitology, Institute of Tropical Health, IDISNA, University of Navarra, 31008 Pamplona, Spain; (M.B.); (A.N.); (A.Z.-R.); (M.S.-B.)
| | - Eneko Larrañeta
- Medical Biology Centre, School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (E.L.); (R.F.D.)
| | - Ryan F. Donnelly
- Medical Biology Centre, School of Pharmacy, Queen’s University Belfast, 97 Lisburn Road, Belfast BT9 7BL, UK; (E.L.); (R.F.D.)
| | - Carlos Gamazo
- Department of Microbiology and Parasitology, Institute of Tropical Health, IDISNA, University of Navarra, 31008 Pamplona, Spain; (M.B.); (A.N.); (A.Z.-R.); (M.S.-B.)
- Correspondence: (C.G.); (J.M.I.)
| | - Juan M. Irache
- Department of Pharmacy and Pharmaceutical Technology, University of Navarra, 31008 Pamplona, Spain
- Correspondence: (C.G.); (J.M.I.)
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Romhányi D, Szabó K, Kemény L, Sebestyén E, Groma G. Transcriptional Analysis-Based Alterations Affecting Neuritogenesis of the Peripheral Nervous System in Psoriasis. Life (Basel) 2022; 12:111. [PMID: 35054504 PMCID: PMC8778302 DOI: 10.3390/life12010111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 01/03/2022] [Accepted: 01/04/2022] [Indexed: 11/17/2022] Open
Abstract
An increasing amount of evidence indicates the critical role of the cutaneous nervous system in the initiation and maintenance of psoriatic skin lesions by neurogenic inflammation. However, molecular mechanisms affecting cutaneous neurons are largely uncharacterized. Therefore, we reanalyzed a psoriatic RNA sequencing dataset from published transcriptome experiments of nearly 300 individuals. Using the Ingenuity Pathway Analysis software, we associated several hundreds of differentially expressed transcripts (DETs) to nervous system development and functions. Since neuronal projections were previously reported to be affected in psoriasis, we performed an in-depth analysis of neurite formation-related process. Our in silico analysis suggests that SEMA-PLXN and ROBO-DCC-UNC5 regulating axonal growth and repulsion are differentially affected in non-lesional and lesional skin samples. We identified opposing expressional alterations in secreted ligands for axonal guidance signaling (RTN4/NOGOA, NTNs, SEMAs, SLITs) and non-conventional axon guidance regulating ligands, including WNT5A and their receptors, modulating axon formation. These differences in neuritogenesis may explain the abnormal cutaneous nerve filament formation described in psoriatic skin. The processes also influence T-cell activation and infiltration, thus highlighting an additional angle of the crosstalk between the cutaneous nervous system and the immune responses in psoriasis pathogenesis, in addition to the known neurogenic pro-inflammatory mediators.
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Affiliation(s)
- Dóra Romhányi
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
| | - Kornélia Szabó
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- Hungarian Centre of Excellence for Molecular Medicine-University of Szeged Skin Research Group (HCEMM-USZ Skin Research Group), University of Szeged, H-6720 Szeged, Hungary
- Eötvös Loránd Research Network, MTA-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
| | - Lajos Kemény
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- Hungarian Centre of Excellence for Molecular Medicine-University of Szeged Skin Research Group (HCEMM-USZ Skin Research Group), University of Szeged, H-6720 Szeged, Hungary
- Eötvös Loránd Research Network, MTA-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
| | - Endre Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, H-1085 Budapest, Hungary;
| | - Gergely Groma
- Department of Dermatology and Allergology, University of Szeged, H-6720 Szeged, Hungary; (D.R.); (K.S.); (L.K.)
