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Houen G. Auto-immuno-deficiency syndromes. Autoimmun Rev 2024; 23:103610. [PMID: 39209011 DOI: 10.1016/j.autrev.2024.103610] [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: 06/10/2024] [Revised: 08/26/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024]
Abstract
Autoimmune diseases constitute a broad, heterogenous group with many diverse and often overlapping symptoms. Even so, they are traditionally classified as either systemic, rheumatic diseases or organ-directed diseases. Several theories exist about autoimmune diseases, including defective self-recognition, altered self, molecular mimicry, bystander activation and epitope spreading. While there is no consensus about these theories, it is generally accepted that genetic, pre-disposing factors in combination with environmental factors can result in autoimmune disease. The relative contribution of genetic and environmental factors varies between diseases, as does the significance of individual contributing factors within related diseases. Among the genetic factors, molecules involved in antigen (Ag) recognition, processing, and presentation stand out (e.g., MHC I and II) together with molecules involved in immune signaling and regulation of cellular interactions (i.e., immuno-phenotypes). Also, various immuno-deficiencies have been linked to development of autoimmune diseases. Among the environmental factors, infections (e.g., viruses) have attracted most attention, but factors modulating the immune system have also been the subject of much research (e.g., sunlight and vitamin D). Multiple sclerosis currently stands out due to a very strong and proven association with Epstein-Barr virus infection, notably in cases of late infection and in cases of EBV-associated mononucleosis. Thus, a common picture is emerging that both systemic and organ-directed autoimmune diseases may appropriately be described as auto-immuno-deficiency syndromes (AIdeSs), a concept that emphasizes and integrates existing knowledge on the role of immuno-deficiencies and chronic infections with development of overlapping disease syndromes with variable frequencies of autoantibodies and/or autoreactive T cells. This review integrates and exemplifies current knowledge on the interplay of genetically determined immuno-phenotypes and chronic infections in the development of AIdeSs.
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Affiliation(s)
- Gunnar Houen
- Department of Neurology and Translational Research Center (TRACE), Rigshospitalet, Nordstjernevej 42, DK-2600 Glostrup, Denmark; Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense, Denmark.
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2
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Kim KM, D'Elia AM, Rodell CB. Hydrogel-based approaches to target hypersensitivity mechanisms underlying autoimmune disease. Adv Drug Deliv Rev 2024; 212:115395. [PMID: 39004347 DOI: 10.1016/j.addr.2024.115395] [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: 11/08/2023] [Revised: 06/23/2024] [Accepted: 07/08/2024] [Indexed: 07/16/2024]
Abstract
A robust adaptive immune response is essential for combatting pathogens. In the wrong context such as due to genetic and environmental factors, however, the same mechanisms crucial for self-preservation can lead to a loss of self-tolerance. Resulting autoimmunity manifests in the development of a host of organ-specific or systemic autoimmune diseases, hallmarked by aberrant immune responses and tissue damage. The prevalence of autoimmune diseases is on the rise, medical management of which focuses primarily on pharmacological immunosuppression that places patients at a risk of side effects, including opportunistic infections and tumorigenesis. Biomaterial-based drug delivery systems confer many opportunities to address challenges associated with conventional disease management. Hydrogels, in particular, can protect encapsulated cargo (drug or cell therapeutics) from the host environment, afford their presentation in a controlled manner, and can be tailored to respond to disease conditions or support treatment via multiplexed functionality. Moreover, localized delivery to affected sites by these approaches has the potential to concentrate drug action at the site, reduce off-target exposure, and enhance patient compliance by reducing the need for frequent administration. Despite their many benefits for the management of autoimmune disease, such biomaterial-based approaches focus largely on the downstream effects of hypersensitivity mechanisms and have a limited capacity to eradicate the disease. In contrast, direct targeting of mechanisms of hypersensitivity reactions uniquely enables prophylaxis or the arrest of disease progression by mitigating the basis of autoimmunity. One promising approach is to induce self-antigen-specific tolerance, which specifically subdues damaging autoreactivity while otherwise retaining the normal immune responses. In this review, we will discuss hydrogel-based systems for the treatment of autoimmune disease, with a focus on those that target hypersensitivity mechanisms head-on. As the field continues to advance, it will expand the range of therapeutic choices for people coping with autoimmune diseases, providing fresh prospects for better clinical outcomes and improved quality of life.
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Affiliation(s)
- Kenneth M Kim
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA.
| | - Arielle M D'Elia
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
| | - Christopher B Rodell
- Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA; School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA.
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Gao ZX, He T, Zhang P, Hu X, Ge M, Xu YQ, Wang P, Pan HF. Epigenetic regulation of immune cells in systemic lupus erythematosus: insight from chromatin accessibility. Expert Opin Ther Targets 2024; 28:637-649. [PMID: 38943564 DOI: 10.1080/14728222.2024.2375372] [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: 03/19/2024] [Accepted: 06/28/2024] [Indexed: 07/01/2024]
Abstract
INTRODUCTION Systemic Lupus Erythematosus (SLE) is a multi-dimensional autoimmune disease involving numerous tissues throughout the body. The chromatin accessibility landscapes in immune cells play a pivotal role in governing their activation, function, and differentiation. Aberrant modulation of chromatin accessibility in immune cells is intimately associated with the onset and progression of SLE. AREAS COVERED In this review, we described the chromatin accessibility landscapes in immune cells, summarized the recent evidence of chromatin accessibility related to the pathogenesis of SLE, and discussed the potential of chromatin accessibility as a valuable option to identify novel therapeutic targets for this disease. EXPERT OPINION Dynamic changes in chromatin accessibility are intimately related to the pathogenesis of SLE and have emerged as a new direction for exploring its epigenetic mechanisms. The differently accessible chromatin regions in immune cells often contain binding sites for transcription factors (TFs) and cis-regulatory elements such as enhancers and promoters, which may be potential therapeutic targets for SLE. Larger scale cohort studies and integrating epigenomic, transcriptomic, and metabolomic data can provide deeper insights into SLE chromatin biology in the future.
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Affiliation(s)
- Zhao-Xing Gao
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Tian He
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Peng Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xiao Hu
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
- Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Man Ge
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-Qing Xu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Peng Wang
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
- Teaching Center for Preventive Medicine, School of Public Health, Anhui Medical University, Hefei, Anhui, China
| | - Hai-Feng Pan
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China
- Department of Epidemiology, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
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Karthikeyan BS, Hyötyläinen T, Ghaffarzadegan T, Triplett E, Orešič M, Ludvigsson J. Prenatal exposure to environmental contaminants and cord serum metabolite profiles in future immune-mediated diseases. JOURNAL OF EXPOSURE SCIENCE & ENVIRONMENTAL EPIDEMIOLOGY 2024; 34:647-658. [PMID: 38678133 PMCID: PMC11303251 DOI: 10.1038/s41370-024-00680-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 04/17/2024] [Accepted: 04/17/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Prenatal exposure to environmental contaminants is a significant health concern because it has the potential to interfere with host metabolism, leading to adverse health effects in early childhood and later in life. Growing evidence suggests that genetic and environmental factors, as well as their interactions, play a significant role in the development of autoimmune diseases. OBJECTIVE In this study, we hypothesized that prenatal exposure to environmental contaminants impacts cord serum metabolome and contributes to the development of autoimmune diseases. METHODS We selected cord serum samples from All Babies in Southeast Sweden (ABIS) general population cohort, from infants who later developed one or more autoimmune-mediated and inflammatory diseases: celiac disease (CD), Crohn's disease (IBD), hypothyroidism (HT), juvenile idiopathic arthritis (JIA), and type 1 diabetes (T1D) (all cases, N = 62), along with matched controls (N = 268). Using integrated exposomics and metabolomics mass spectrometry (MS) based platforms, we determined the levels of environmental contaminants and metabolites. RESULTS Differences in exposure levels were found between the controls and those who later developed various diseases. High contaminant exposure levels were associated with changes in metabolome, including amino acids and free fatty acids. Specifically, we identified marked associations between metabolite profiles and exposure levels of deoxynivalenol (DON), bisphenol S (BPS), and specific per- and polyfluorinated substances (PFAS). IMPACT STATEMENT Abnormal metabolism is a common feature preceding several autoimmune and inflammatory diseases. However, few studies compared common and specific metabolic patterns preceding these diseases. Here we hypothesized that exposure to environmental contaminants impacts cord serum metabolome, which may contribute to the development of autoimmune diseases. We found differences in exposure levels between the controls and those who later developed various diseases, and importantly, on the metabolic changes associated with the exposures. High contaminant exposure levels were associated with specific changes in metabolome. Our study suggests that prenatal exposure to specific environmental contaminants alters the cord serum metabolomes, which, in turn, might increase the risk of various immune-mediated diseases.