- Eötvös Loránd Research Network, MTA-SZTE Dermatological Research Group, H-6720 Szeged, Hungary
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42
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McClellan S, Pitchaikannu A, Wright R, Bessert D, Iulianelli M, Hazlett LD, Xu S. Prophylactic Knockdown of the miR-183/96/182 Cluster Ameliorates Pseudomonas aeruginosa-Induced Keratitis. Invest Ophthalmol Vis Sci 2021; 62:14. [PMID: 34919120 PMCID: PMC8684302 DOI: 10.1167/iovs.62.15.14] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Purpose Previously, we demonstrated that miR-183/96/182 cluster (miR-183C) knockout mice exhibit decreased severity of Pseudomonas aeruginosa (PA)-induced keratitis. This study tests the hypothesis that prophylactic knockdown of miR-183C ameliorates PA keratitis indicative of a therapeutic potential. Methods Eight-week-old miR-183C wild-type and C57BL/6J inbred mice were used. Locked nucleic acid-modified anti-miR-183C or negative control oligoribonucleotides with scrambled sequences (NC ORNs) were injected subconjunctivally 1 day before and then topically applied once daily for 5 days post-infection (dpi) (strain 19660). Corneal disease was graded at 1, 3, and 5 dpi. Corneas were harvested for RT-PCR, ELISA, immunofluorescence (IF), myeloperoxidase and plate count assays, and flow cytometry. Corneal nerve density was evaluated in flatmounted corneas by IF staining with anti-β-III tubulin antibody. Results Anti-miR-183C downregulated miR-183C in the cornea. It resulted in an increase in IL-1β at 1 dpi, which was decreased at 5 dpi; fewer polymorphonuclear leukocytes (PMNs) at 5 dpi; lower viable bacterial plate count at both 1 and 5 dpi; increased percentages of MHCII+ macrophages (Mϕ) and dendritic cells (DCs), consistent with enhanced activation/maturation; and decreased severity of PA keratitis. Anti-miR-183C treatment in the cornea of naïve mice resulted in a transient reduction of corneal nerve density, which was fully recovered one week after the last anti-miR application. miR-183C targets repulsive axon-guidance receptor molecule Neuropilin 1, which may mediate the effect of anti-miR-183C on corneal nerve regression. Conclusions Prophylactic miR-183C knockdown is protective against PA keratitis through its regulation of innate immunity, corneal innervation, and neuroimmune interactions.
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Affiliation(s)
- Sharon McClellan
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Ahalya Pitchaikannu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Robert Wright
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Denise Bessert
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Mason Iulianelli
- Departments of Biological Sciences and Public Health, College of Liberal Arts and Sciences, Wayne State University, Detroit, Michigan, United States
| | - Linda D Hazlett
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
| | - Shunbin Xu
- Department of Ophthalmology, Visual and Anatomical Sciences, School of Medicine, Wayne State University, Detroit, Michigan, United States
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43
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Shi W, Sheng X, Dorr KM, Hutton JE, Emerson JI, Davies HA, Andrade TD, Wasson LK, Greco TM, Hashimoto Y, Federspiel JD, Robbe ZL, Chen X, Arnold AP, Cristea IM, Conlon FL. Cardiac proteomics reveals sex chromosome-dependent differences between males and females that arise prior to gonad formation. Dev Cell 2021; 56:3019-3034.e7. [PMID: 34655525 PMCID: PMC9290207 DOI: 10.1016/j.devcel.2021.09.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 07/22/2021] [Accepted: 09/23/2021] [Indexed: 01/03/2023]
Abstract
Sex disparities in cardiac homeostasis and heart disease are well documented, with differences attributed to actions of sex hormones. However, studies have indicated sex chromosomes act outside of the gonads to function without mediation by gonadal hormones. Here, we performed transcriptional and proteomics profiling to define differences between male and female mouse hearts. We demonstrate, contrary to current dogma, cardiac sex disparities are controlled not only by sex hormones but also through a sex-chromosome mechanism. Using Turner syndrome (XO) and Klinefelter (XXY) models, we find the sex-chromosome pathway is established by X-linked gene dosage. We demonstrate cardiac sex disparities occur at the earliest stages of heart formation, a period before gonad formation. Using these datasets, we identify and define a role for alpha-1B-glycoprotein (A1BG), showing loss of A1BG leads to cardiac defects in females, but not males. These studies provide resources for studying sex-biased cardiac disease states.
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Affiliation(s)
- Wei Shi
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Xinlei Sheng
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA
| | - Kerry M Dorr
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Josiah E Hutton
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA
| | - James I Emerson
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Haley A Davies
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Tia D Andrade
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Lauren K Wasson
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Todd M Greco
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA
| | - Yutaka Hashimoto
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA
| | - Joel D Federspiel
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA
| | - Zachary L Robbe
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA
| | - Xuqi Chen
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Arthur P Arnold
- Department of Integrative Biology & Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Ileana M Cristea
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, NJ 08544, USA.
| | - Frank L Conlon
- Department of Biology and Genetics, McAllister Heart Institute, UNC-Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
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44
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Lutz CT, Livas L, Presnell SR, Sexton M, Wang P. Gender Differences in Urothelial Bladder Cancer: Effects of Natural Killer Lymphocyte Immunity. J Clin Med 2021; 10:5163. [PMID: 34768683 PMCID: PMC8584838 DOI: 10.3390/jcm10215163] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Revised: 10/13/2021] [Accepted: 10/29/2021] [Indexed: 02/07/2023] Open
Abstract
Men are more likely to develop cancer than women. In fact, male predominance is one of the most consistent cancer epidemiology findings. Additionally, men have a poorer prognosis and an increased risk of secondary malignancies compared to women. These differences have been investigated in order to better understand cancer and to better treat both men and women. In this review, we discuss factors that may cause this gender difference, focusing on urothelial bladder cancer (UBC) pathogenesis. We consider physiological factors that may cause higher male cancer rates, including differences in X chromosome gene expression. We discuss how androgens may promote bladder cancer development directly by stimulating bladder urothelium and indirectly by suppressing immunity. We are particularly interested in the role of natural killer (NK) cells in anti-cancer immunity.
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Affiliation(s)
- Charles T. Lutz
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA; (L.L.); (S.R.P.); (M.S.)
- Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40536, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA;
| | - Lydia Livas
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA; (L.L.); (S.R.P.); (M.S.)
| | - Steven R. Presnell
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA; (L.L.); (S.R.P.); (M.S.)
| | - Morgan Sexton
- Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY 40536, USA; (L.L.); (S.R.P.); (M.S.)
| | - Peng Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA;
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
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45
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Glover K, Mishra D, Singh TRR. Epidemiology of Ocular Manifestations in Autoimmune Disease. Front Immunol 2021; 12:744396. [PMID: 34795665 PMCID: PMC8593335 DOI: 10.3389/fimmu.2021.744396] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Accepted: 10/14/2021] [Indexed: 01/19/2023] Open
Abstract
The global prevalence of autoimmune diseases is increasing. As a result, ocular complications, ranging from minor symptoms to sight-threatening scenarios, associated with autoimmune diseases have also risen. These ocular manifestations can result from the disease itself or treatments used to combat the primary autoimmune disease. This review provides detailed insights into the epidemiological factors affecting the increasing prevalence of ocular complications associated with several autoimmune disorders.
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Affiliation(s)
| | | | - Thakur Raghu Raj Singh
- School of Pharmacy, Medical Biology Centre, Queen’s University Belfast, Belfast, United Kingdom
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46
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Takakura Y, Hori N, Terada N, Machida M, Yamaguchi N, Takano H, Yamaguchi N. VGLL3 activates inflammatory responses by inducing interleukin-1α secretion. FASEB J 2021; 35:e21996. [PMID: 34679187 DOI: 10.1096/fj.202100679rr] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 09/05/2021] [Accepted: 10/04/2021] [Indexed: 01/10/2023]
Abstract
Vestigial-like family member 3 (VGLL3), a member of the vestigial-like family, is a cofactor of the TEA-domain-containing transcription factor (TEAD). Although elevation in VGLL3 expression is associated with inflammatory diseases, such as inflammatory sarcomas and autoimmune diseases, the molecular mechanisms underlying VGLL3-mediated inflammation remain largely unknown. In this study, we analyzed the relationship between elevated VGLL3 expression and the levels of NF-κB, a transcription factor that plays a pivotal role in inflammation. NF-κB was found to be activated in a cell line stably expressing VGLL3. Mechanistically, VGLL3 was shown to promote the expression and secretion of the potent NF-κB-activating cytokine interleukin (IL)-1α, probably through its association with TEADs. As VGLL3 is a target of transforming growth factor β (TGF-β) signaling, we analyzed IL-1α induction upon TGF-β stimulation. TGF-β stimulation was observed to induce IL-1α secretion and NF-κB activation, and VGLL3 was associated with this phenomenon. The TGF-β transcription factors Smad3 and Smad4 were shown to be necessary for inducing VGLL3 and IL-1α expression. Lastly, we found that VGLL3-dependent IL-1α secretion is involved in constitutive NF-κB activation in highly malignant breast cancer cells. Collectively, the findings suggested that VGLL3 expression and TGF-β stimulation activate the inflammatory response by inducing IL-1α secretion.