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Affiliation(s)
- Bagavathy Shanmugam Karthikeyan
- School of Science and Technology, Örebro University, SE-702 81, Örebro, Sweden
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-702 81, Örebro, Sweden
| | - Tuulia Hyötyläinen
- School of Science and Technology, Örebro University, SE-702 81, Örebro, Sweden
| | | | - Eric Triplett
- Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences University of Florida, Gainesville, 32611-0700, FL, USA
| | - Matej Orešič
- School of Medical Sciences, Faculty of Medicine and Health, Örebro University, SE-702 81, Örebro, Sweden.
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, FI-20520, Finland.
| | - Johnny Ludvigsson
- Crown Princess Victoria's Children's Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, SE-581 85, Sweden
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Mine K, Nagafuchi S, Akazawa S, Abiru N, Mori H, Kurisaki H, Shimoda K, Yoshikai Y, Takahashi H, Anzai K. TYK2 signaling promotes the development of autoreactive CD8 + cytotoxic T lymphocytes and type 1 diabetes. Nat Commun 2024; 15:1337. [PMID: 38351043 PMCID: PMC10864272 DOI: 10.1038/s41467-024-45573-9] [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: 08/16/2023] [Accepted: 01/25/2024] [Indexed: 02/16/2024] Open
Abstract
Tyrosine kinase 2 (TYK2), a member of the JAK family, has attracted attention as a potential therapeutic target for autoimmune diseases. However, the role of TYK2 in CD8+ T cells and autoimmune type 1 diabetes (T1D) is poorly understood. In this study, we generate Tyk2 gene knockout non-obese diabetes (NOD) mice and demonstrate that the loss of Tyk2 inhibits the development of autoreactive CD8+ T-BET+ cytotoxic T lymphocytes (CTLs) by impairing IL-12 signaling in CD8+ T cells and the CD8+ resident dendritic cell-driven cross-priming of CTLs in the pancreatic lymph node (PLN). Tyk2-deficient CTLs display reduced cytotoxicity. Increased inflammatory responses in β-cells with aging are dampened by Tyk2 deficiency. Furthermore, treatment with BMS-986165, a selective TYK2 inhibitor, inhibits the expansion of T-BET+ CTLs, inflammation in β-cells and the onset of autoimmune T1D in NOD mice. Thus, our study reveals the diverse roles of TYK2 in driving the pathogenesis of T1D.
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Affiliation(s)
- Keiichiro Mine
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan.
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
| | - Seiho Nagafuchi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Satoru Akazawa
- Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Norio Abiru
- Department of Endocrinology and Metabolism, Unit of Translational Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
- Midori Clinic, Nagasaki, Japan
| | - Hitoe Mori
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Hironori Kurisaki
- Department of Medical Science and Technology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kazuya Shimoda
- Division of Hematology, Diabetes, and Endocrinology, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Yasunobu Yoshikai
- Division of Host Defense, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
- Liver Center, Saga University Hospital, Saga University, Saga, Japan
| | - Keizo Anzai
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
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Araki Y, Mimura T. Epigenetic Dysregulation in the Pathogenesis of Systemic Lupus Erythematosus. Int J Mol Sci 2024; 25:1019. [PMID: 38256093 PMCID: PMC10816225 DOI: 10.3390/ijms25021019] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/05/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease in which immune disorders lead to autoreactive immune responses and cause inflammation and tissue damage. Genetic and environmental factors have been shown to trigger SLE. Recent evidence has also demonstrated that epigenetic factors contribute to the pathogenesis of SLE. Epigenetic mechanisms play an important role in modulating the chromatin structure and regulating gene transcription. Dysregulated epigenetic changes can alter gene expression and impair cellular functions in immune cells, resulting in autoreactive immune responses. Therefore, elucidating the dysregulated epigenetic mechanisms in the immune system is crucial for understanding the pathogenesis of SLE. In this paper, we review the important roles of epigenetic disorders in the pathogenesis of SLE.
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Affiliation(s)
- Yasuto Araki
- Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama 350-0495, Japan;
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Rizzo F, Houen G. Editorial: Immune evasion mechanisms and their role in the pathogenesis of autoimmune disorders. Front Immunol 2023; 14:1267922. [PMID: 37781356 PMCID: PMC10535089 DOI: 10.3389/fimmu.2023.1267922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 08/22/2023] [Indexed: 10/03/2023] Open
Affiliation(s)
- Fabiana Rizzo
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Gunnar Houen
- Department of Neurology, Rigshospitalet, Research Park, Glostrup, Denmark
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Szałach ŁP, Lisowska KA, Cubała WJ, Barbuti M, Perugi G. The immunomodulatory effect of lithium as a mechanism of action in bipolar disorder. Front Neurosci 2023; 17:1213766. [PMID: 37662097 PMCID: PMC10469704 DOI: 10.3389/fnins.2023.1213766] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 08/04/2023] [Indexed: 09/05/2023] Open
Abstract
Bipolar disorder (BD) is a chronic mental disorder characterized by recurrent episodes of mania and depression alternating with periods of euthymia. Although environmental and genetic factors have been described, their pathogenesis is not fully understood. Much evidence suggests a role for inflammatory mediators and immune dysregulation in the development of BD. The first-line treatment in BD are mood-stabilizing agents, one of which is lithium (Li) salts. The Li mechanism of action is not fully understood, but it has been proposed that its robust immunomodulatory properties might be one of the mechanisms responsible for its effectiveness. In this article, the authors present the current knowledge about immune system changes accompanying BD, as well as the immunomodulatory effect of lithium. The results of studies describing connections between immune system changes and lithium effectiveness are often incoherent. Further research is needed to understand the connection between immune system modulation and the therapeutic action of lithium in BD.
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Affiliation(s)
- Łukasz P. Szałach
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Katarzyna A. Lisowska
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Wiesław J. Cubała
- Department of Psychiatry, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Margherita Barbuti
- Psychiatry Unit 2, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Giulio Perugi
- Psychiatry Unit 2, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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Lagacé F, D’Aguanno K, Prosty C, Laverde-Saad A, Cattelan L, Ouchene L, Oliel S, Genest G, Doiron P, Richer V, Jfri A, O’Brien E, Lefrançois P, Powell M, Moreau L, Litvinov IV, Muntyanu A, Netchiporouk E. The Role of Sex and Gender in Dermatology - From Pathogenesis to Clinical Implications. J Cutan Med Surg 2023; 27:NP1-NP36. [PMID: 37401812 PMCID: PMC10486181 DOI: 10.1177/12034754231177582] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 03/29/2023] [Accepted: 04/09/2023] [Indexed: 07/05/2023]
Abstract
BACKGROUND Sex and gender have increasingly been recognized as significant risk factors for many diseases, including dermatological conditions. Historically, sex and gender have often been grouped together as a single risk factor in the scientific literature. However, both may have a distinct impact on disease incidence, prevalence, clinical presentation, severity, therapeutic response, and associated psychological distress. OBJECTIVES AND PROJECT DESCRIPTION The mechanisms that underlie differences in skin diseases between males, females, men, and women remain largely unknown. The specific objectives of this review paper are:To highlight the biological differences between males and females (sex), as well as the sociocultural differences between men and women (gender) and how they impact the integumentary system.To perform a literature review to identify important sex- and gender-related epidemiological and clinical differences for various skin conditions belonging to a range of disease categories and to discuss possible biological and sociocultural factors that could explain the observed differences.To discuss dermatological skin conditions and gender-affirming treatments within the transgender community, a population of individuals who have a gender identity which is different than the gender identity they were assigned at birth. FUTURE IMPACT With the rising number of individuals that identify as non-binary or transgender within our increasingly diverse communities, it is imperative to recognize gender identity, gender, and sex as distinct entities. By doing so, clinicians will be able to better risk-stratify their patients and select treatments that are most aligned with their values. To our knowledge, very few studies have separated sex and gender as two distinct risk factors within the dermatology literature. Our article also has the potential to help guide future prevention strategies that are patient-tailored rather than using a universal approach.
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Affiliation(s)
- François Lagacé
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | | | - Connor Prosty
- Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Alexandra Laverde-Saad
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Leila Cattelan
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Lydia Ouchene
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Sarah Oliel
- Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Genevieve Genest
- Division of Allergy and Immunology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Philip Doiron
- Division of Dermatology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vincent Richer
- Department of Dermatology and Skin Science, University of British Columbia, Vancouver, BC, Canada
| | - Abdulhadi Jfri
- Department of Dermatology, Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Elizabeth O’Brien
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Philippe Lefrançois
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Mathieu Powell
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Linda Moreau
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Ivan V. Litvinov
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Anastasiya Muntyanu
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
| | - Elena Netchiporouk
- Division of Dermatology, Faculty of Medicine, McGill University, Montréal, Québec, Canada
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Zhang T, Xie Q, Wang L, Wang Y, Yan Z, Li Z, Teng Y, Xu Z, Chen Y, Pan F, Tao J, Cai J, Liang C, Pan H, Su H, Cheng J, Hu W, Zou Y. Impact of climate factors and climate-gene interaction on systemic lupus erythematosus patients' response to glucocorticoids therapy. J Clin Lab Anal 2023; 37:e24945. [PMID: 37488812 PMCID: PMC10492452 DOI: 10.1002/jcla.24945] [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: 11/09/2022] [Revised: 06/08/2023] [Accepted: 07/11/2023] [Indexed: 07/26/2023] Open
Abstract
BACKGROUND Glucocorticoids (GCs) were the essential drugs for systemic lupus erythematosus (SLE). However, different patients differ substantially in their response to GCs treatment. Our current study aims at investigating whether climate variability and climate-gene interaction influence SLE patients' response to the therapy of GCs. METHODS In total, 778 SLE patients received therapy of GCs for a study of 12-week follow-up. The efficacy of GCs treatment was evaluated using the Systemic Lupus Erythematosus Disease Activity Index. The climatic data were provided by China Meteorological Data Service Center. Additive and multiplicative interactions were examined. RESULTS Compared with patients with autumn onset, the efficacy of GCs in patients with winter onset is relatively poor (ORadj = 1.805, 95%CIadj : 1.181-3.014, padj = 0.020). High mean relative humidity during treatment decreased the efficacy of GCs (ORadj = 1.033, 95%CIadj : 1.008-1.058, padj = 0.011), especially in female (ORadj = 1.039, 95%CIadj : 1.012-1.067, padj = 0.004). There was a significant interaction between sunshine during treatment and TRAP1 gene rs12597773 on GCs efficacy (Recessive model: AP = 0.770). No evidence of significant interaction was found between climate factors and the GR gene polymorphism on the improved GCs efficacy in the additive model. Multiplicative interaction was found between humidity in the month prior to treatment and GR gene rs4912905 on GCs efficacy (Dominant model: OR = 0.470, 95%CI: 0.244-0.905, p = 0.024). CONCLUSIONS Our findings suggest that climate variability influences SLE patients' response to the therapy of GCs. Interactions between climate and TRAP1/GR gene polymorphisms were related to GCs efficacy. The results guide the individualized treatment of SLE patients.
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Affiliation(s)
- Tingyu Zhang
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Qiaomei Xie
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Linlin Wang
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Yuhua Wang
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Ziye Yan
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Zhen Li
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Ying Teng
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Zhiwei Xu
- School of Public Health, Faculty of MedicineUniversity of QueenslandHerstonQueenslandAustralia
| | - Yangfan Chen
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Faming Pan
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Jinhui Tao
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of University of Science and Technology of ChinaHefeiAnhuiChina
| | - Jing Cai
- Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiAnhuiChina
| | - Chunmei Liang
- Department of Laboratory Medicine, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
| | - Haifeng Pan
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Hong Su
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Jian Cheng
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
| | - Wenbiao Hu
- School of Public Health and Social WorkQueensland University of TechnologyBrisbaneQueenslandAustralia
| | - Yanfeng Zou
- Department of Epidemiology and Biostatistics, School of Public HealthAnhui Medical UniversityHefeiAnhuiChina
- The Key Laboratory of Anhui Medical Autoimmune DiseasesHefeiAnhuiChina
- Key Laboratory of Dermatology (Anhui Medical University)Ministry of EducationHefeiAnhuiChina
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11
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Milo T, Korem Kohanim Y, Toledano Y, Alon U. Autoimmune thyroid diseases as a cost of physiological autoimmune surveillance. Trends Immunol 2023; 44:365-371. [PMID: 37061365 DOI: 10.1016/j.it.2023.03.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 03/09/2023] [Accepted: 03/09/2023] [Indexed: 04/17/2023]
Abstract
Graves' disease (GD) and Hashimoto's thyroiditis (HT) are common autoimmune diseases of the thyroid gland, causing hyperthyroidism and hypothyroidism, respectively. Despite their opposing clinical manifestation, they have several enigmatic links. Here, we propose that GD and HT have the same fundamental origin: both diseases are the cost of a beneficial physiological process called autoimmune surveillance of hypersecreting mutants. Autoreactive T cells selectively eliminate mutant cells that hypersecrete the hormones and threaten to become toxic nodules. These T cells can trigger a humoral response in susceptible individuals, leading to the production of antibodies against thyroid antigens. This shared origin can explain similarities in incidence and risk factors between HT and GD, despite their opposite clinical phenotypes.
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Affiliation(s)
- Tomer Milo
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel
| | - Yael Korem Kohanim
- Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Yoel Toledano
- Division of Maternal Fetal Medicine, Helen Schneider Women's Hospital, Rabin Medical Center, Petah Tikva, 4941492 Israel
| | - Uri Alon
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, 76100, Israel.
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12
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Kim HJ, Hong G, Hwang J, Kazmi SZ, Kim KH, Kang T, Swan H, Cha J, Kim YS, Kim KU, Hann HJ, Ahn HS. Familial Risk of Graves' Disease among First-Degree Relatives and Interaction with Smoking: A Population-Based Study. J Clin Endocrinol Metab 2023:7049295. [PMID: 36808421 DOI: 10.1210/clinem/dgad083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Revised: 02/03/2023] [Accepted: 02/08/2023] [Indexed: 02/23/2023]
Abstract
OBJECTIVE Population-based studies on the familial aggregation of Graves' disease (GD) are scarce and gene-environment interactions are not well-studied. We evaluated the familial aggregation of GD and assessed interactions between family history and smoking. METHODS Using the National Health Insurance database, which includes information on familial relationships and lifestyle risk factors, we identified 5,524,403 individuals with first-degree relatives (FDRs). Familial risk was calculated using hazard ratios (HRs), which compare the risk of individuals with and without affected FDRs. Interactions between smoking and family history were assessed on an additive scale using relative excess risk due to interaction (RERI). RESULTS The HR among individuals with affected FDRs was 3.39 (95% CI 3.30-3.48) compared to those without affected FDR, and among individuals with affected twin, brother, sister, father and mother the HRs were 36.53 (23.85-53.54), 5.26 (4.89-5.66), 4.12 (3.88-4.38), 3.34 (3.16-3.54), and 2.63 (2.53-2.74), respectively. Individuals with both a positive family history and smoking had an increased risk of disease (HR 4.68) with statistically significant interaction (RERI 0.94 95% CI 0.74-1.19). Heavy smokers with a positive family history showed a nearly 6-fold increased risk, which was higher than moderate smoking, suggesting a dose-response interaction pattern. Current smoking also showed a statistically significant interaction with family history (RERI 0.52 95% CI 0.22-0.82), while this was not observed for former smoking. CONCLUSION A gene-environment interaction can be suggested between smoking and GD-associated genetic factors, which diminishes after smoking cessation. Smokers with a positive family history should be considered a high-risk group and smoking cessation should be advised.
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Affiliation(s)
- Hyun Jung Kim
- Department of Preventive Medicine, Korea University, Seoul, Korea
| | - Gahwi Hong
- Department of Preventive Medicine, Korea University, Seoul, Korea
| | - Jungyun Hwang
- College of Medicine, Hallym University, Chuncheon, Korea
| | | | - Kyoung-Hoon Kim
- Evidence-based Research Division, Health Insurance Review and Assessment Service, Wonju, Korea Health and Wellness college, Sungshin Women's University Woonjung Green Campus, Seoul, Korea
| | - Taeuk Kang
- Department of Public Health, Korea University, Seoul, Korea
| | - Heather Swan
- Department of Preventive Medicine, Korea University, Seoul, Korea
| | - Jaewoo Cha
- Department of Nursing, Seojeong University, Yangju, Korea
| | - Young Shin Kim
- Department of Preventive Medicine, Korea University, Seoul, Korea
| | | | - Hoo Jae Hann
- Medical Research Institute, Ewha Womans University, Seoul, Korea
| | - Hyeong Sik Ahn
- Department of Preventive Medicine, Korea University, Seoul, Korea
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13
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Song Y, Xing C, Lu T, Liu C, Wang W, Wang S, Feng X, Bi J, Wang Q, Lai C. Aberrant Dendritic Cell Subsets in Patients with Myasthenia Gravis and Related Clinical Features. Neuroimmunomodulation 2023; 30:69-80. [PMID: 36780882 DOI: 10.1159/000529626] [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: 05/19/2022] [Accepted: 12/13/2022] [Indexed: 02/15/2023] Open
Abstract
INTRODUCTION Dendritic cells (DCs) play critical roles in the pathogenesis of myasthenia gravis (MG), and a series of DC-based experimental strategies for MG have recently been developed. However, the definite roles of different DC subsets in the mechanism of MG have scarcely been covered by previous studies. The present study aimed to investigate the levels of three main DC subsets, plasmacytoid DCs (pDCs) (CD303 positive) and two distinct subsets of conventional DCs (cDCs), namely CD1c+ cDCs and CD141+ cDCs, in MG patients and analyze related clinical features. METHODS From January 2016 to December 2020, 160 newly diagnosed MG patients and matched healthy controls (n = 160) were included in the study, and their clinical data were collected. The blood samples from MG patients before treatment and controls were collected for flow cytometry analysis. A total of 14 MG thymoma, 24 control thymoma, and 3 thymic cysts were used to immunostain the DC subsets. RESULTS The flow cytometry analysis showed a significantly higher frequency of circulating pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients than in healthy controls (p < 0.001 for all). Patients with early-onset MG (<50 years old) had a lower frequency of circulating pDCs but a higher frequency of circulating CD1c+ cDCs than those with late-onset MG (≥50 years old) (p = 0.014 and p = 0.025, respectively). The frequency of circulating pDCs was positively associated with the clinical severity of late-onset MG patients (r = 0.613, p < 0.001). 64.3% (9/14) of MG thymoma is of type B2 under the World Health Organization classification, which is higher than that in control thymoma (33.3%, 8/24) (p = 0.019). For type B2 thymoma, there were significantly more pDCs but fewer CD1c+ cDCs in MG thymoma than in the controls. CONCLUSION The distribution of aberrant pDCs, CD1c+ cDCs, and CD141+ cDCs in MG patients displayed age- and thymoma-related differences, which may contribute to the impaired immune tolerance and lead to the onset of MG.