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Affiliation(s)
- Yuki Takakura
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Naoto Hori
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.,Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Natsumi Terada
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Moeka Machida
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.,Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Naoto Yamaguchi
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Hiroyuki Takano
- Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
| | - Noritaka Yamaguchi
- Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan.,Department of Molecular Cardiovascular Pharmacology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba, Japan
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47
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Popper H, Stacher-Priehse E, Brcic L, Nerlich A. Lung fibrosis in autoimmune diseases and hypersensitivity: how to separate these from idiopathic pulmonary fibrosis. Rheumatol Int 2021; 42:1321-1330. [PMID: 34605934 PMCID: PMC9287245 DOI: 10.1007/s00296-021-05002-2] [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: 07/23/2021] [Accepted: 09/15/2021] [Indexed: 11/29/2022]
Abstract
Lung involvement in autoimmune diseases (AID) is uncommon, but may precede other organ manifestations. A diagnostic problem is chronicity presenting with lung fibrosis. A new category of interstitial pneumonia with autoimmune features for patients with clinical symptoms of AID and presenting with usual interstitial pneumonia (UIP) enables antifibrotic treatment for these patients. Hypersensitivity pneumonia (HP) and other forms of lung fibrosis were not included into this category. As these diseases based on adverse immune reactions often present with unspecific clinical symptoms, a specified pathological diagnosis will assist the clinical evaluation. We aimed to establish etiology-relevant differences of patterns associated with AID or HP combined with lung fibrosis. We retrospectively evaluated 51 cases of AID, and 29 cases of HP with lung fibrosis, and compared these to 24 cases of idiopathic pulmonary fibrosis (UIP/IPF). Subacute AID and HP most often presented with organizing pneumonia (OP), whereas chronicity was associated with UIP. Unspecified fibrosis was seen in a few cases, whereas NSIP pattern was rare. In 9 cases, the underlying etiology could not be defined. Statistically significant features differentiating chronic AID or HP from UIP/IPF are lymphocytic infiltrations into myofibroblastic/fibroblastic foci. Other features significantly associated with AID and HP were granulomas, isolated Langhans giant cells, and protein deposits, but seen in only a minority of cases. A combination of UIP with one of these features enabled a specific etiology-based diagnosis. Besides the antifibrotic drug regimen, additional therapies might be considered.
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Affiliation(s)
- Helmut Popper
- Medical University Graz, Diagnostic and Research Institute of Pathology, Neue Stiftingtalstr. 6, 8036, Graz, Austria.
| | | | - Luka Brcic
- Medical University Graz, Diagnostic and Research Institute of Pathology, Neue Stiftingtalstr. 6, 8036, Graz, Austria
| | - Andreas Nerlich
- Department of Pathology, Teaching Hospital Munich-Bogenhausen, Munich, Germany
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48
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Hartman RJG, Mokry M, Pasterkamp G, den Ruijter HM. Sex-dependent gene co-expression in the human body. Sci Rep 2021; 11:18758. [PMID: 34548535 PMCID: PMC8455523 DOI: 10.1038/s41598-021-98059-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 08/11/2021] [Indexed: 11/09/2022] Open
Abstract
Many pathophysiological mechanisms in human health and disease are dependent on sex. Systems biology approaches are successfully used to decipher human disease etiology, yet the effect of sex on gene network biology is mostly unknown. To address this, we used RNA-sequencing data of over 700 individuals spanning 24 tissues from the Genotype-Tissue Expression project to generate a whole-body gene co-expression map and quantified the sex differences per tissue. We found that of the 13,787 genes analyzed in 24 tissues, 29.5% of the gene co-expression is influenced by sex. For example, skeletal muscle was predominantly enriched with genes co-expressed stronger in males, whereas thyroid primarily contained genes co-expressed stronger in females. This was accompanied by consistent sex differences in pathway enrichment, including hypoxia, epithelial-to-mesenchymal transition, and inflammation over the human body. Furthermore, multi-organ analyses revealed consistent sex-dependent gene co-expression over numerous tissues which was accompanied by enrichment of transcription factor binding motifs in the promoters of these genes. Finally, we show that many sex-biased genes are associated with sex-biased diseases, such as autoimmunity and cancer, and more often the target of FDA-approved drugs than non-sexbiased genes. Our study suggests that sex affects biological gene networks by differences in gene co-expression and that attention to the effect of sex on biological responses to medical drugs is warranted.