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Affiliation(s)
- Yan Song
- Department of Neurology, The Second Hospital of Shandong University, Jinan, China
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Chunye Xing
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Tianyang Lu
- Department of Public Health, Monash University, Melbourne, Victoria, Australia
| | - Chen Liu
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Wei Wang
- Department of Pathology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Shaoqiang Wang
- Department of Thoracic Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, China
| | - Xungang Feng
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, China
| | - Jianzhong Bi
- Department of Neurology, The Second Hospital of Shandong University, Jinan, China
| | - Qian Wang
- Department of Neurology, The First Hospital of Tsinghua University, Beijing, China
| | - Chao Lai
- Department of Neurology, The Second Hospital of Shandong University, Jinan, China
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14
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Miller FW. The increasing prevalence of autoimmunity and autoimmune diseases: an urgent call to action for improved understanding, diagnosis, treatment, and prevention. Curr Opin Immunol 2023; 80:102266. [PMID: 36446151 PMCID: PMC9918670 DOI: 10.1016/j.coi.2022.102266] [Citation(s) in RCA: 149] [Impact Index Per Article: 74.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2022] [Accepted: 11/04/2022] [Indexed: 11/27/2022]
Abstract
Autoimmunity is characterized by self-reactive immune components and autoimmune disease by autoimmunity plus pathology. Both autoimmunity and autoimmune diseases are dramatically increasing in many parts of the world, likely as a result of changes in our exposures to environmental factors. Current evidence implicates the momentous alterations in our foods, xenobiotics, air pollution, infections, personal lifestyles, stress, and climate change as causes for these increases. Autoimmune diseases have a major impact on the individuals and families they affect, as well as on our society and healthcare costs, and current projections suggest they may soon take their place among the predominant medical disorders. This necessitates that we increase the scope and scale of our efforts, and coordinate our resources and studies, to understand autoimmune disease risk factors and pathogeneses and improve our diagnostic, therapeutic, and preventive approaches, as the costs of inaction will be profound and far greater without such investments.
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Affiliation(s)
- Frederick W Miller
- Environmental Autoimmunity Group, Clinical Research Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Bldg. 101, Maildrop A2-03, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA.
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15
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Wang H, Wu H, Li KD, Wang YY, Huang RG, Du YJ, Jin X, Zhang QR, Li XB, Li BZ. Intestinal fungi and systemic autoimmune diseases. Autoimmun Rev 2023; 22:103234. [PMID: 36423833 DOI: 10.1016/j.autrev.2022.103234] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 11/17/2022] [Indexed: 11/23/2022]
Abstract
Nearly 20 years of studies have shown that fungi and the human immune system (non-specific immunity and specific immunity) and bacterial--fungal interactions maintain a balance that can't lead to diseases. Fungi--microorganism that lives in human intestine--may play an important role in human health and disease. Population studies and animal models in some diseases have found the changes in the diversity and composition of fungi. The dysregulation of the fungi can disrupt the normal "running" of the immune system and bacteria, which triggers the development of inflammatory diseases. The latest studies of fungi in inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and type 1 diabetes mellitus were summarized. This review considers how the healthy host protect against the potential harm of intestinal fungi through the immune system and how fungal dysregulation alters host immunity.
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Affiliation(s)
- Hua Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Hong Wu
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Kai-Di Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yi-Yu Wang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Rong-Gui Huang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Yu-Jie Du
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Xue Jin
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Qian-Ru Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China; Department of Cardiovascular Surgery, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Xian-Bao Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China
| | - Bao-Zhu Li
- Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, Hefei, Anhui, China; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, Anhui, China.
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16
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Evolving understandings for the roles of non-coding RNAs in autoimmunity and autoimmune disease. J Autoimmun 2022:102948. [DOI: 10.1016/j.jaut.2022.102948] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Accepted: 10/24/2022] [Indexed: 11/09/2022]
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17
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Pang H, Lin J, Luo S, Huang G, Li X, Xie Z, Zhou Z. The missing heritability in type 1 diabetes. Diabetes Obes Metab 2022; 24:1901-1911. [PMID: 35603907 PMCID: PMC9545639 DOI: 10.1111/dom.14777] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/04/2022] [Accepted: 05/17/2022] [Indexed: 12/15/2022]
Abstract
Type 1 diabetes (T1D) is a complex autoimmune disease characterized by an absolute deficiency of insulin. It affects more than 20 million people worldwide and imposes an enormous financial burden on patients. The underlying pathogenic mechanisms of T1D are still obscure, but it is widely accepted that both genetics and the environment play an important role in its onset and development. Previous studies have identified more than 60 susceptible loci associated with T1D, explaining approximately 80%-85% of the heritability. However, most identified variants confer only small increases in risk, which restricts their potential clinical application. In addition, there is still a so-called 'missing heritability' phenomenon. While the gap between known heritability and true heritability in T1D is small compared with that in other complex traits and disorders, further elucidation of T1D genetics has the potential to bring novel insights into its aetiology and provide new therapeutic targets. Many hypotheses have been proposed to explain the missing heritability, including variants remaining to be found (variants with small effect sizes, rare variants and structural variants) and interactions (gene-gene and gene-environment interactions; e.g. epigenetic effects). In the following review, we introduce the possible sources of missing heritability and discuss the existing related knowledge in the context of T1D.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Jian Lin
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Shuoming Luo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Xia Li
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and EndocrinologyThe Second Xiangya Hospital of Central South UniversityChangshaChina
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18
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Dinse GE, Co CA, Parks CG, Weinberg CR, Xie G, Chan EKL, Birnbaum LS, Miller FW. Expanded assessment of xenobiotic associations with antinuclear antibodies in the United States, 1988-2012. ENVIRONMENT INTERNATIONAL 2022; 166:107376. [PMID: 35785669 PMCID: PMC9792625 DOI: 10.1016/j.envint.2022.107376] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 06/02/2022] [Accepted: 06/22/2022] [Indexed: 05/11/2023]
Abstract
BACKGROUND The prevalence of autoimmunity in the U.S. has increased recently for undetermined reasons. Little is known about associations between autoimmunity and environmental causes. OBJECTIVES In a large representative sample of the U.S. population, we expanded our prior exploratory study of how exposures to selected xenobiotics and dioxin-like (DL) mixtures relate to antinuclear antibodies (ANA), the most common biomarker of autoimmunity. METHODS We analyzed cross-sectional data on 12,058 participants aged ≥ 12 years from three time periods of the National Health and Nutrition Examination Survey between 1988 and 2012, of whom 14% were ANA-positive. We used lognormal regression models and censored-data methods to estimate ANA associations with xenobiotic concentrations overall and in sex, age, and race/ethnicity subgroups. Our analyses adjusted for potential confounders and appropriately handled concentrations below detection limits. RESULTS Observed ANA associations were positive for most DL compounds and nonDL polychlorinated biphenyls (PCBs), negative for most phthalates, and mixed for other xenobiotic classes. After correcting for multiple comparisons, some associations remained statistically significant. In subgroup analyses, the most significant finding was a positive ANA association with N-acetyl-S-(2-hydroxy-3-butenyl)-L-cysteine (MHB2) in males, followed by positive associations with 2,2',3,5'-tetrachlorobiphenyl (PCB 44), 2,2',4,5'-tetrachlorobiphenyl (PCB 49), and 2,2',3,4',5',6-hexachlorobiphenyl (PCB 149) in 12-19 year-olds, and with 3,4,4',5-tetrachlorobiphenyl (PCB 81), 2,2',3,3',4,4',5,5',6-nonachlorobiphenyl (PCB 206), and N-acetyl-S-(phenyl)-L-cysteine (PMA) in Mexican Americans. Negative associations were found with mono-benzyl phthalate (MBzP) in 20-49 year-olds and mono-n-butyl phthalate (MnBP) in 12-19 year-olds. In overall analyses, combining stratum-specific results across race/ethnicity strata revealed a positive ANA association with PCB 81 and a negative ANA association with N-acetyl-S-(2-hydroxyethyl)-L-cysteine (HEMA). DISCUSSION This study identified potential associations between ANA and various xenobiotics. Further investigation to confirm these observations and elucidate effects of certain xenobiotics on immune regulation could have important mechanistic, preventive, and treatment implications for a variety of immune-mediated disorders.
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Affiliation(s)
- Gregg E Dinse
- Public Health & Scientific Research, Social & Scientific Systems, Durham, NC, USA.
| | - Caroll A Co
- Public Health & Scientific Research, Social & Scientific Systems, Durham, NC, USA.
| | - Christine G Parks
- Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Clarice R Weinberg
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Guanhua Xie
- Public Health & Scientific Research, Social & Scientific Systems, Durham, NC, USA.
| | - Edward K L Chan
- Department of Oral Biology, University of Florida, Gainesville, FL, USA.
| | - Linda S Birnbaum
- Mechanistic Toxicology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
| | - Frederick W Miller
- Environmental Autoimmunity Group, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.
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19
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Lenti MV, Rossi CM, Melazzini F, Gastaldi M, Bugatti S, Rotondi M, Bianchi PI, Gentile A, Chiovato L, Montecucco C, Corazza GR, Di Sabatino A. Seronegative autoimmune diseases: A challenging diagnosis. Autoimmun Rev 2022; 21:103143. [PMID: 35840037 DOI: 10.1016/j.autrev.2022.103143] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/10/2022] [Indexed: 12/19/2022]
Abstract
Autoimmune diseases (AID) are increasingly prevalent conditions which comprise more than 100 distinct clinical entities that are responsible for a great disease burden worldwide. The early recognition of these diseases is key for preventing their complications and for tailoring proper management. In most cases, autoantibodies, regardless of their potential pathogenetic role, can be detected in the serum of patients with AID, helping clinicians in making a definitive diagnosis and allowing screening strategies for early -and sometimes pre-clinical- diagnosis. Despite their undoubted crucial role, in a minority of cases, patients with AID may not show any autoantibody, a condition that is referred to as seronegative AID. Suboptimal accuracy of the available laboratory tests, antibody absorption, immunosuppressive therapy, immunodeficiencies, antigen exhaustion, and immunosenescence are the main possible determinants of seronegative AID. Indeed, in seronegative AID, the diagnosis is more challenging and must rely on clinical features and on other available tests, often including histopathological evaluation and radiological diagnostic tests. In this review, we critically dissect, in a narrative fashion, the possible causes of seronegativity, as well as the diagnostic and management implications, in several AID including autoimmune gastritis, celiac disease, autoimmune liver disease, rheumatoid arthritis, autoimmune encephalitis, myasthenia gravis, Sjögren's syndrome, antiphospholipid syndrome, and autoimmune thyroid diseases.
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Affiliation(s)
- Marco Vincenzo Lenti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Carlo Maria Rossi
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Federica Melazzini
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Matteo Gastaldi
- Neuroimmunology Laboratory, IRCCS Mondino Foundation, Pavia, Italy
| | - Serena Bugatti
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Unit of Rheumatology, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Mario Rotondi
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, Pavia, Italy
| | - Paola Ilaria Bianchi
- Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Antonella Gentile
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Luca Chiovato
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, Laboratory for Endocrine Disruptors, Pavia, Italy
| | - Carlomaurizio Montecucco
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Unit of Rheumatology, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Gino Roberto Corazza
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy
| | - Antonio Di Sabatino
- Department of Internal Medicine and Medical Therapeutics, University of Pavia, Pavia, Italy; Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, Pavia, Italy.
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20
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Soriano VX, Peters RL, Moreno-Betancur M, Ponsonby AL, Gell G, Odoi A, Perrett KP, Tang MLK, Gurrin LC, Allen KJ, Dharmage SC, Koplin JJ. Association Between Earlier Introduction of Peanut and Prevalence of Peanut Allergy in Infants in Australia. JAMA 2022; 328:48-56. [PMID: 35788795 PMCID: PMC9257582 DOI: 10.1001/jama.2022.9224] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 05/27/2022] [Indexed: 01/07/2023]
Abstract
Importance Randomized clinical trials showed that earlier peanut introduction can prevent peanut allergy in select high-risk populations. This led to changes in infant feeding guidelines in 2016 to recommend early peanut introduction for all infants to reduce the risk of peanut allergy. Objective To measure the change in population prevalence of peanut allergy in infants after the introduction of these new guidelines and evaluate the association between early peanut introduction and peanut allergy. Design Two population-based cross-sectional samples of infants aged 12 months were recruited 10 years apart using the same sampling frame and methods to allow comparison of changes over time. Infants were recruited from immunization centers around Melbourne, Australia. Infants attending their 12-month immunization visit were eligible to participate (eligible age range, 11-15 months), regardless of history of peanut exposure or allergy history. Exposures Questionnaires collected data on demographics, food allergy risk factors, peanut introduction, and reactions. Main Outcome and Measures All infants underwent skin prick tests to peanut and those with positive results underwent oral food challenges. Prevalence estimates were standardized to account for changes in population demographics over time. Results This study included 7209 infants (1933 in 2018-2019 and 5276 in 2007-2011). Of the participants in the older vs more recent cohort, 51.8% vs 50.8% were male; median (IQR) ages were 12.5 (12.2-13.0) months vs 12.4 (12.2-12.9) months. There was an increase in infants of East Asian ancestry over time (16.5% in 2018-2019 vs 10.5% in 2007-2011), which is a food allergy risk factor. After standardizing for infant ancestry and other demographics changes, peanut allergy prevalence was 2.6% (95% CI, 1.8%-3.4%) in 2018-2019, compared with 3.1% in 2007-2011 (difference, -0.5% [95% CI, -1.4% to 0.4%]; P = .26). Earlier age of peanut introduction was significantly associated with a lower risk of peanut allergy among infants of Australian ancestry in 2018-2019 (age 12 months compared with age 6 months or younger: adjusted odds ratio, 0.08 [05% CI, 0.02-0.36]; age 12 months compared with 7 to less than 10 months: adjusted odds ratio, 0.09 [95% CI, 0.02-0.53]), but not significant among infants of East Asian ancestry (P for interaction = .002). Conclusions and Relevance In cross-sectional analyses, introduction of a guideline recommending early peanut introduction in Australia was not associated with a statistically significant lower or higher prevalence of peanut allergy across the population.
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Affiliation(s)
- Victoria X. Soriano
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
| | - Rachel L. Peters
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Margarita Moreno-Betancur
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Anne-Louise Ponsonby
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia
- School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia
| | - Grace Gell
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
| | - Alexsandria Odoi
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
| | - Kirsten P. Perrett
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Mimi L. K. Tang
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Allergy and Immunology, Royal Children’s Hospital, Parkville, Victoria, Australia
| | - Lyle C. Gurrin
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia
| | | | - Shyamali C. Dharmage
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia
| | - Jennifer J. Koplin
- Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia
- Centre for Food and Allergy Research (CFAR), Murdoch Children’s Research Institute, Parkville, Victoria, Australia
- School of Population and Global Health, University of Melbourne, Parkville, Victoria, Australia
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21
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Connell SJ, Jabbari A. The current state of knowledge of the immune ecosystem in alopecia areata. Autoimmun Rev 2022; 21:103061. [PMID: 35151885 PMCID: PMC9018517 DOI: 10.1016/j.autrev.2022.103061] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Accepted: 02/09/2022] [Indexed: 12/18/2022]
Abstract
Alopecia areata (AA) is an autoimmune disease that affects approximately 2% of the general population. Patients with AA most commonly present with one or more patches of hair loss on the scalp in defined circular areas. A fraction of patients progress to more severe forms of the disease, in some cases with involvement of all body surfaces. The healthy anagen stage hair follicle is considered an immune privileged site, described as an environment that suppresses inflammatory immune responses. However, in AA, this immune privileged state collapses and marks the hair follicle as a target for the immune system, resulting in peri- and intrafollicular infiltration by lymphocytes. The complexity of the inflammatory ecosystem of the immune response to the hair follicle, and the relationships between the cellular and soluble participants, in AA remains incompletely understood. Many studies have demonstrated the presence of various immune cells around diseased hair follicles; however, often little is known about their respective contributions to AA pathogenesis. Furthering our understanding of the mechanisms of disease in AA is essential for the novel identification of targeted therapeutics that are efficacious and have few unintended effects.