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Affiliation(s)
- Robin J G Hartman
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands
| | - Michal Mokry
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.,Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Gerard Pasterkamp
- Central Diagnostics Laboratory, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands
| | - Hester M den Ruijter
- Laboratory of Experimental Cardiology, University Medical Center Utrecht, University Utrecht, Heidelberglaan 100, 3584CX, Utrecht, The Netherlands.
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49
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Xing E, Billi AC, Gudjonsson JE. Sex Bias and Autoimmune Diseases. J Invest Dermatol 2021; 142:857-866. [PMID: 34362556 DOI: 10.1016/j.jid.2021.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 06/03/2021] [Accepted: 06/15/2021] [Indexed: 02/08/2023]
Abstract
Sex bias in immune function has been well-described, and women have been shown to counter immunologically stimulating phenomena such as infection, malignancy, and trauma with more protective responses than men. Heightened immunity in women may also result in a predisposition for loss of self-tolerance and development of autoimmunity, reflected by the overwhelming female sex bias of patients with autoimmune diseases. In this review, we discuss the postulated evolutionary etiologies for sexual dimorphism in immunity. We also review the molecular mechanisms underlying divergent immune responses in men and women, including sex hormone effects, X chromosome dosage, and autosomal sex-biased genes. With increasing evidence that autoimmune disease susceptibility is influenced by numerous hormonal and genetic factors, a comprehensive understanding of these topics may facilitate the development of much-needed targeted therapeutics.
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Affiliation(s)
- Enze Xing
- Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Allison C Billi
- Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Johann E Gudjonsson
- Department of Dermatology, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA; A. Alfred Taubman Medical Research Institute, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
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50
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Alghamdi MF, Redwan EM. Advances in the diagnosis of autoimmune diseases based on citrullinated peptides/proteins. Expert Rev Mol Diagn 2021; 21:685-702. [PMID: 34024239 DOI: 10.1080/14737159.2021.1933946] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Introduction: Autoimmune diseases are still one of the hard obstacles associated with humanity. There are many exogenous and endogenous etiological factors behind autoimmune diseases, which may be combined or dispersed to stimulate the autoimmune responses. Protein citrullination represents one of these factors. Harnessing specific citrullinated proteins/peptides could early predict and/or diagnose some of the autoimmune diseases. Many generations of diagnostic tools based on citrullinated peptides with comparable specificity/sensitivity are available worldwide.Areas covered: In this review, we discuss the deimination reaction behind the citrullination of most known autoantigens targeted, different generations of diagnostic tools based on citrullinated probes with specificity/sensitivity of each as well as newly developed assays. Furthermore, the most advanced molecular analytical tools to detect the citrullinated residues in the biological fluid and their performance are also evaluated, providing new avenues to early detect autoimmune diseases with high accuracy.Expert opinion: With the current specificity/sensitivity tools available for autoimmune disease detection, emphasis must be placed on developing more advance and effective, early, rapid, and simple diagnostic devices for autoimmune disease monitoring (similar to a portable device for sugar test at home). The molecular analytical devices with dual and/or multiplexe functions should be more simplified and invested in clinical laboratories.
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Affiliation(s)
- Mohammed F Alghamdi
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Laboratory Department, University Medical Services Center, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Elrashdy M Redwan
- Biological Sciences Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia.,Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria, Egypt
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