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22
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Saurabh R, Fouodo CJK, König IR, Busch H, Wohlers I. A survey of genome-wide association studies, polygenic scores and UK Biobank highlights resources for autoimmune disease genetics. Front Immunol 2022; 13:972107. [PMID: 35990650 PMCID: PMC9388859 DOI: 10.3389/fimmu.2022.972107] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Accepted: 07/12/2022] [Indexed: 12/04/2022] Open
Abstract
Autoimmune diseases share a general mechanism of auto-antigens harming tissues. Still. they are phenotypically diverse, with genetic as well as environmental factors contributing to their etiology at varying degrees. Associated genomic loci and variants have been identified in numerous genome-wide association studies (GWAS), whose results are increasingly used for polygenic scores (PGS) that are used to predict disease risk. At the same time, a technological shift from genotyping arrays to next generation sequencing (NGS) is ongoing. NGS allows the identification of virtually all - including rare - genetic variants, which in combination with methodological developments promises to improve the prediction of disease risk and elucidate molecular mechanisms underlying disease. Here we review current, publicly available autoimmune disease GWAS and PGS data based on information from the GWAS and PGS catalog, respectively. We summarize autoimmune diseases investigated, respective studies conducted and their results. Further, we review genetic data and autoimmune disease patients in the UK Biobank (UKB), the largest resource for genetic and phenotypic data available for academic research. We find that only comparably prevalent autoimmune diseases are covered by the UKB and at the same time assessed by both GWAS and PGS catalogs. These are systemic (systemic lupus erythematosus) as well as organ-specific, affecting the gastrointestinal tract (inflammatory bowel disease as well as specifically Crohn's disease and ulcerative colitis), joints (juvenile ideopathic arthritis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis), glands (Sjögren syndrome), the nervous system (multiple sclerosis), and the skin (vitiligo).
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Affiliation(s)
- Rochi Saurabh
- Medical Systems Biology, Lübeck Institute for Experimental Dermatology (LIED) and Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Césaire J K Fouodo
- Institute of Medical Biometry and Statistics (IMBS), University of Lübeck, Lübeck, Germany
| | - Inke R König
- Institute of Medical Biometry and Statistics (IMBS), University of Lübeck, Lübeck, Germany
| | - Hauke Busch
- Medical Systems Biology, Lübeck Institute for Experimental Dermatology (LIED) and Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
| | - Inken Wohlers
- Medical Systems Biology, Lübeck Institute for Experimental Dermatology (LIED) and Institute for Cardiogenetics, University of Lübeck, Lübeck, Germany
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23
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Li X, Zhu J, Peng Y, Guan H, Chen J, Wang Z, Zheng D, Cheng N, Wang H. Association of Polymorphisms in Inflammatory Cytokines Encoding Genes With Anti-N-methyl-D-Aspartate Receptor Encephalitis in the Southern Han Chinese. Front Neurol 2020; 11:553355. [PMID: 33362683 PMCID: PMC7759490 DOI: 10.3389/fneur.2020.553355] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Accepted: 08/20/2020] [Indexed: 11/13/2022] Open
Abstract
Background: Single nucleotide polymorphisms (SNPs) that occur within genes encoding inflammatory cytokines can result in quantitative or qualitative changes in their expression or functionality, potentially leading to the development of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study sought to evaluate the relationship between SNPs in inflammatory cytokines genes and the incidence of anti-NMDAR encephalitis in the Southern Han Chinese. Methods: In total, we enrolled 107 patients with anti-NMDAR encephalitis as well as 202 inpatient controls who had no first-degree relative with autoimmune diseases. Genotyping determination of all 309 patients was conducted for the IL-1β rs16944, IL-4 rs2243250, IL-4 rs2070874, IL-6 rs1800796, IL-10 rs1800872, and IL-17 rs2275913 gene SNPs. Results: We observed statistically significant differences in the frequencies of G allele in IL-1β rs16944 between anti-NMDAR encephalitis and controls (p = 0.017). Also, IL-1β, IL-4, IL-6, IL-10, and IL-17 SNPs were not associated with the disease (p > 0.05). Conclusions: We found that patients with anti-NMDAR encephalitis exhibit a distinct immunological profile, and we found that the decreased frequency of G allele in IL-1β rs16944 showed a protective role for anti-NMDAR encephalitis in the Southern Han Chinese.
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Affiliation(s)
- Xing Li
- Department of Neurology, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China
| | - Jiajia Zhu
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Peng
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongbing Guan
- Key Laboratory of Oral Medicine, Guangzhou Institute of Oral Disease, Affiliated Stomatology Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jinyu Chen
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhanhang Wang
- Department of Neurology, Guangdong 999 Brain Hospital, Guangzhou, China
| | - Dong Zheng
- Department of Neurology, Brain Hospital Affiliated to Guangzhou Medical University, Guangzhou, China
| | - Nan Cheng
- Hospital Affiliated to Institute of Neurology, Anhui University of Traditional Chinese Medicine, Hefei, China
| | - Honghao Wang
- Department of Neurology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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24
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Satta N, Frias MA, Vuilleumier N, Pagano S. Humoral Immunity Against HDL Particle: A New Perspective in Cardiovascular Diseases? Curr Pharm Des 2020; 25:3128-3146. [PMID: 31470782 DOI: 10.2174/1381612825666190830164917] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2019] [Accepted: 08/24/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND Autoimmune diseases are closely associated with cardiovascular diseases (CVD). Over the last decades, the comprehension of atherosclerosis, the principal initiator of CVD, evolved from a lipidcentered disease to a predominant inflammatory and immune response-driven disease displaying features of autoimmunity against a broad range of auto-antigens, including lipoproteins. Among them, high density lipoproteins (HDL) are important actors of cholesterol transport and bear several anti-atherogenic properties, raising a growing interest as therapeutic targets to decrease atherosclerosis and CVD burden, with nevertheless rather disappointing results so far. Reflecting HDL composition complexity, autoimmune responses and autoantibodies against various HDL components have been reported. RESULTS In this review, we addressed the important complexity of humoral autoimmunity towards HDL and particularly how this autoimmune response could help improving our understanding of HDL biological implication in atherosclerosis and CVD. We also discussed several issues related to specific HDL autoantibody subclasses characteristics, including etiology, prognosis and pathological mechanisms according to Rose criteria. CONCLUSION Finally, we addressed the possible clinical value of using these antibodies not only as potential biomarkers of atherogenesis and CVD, but also as a factor potentially mitigating the benefit of HDL-raising therapies.
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Affiliation(s)
- Nathalie Satta
- Division of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, 4 rue Gabrielle Perret-Gentil, 1205 Geneva, Switzerland.,Department of Medical Specialties, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland
| | - Miguel A Frias
- Division of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, 4 rue Gabrielle Perret-Gentil, 1205 Geneva, Switzerland.,Department of Medical Specialties, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland
| | - Nicolas Vuilleumier
- Division of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, 4 rue Gabrielle Perret-Gentil, 1205 Geneva, Switzerland.,Department of Medical Specialties, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland
| | - Sabrina Pagano
- Division of Laboratory Medicine, Department of Diagnostic, Geneva University Hospitals, 4 rue Gabrielle Perret-Gentil, 1205 Geneva, Switzerland.,Department of Medical Specialties, Faculty of Medicine, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland
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25
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Talotta R, Atzeni F, Laska MJ. The contribution of HERV-E clone 4-1 and other HERV-E members to the pathogenesis of rheumatic autoimmune diseases. APMIS 2020; 128:367-377. [PMID: 32202683 DOI: 10.1111/apm.13039] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/26/2020] [Indexed: 12/16/2022]
Abstract
Human endogenous retroviruses (HERV)-E consist of a family of more than 1300 elements, stably integrated in the human genome. Some of them are full-length proviruses able to synthesize the viral proteins gag, pol and env. The reactivation of HERV-E elements has been associated to placentation, cancer and autoimmunity. In this narrative review, we aimed to report the status of the art concerning the involvement of HERV-E in rheumatic autoimmune diseases. Following a research on PubMed database, a total of 87 articles were selected. The highest amount of evidence derives from studies on systemic lupus erythematosus (SLE), whereas a few to no data are available on other immune-mediated diseases. In SLE, the hyper-expression of HERV-E clone 4-1 in peripheral blood mononuclear cells or differentiated lymphocytes has been associated with disease activity and autoantibody production. It is likely that HERV-E take part to the pathogenesis of rheumatic autoimmune diseases but additional research is needed.
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Affiliation(s)
- Rossella Talotta
- Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Messina, Azienda Ospedaliera "Gaetano Martino", Messina, Italy
| | - Fabiola Atzeni
- Department of Clinical and Experimental Medicine, Rheumatology Unit, University of Messina, Azienda Ospedaliera "Gaetano Martino", Messina, Italy
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26
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Roberts MH, Erdei E. Comparative United States autoimmune disease rates for 2010-2016 by sex, geographic region, and race. Autoimmun Rev 2020; 19:102423. [PMID: 31733367 PMCID: PMC6925958 DOI: 10.1016/j.autrev.2019.102423] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 06/23/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE AIDs may disproportionately impact specific racial groups, but autoimmune (AID) prevalence information by minority racial group is sparse for many AIDs. The objective of this analysis was to supplement previously published AID prevalence rates by providing information on race rate ratios (minority race populations compared to Caucasian populations) in the United States. Preliminary to estimating race rate ratios, contemporary US-specific, health care utilization-based AID prevalence rates and female-to-male ratios were estimated and compared to previously published AID prevalence rates. METHODS We used a large national electronic medical record database of 52 million individuals to estimate age-adjusted direct standardized rates for 22 AIDs for 2010 through 2016 by gender, race, and US census division. These were compared to previously published estimates. RESULTS Female-to-male ratios were comparable with published studies. Almost all observed Multiracial AID rates were significantly higher than Caucasian rates, as well as 9 of 22 AID rates observed among Native Americans and 8 of 22 AID rates estimated among African-American patients. Regional variation was noted: highest African-American systemic lupus erythematosus rates were observed in the West North Central and South Atlantic divisions, highest African-American multiple sclerosis rates in the South Atlantic and Pacific divisions, and highest Native American rheumatoid arthritis rates in the West North Central, Mountain, and Pacific divisions. CONCLUSIONS Substantial AID heterogeneity exists by race and by geographic area. An important research area is further exploring factors related to heterogeneity such as potential interactions between genetic susceptibility and environmental factors.
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Affiliation(s)
- Melissa H Roberts
- University of New Mexico, College of Pharmacy, Albuquerque, NM, USA.
| | - Esther Erdei
- University of New Mexico, College of Pharmacy, Albuquerque, NM, USA.
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27
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Popperud TH, Boldingh MI, Brunborg C, Faiz KW, Heldal AT, Maniaol AH, Müller KI, Rasmussen M, Øymar K, Kerty E. Juvenile myasthenia gravis in Norway: A nationwide epidemiological study. Eur J Paediatr Neurol 2017; 21:312-317. [PMID: 27666466 DOI: 10.1016/j.ejpn.2016.09.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 08/17/2016] [Accepted: 09/03/2016] [Indexed: 10/21/2022]
Abstract
BACKGROUND The aim of this study was to assess the incidence rate and prevalence of autoimmune myasthenia gravis (MG) among children in Norway. METHODS This retrospective population-based study was performed in Norway from January 2012 to December 2013. Cases of juvenile MG (JMG) with onset < 18 years were identified through searches in coding systems of electronic patient records at the 15 main hospitals in Norway from 1989 to 2013. In addition, the acetylcholine receptor antibody database at Haukeland University Hospital and the clinical nationwide MG database at Oslo University Hospital were searched for cases of JMG. Diagnosis and age at onset were verified through medical records. Incidence and prevalence rates were calculated using the Norwegian population as reference. RESULTS In total 63 unique JMG cases were identified. This corresponds to an average annual incidence rate of 1.6 per million. Incidence rate was stable over the study period. Prevalence of JMG was 3.6-13.8 per million. Females constituted the majority of JMG cases (55 vs 8 males). The risk of JMG was higher among females both in the postpubertal and prepubertal group (p < 0.001 and p = 0.02, respectively). CONCLUSION This study confirms the rarity of JMG in Norway, especially among males, and shows a stable incidence rate over the last 25 years.
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Affiliation(s)
- T H Popperud
- Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
| | - M I Boldingh
- Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - C Brunborg
- Oslo Centre for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway
| | - K W Faiz
- Department of Neurology, Akershus University Hospital, Lørenskog, Norway
| | - A T Heldal
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - A H Maniaol
- Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - K I Müller
- Department of Neurology and National Neuromuscular Centre, University Hospital of North Norway, Tromsø, Norway; Department of Clinical Medicine, UiT - The Artic University of Norway, Tromsø, Norway
| | - M Rasmussen
- Department of Clinical Neuroscience for Children, Section for Child Neurology, Oslo University Hospital, Oslo, Norway; Unit for Hereditary and Inborn Neuromuscular Disorders, Department of Neurology, Oslo University Hospital, Oslo, Norway
| | - K Øymar
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pediatrics, Stavanger University Hospital, Stavanger, Norway
| | - E Kerty
- Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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28
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The Histone Modification Code in the Pathogenesis of Autoimmune Diseases. Mediators Inflamm 2017; 2017:2608605. [PMID: 28127155 PMCID: PMC5239974 DOI: 10.1155/2017/2608605] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/08/2016] [Indexed: 12/19/2022] Open
Abstract
Autoimmune diseases are chronic inflammatory disorders caused by a loss of self-tolerance, which is characterized by the appearance of autoantibodies and/or autoreactive lymphocytes and the impaired suppressive function of regulatory T cells. The pathogenesis of autoimmune diseases is extremely complex and remains largely unknown. Recent advances indicate that environmental factors trigger autoimmune diseases in genetically predisposed individuals. In addition, accumulating results have indicated a potential role of epigenetic mechanisms, such as histone modifications, in the development of autoimmune diseases. Histone modifications regulate the chromatin states and gene transcription without any change in the DNA sequence, possibly resulting in phenotype alteration in several different cell types. In this paper, we discuss the significant roles of histone modifications involved in the pathogenesis of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, primary biliary cirrhosis, and type 1 diabetes.
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29
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Watanabe M, Honda C, Iwatani Y, Yorifuji S, Iso H, Kamide K, Hatazawa J, Kihara S, Sakai N, Watanabe H, Makimoto K, Watanabe M, Honda C, Iwatani Y. Within-pair differences of DNA methylation levels between monozygotic twins are different between male and female pairs. BMC Med Genomics 2016; 9:55. [PMID: 27561550 PMCID: PMC5000519 DOI: 10.1186/s12920-016-0217-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2016] [Accepted: 08/14/2016] [Indexed: 01/05/2023] Open
Abstract
Background DNA methylation levels will be important for detection of epigenetic effects. However, there are few reports showing sex-related differences in the sensitivity to DNA methylation. To evaluate their sex-related individual differences in the sensitivity to methylation rigorously, we performed a systematic analysis of DNA methylation in monozygotic twins, an optimal model to evaluate them because the genetic backgrounds are the same. Results We examined 30 male and 43 female older monozygotic twin pairs recruited from the registry established by the Center for Twin Research, Osaka University. Their methylation levels were determined using the Infinium HumanMethylation450 BeadChip Kit (Illumina), which interrogated 485577 highly informative CpG sites at the single-nucleotide resolution, and the median methylation level was calculated for each of the 25657 CpG islands. Within-pair differences of methylation levels (WPDMs) were greater in male pairs than female pairs for 86.0 % of autosomal CpG islands, but were higher in female pairs than male pairs for 76.7 % of X chromosomal CpG islands. Mean WPDMs of CpG islands in each autosomal chromosome were significantly higher in male pairs than in female whereas that in X chromosome was significantly higher in female pairs than in male. Multiple comparison indicated that WPDMs in three autosomal and two X-chromosomal CpG islands were significantly greater in male pairs, whereas those in 22 X-chromosomal CpG islands were significantly greater in female pairs. Conclusion Sex-related differences were present in the WPDMs of CpG islands in individuals with the same genetic background. These differences may be associated with the sexual influences in susceptibility of some diseases. Electronic supplementary material The online version of this article (doi:10.1186/s12920-016-0217-2) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Mikio Watanabe
- Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka, 565-0871, Japan. .,Center for Twin Research, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, 565-0871, Osaka, Japan.
| | - Chika Honda
- Center for Twin Research, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, 565-0871, Osaka, Japan
| | | | | | | | | | | | | | | | | | | | | | | | | | - Yoshinori Iwatani
- Department of Biomedical Informatics, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, Osaka, 565-0871, Japan. .,Center for Twin Research, Osaka University Graduate School of Medicine, Yamadaoka 1-7, Suita, 565-0871, Osaka, Japan.
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30
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Bhise V, Dhib-Jalbut S. Further understanding of the immunopathology of multiple sclerosis: impact on future treatments. Expert Rev Clin Immunol 2016; 12:1069-89. [PMID: 27191526 DOI: 10.1080/1744666x.2016.1191351] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION The understanding of the immunopathogenesis of multiple sclerosis (MS) has expanded with more research into T-cell subtypes, cytokine contributors, B-cell participation, mitochondrial dysfunction, and more. Treatment options have rapidly expanded with three relatively recent oral therapy alternatives entering the arena. AREAS COVERED In the following review, we discuss current mechanisms of immune dysregulation in MS, how they relate to current treatments, and the impact these findings will have on the future of therapy. Expert commentary: The efficacy of these medications and understanding their mechanisms of actions validates the immunopathogenic mechanisms thought to underlie MS. Further research has exposed new targets, while new promising therapies have shed light on new aspects into the pathophysiology of MS.
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Affiliation(s)
- Vikram Bhise
- a Rutgers Biomedical and Health Sciences - Departments of Pediatrics , Robert Wood Johnson Medical School , New Brunswick , NJ , USA
| | - Suhayl Dhib-Jalbut
- b Rutgers Biomedical and Health Sciences - Departments of Neurology , Robert Wood Johnson Medical School , New Brunswick , NJ , USA
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31
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Anaya JM, Ramirez-Santana C, Alzate MA, Molano-Gonzalez N, Rojas-Villarraga A. The Autoimmune Ecology. Front Immunol 2016; 7:139. [PMID: 27199979 PMCID: PMC4844615 DOI: 10.3389/fimmu.2016.00139] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2015] [Accepted: 03/29/2016] [Indexed: 12/21/2022] Open
Abstract
Autoimmune diseases (ADs) represent a heterogeneous group of disorders that affect specific target organs or multiple organ systems. These conditions share common immunopathogenic mechanisms (i.e., the autoimmune tautology), which explain the clinical similarities they have among them as well as their familial clustering (i.e., coaggregation). As part of the autoimmune tautology, the influence of environmental exposure on the risk of developing ADs is paramount (i.e., the autoimmune ecology). In fact, environment, more than genetics, shapes immune system. Autoimmune ecology is akin to exposome, that is all the exposures - internal and external - across the lifespan, interacting with hereditary factors (both genetics and epigenetics) to favor or protect against autoimmunity and its outcomes. Herein, we provide an overview of the autoimmune ecology, focusing on the immune response to environmental agents in general, and microbiota, cigarette smoking, alcohol and coffee consumption, socioeconomic status (SES), gender and sex hormones, vitamin D, organic solvents, and vaccines in particular. Inclusion of the autoimmune ecology in disease etiology and health will improve the way personalized medicine is currently conceived and applied.
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Affiliation(s)
- Juan-Manuel Anaya
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Carolina Ramirez-Santana
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Maria A Alzate
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Nicolas Molano-Gonzalez
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
| | - Adriana Rojas-Villarraga
- Center for Autoimmune Diseases Research (CREA), School of Medicine and Health Sciences, Universidad del Rosario , Bogotá , Colombia
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32
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Dinse GE, Jusko TA, Whitt IZ, Co CA, Parks CG, Satoh M, Chan EK, Rose KM, Walker NJ, Birnbaum LS, Zeldin DC, Weinberg CR, Miller FW. Associations Between Selected Xenobiotics and Antinuclear Antibodies in the National Health and Nutrition Examination Survey, 1999-2004. ENVIRONMENTAL HEALTH PERSPECTIVES 2016; 124:426-36. [PMID: 26252071 PMCID: PMC4829978 DOI: 10.1289/ehp.1409345] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 08/04/2015] [Indexed: 05/25/2023]
Abstract
BACKGROUND Potential associations between background environmental chemical exposures and autoimmunity are understudied. OBJECTIVES Our exploratory study investigated exposure to individual environmental chemicals and selected mixtures in relation to the presence of antinuclear antibodies (ANA), a widely used biomarker of autoimmunity, in a representative sample of the U.S. METHODS This cross-sectional analysis used data on 4,340 participants from the National Health and Nutrition Examination Survey (1999-2004), of whom 14% were ANA positive, to explore associations between ANA and concentrations of dioxins, dibenzofurans, polychlorinated biphenyls, organochlorines, organophosphates, phenols, metals, and other environmental exposures and metabolites measured in participants' serum, whole blood, or urine. For dioxin-like compounds with toxic equivalency factors, we developed and applied a new statistical approach to study selected mixtures. Lognormal models and censored-data methods produced estimates of chemical associations with ANA in males, nulliparous females, and parous females; these estimates were adjusted for confounders and accommodated concentrations below detectable levels. RESULTS Several associations between chemical concentration and ANA positivity were observed, but only the association in males exposed to triclosan remained statistically significant after correcting for multiple comparisons (mean concentration ratio = 2.8; 95% CI: 1.8, 4.5; p < 0.00001). CONCLUSIONS These data suggest that background levels of most xenobiotic exposures typical in the U.S. population are not strongly associated with ANA. Future studies should ideally reduce exposure misclassification by including prospective measurement of the chemicals of concern and should track changes in ANA and other autoantibodies over time. CITATION Dinse GE, Jusko TA, Whitt IZ, Co CA, Parks CG, Satoh M, Chan EKL, Rose KM, Walker NJ, Birnbaum LS, Zeldin DC, Weinberg CR, Miller FW. 2016. Associations between selected xenobiotics and antinuclear antibodies in the National Health and Nutrition Examination Survey, 1999-2004. Environ Health Perspect 124:426-436; http://dx.doi.org/10.1289/ehp.1409345.
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Affiliation(s)
- Gregg E. Dinse
- Biostatistics Center, Social & Scientific Systems, Inc., Durham, North Carolina, USA
| | - Todd A. Jusko
- Departments of Public Health Sciences and Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Irene Z. Whitt
- Division of Rheumatology and Immunology, Department of Internal Medicine, Duke University, Durham, North Carolina, USA
| | - Caroll A. Co
- Biostatistics Center, Social & Scientific Systems, Inc., Durham, North Carolina, USA
| | - Christine G. Parks
- Epidemiology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Research Triangle Park, North Carolina, USA
| | - Minoru Satoh
- Department of Clinical Nursing, University of Occupational and Environmental Health, Kitakyushu, Fukuoka, Japan
| | - Edward K.L. Chan
- Department of Oral Biology, University of Florida, Gainesville, Florida, USA
| | - Kathryn M. Rose
- Biostatistics Center, Social & Scientific Systems, Inc., Durham, North Carolina, USA
| | - Nigel J. Walker
- Division of the National Toxicology Program, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA
| | - Linda S. Birnbaum
- Laboratory of Toxicology and Toxicokinetics, National Cancer Institute, NIH, DHHS, Research Triangle Park, North Carolina, USA
| | | | - Clarice R. Weinberg
- Biostatistics and Computational Biology Branch, NIEHS, NIH, DHHS, Research Triangle Park, North Carolina, USA
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DNA methylation perspectives in the pathogenesis of autoimmune diseases. Clin Immunol 2016; 164:21-7. [PMID: 26821302 DOI: 10.1016/j.clim.2016.01.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 01/23/2016] [Accepted: 01/23/2016] [Indexed: 12/19/2022]
Abstract
DNA methylation is now widely recognized as being critical to maintain the function of immune cells. Recent studies suggest that aberrant DNA methylation levels not only can result in immune cells autoreactivity in vitro, but also are related to autoimmunity in vivo. Environmental factors and genetic polymorphisms cause abnormal methylation, which affects the expression of certain immune-related genes, being becoming hot spot of explaining the mechanism of autoimmune diseases. This paper reviews the importance of abnormal methylation during the development of common autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and type 1 diabetes, aiming at a better understanding of the pathogenesis of autoimmune diseases and providing new ideas for the treatment of these diseases.
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Abstract
PURPOSE OF REVIEW Recent studies indicate a role for immune dysregulation in the pathogenesis of multiple sclerosis, an inflammatory demyelinating and degenerative disease of the central nervous system. This review addresses the current mechanisms of immune dysregulation in the development of multiple sclerosis, including the impact of environmental risk factors on immunity in both multiple sclerosis and its animal models. RECENT FINDINGS CD4 T-helper (Th) cells have long been implicated as the main drivers of pathogenesis of multiple sclerosis. However, current studies indicate that multiple sclerosis is largely a heterogeneous disease process, which involves both innate and adaptive immune-mediated inflammatory mechanisms that ultimately contribute to demyelination and neurodegeneration. Therefore, B cells, CD8 T cells, and microglia/macrophages can also play an important role in the immunopathogenesis of multiple sclerosis apart from proinflammatory CD4 Th1/Th17 cell subsets. Furthermore, increasing evidence indicates that environmental risk factors, such as Vitamin D deficiency, Epstein-Barr virus, smoking, Western diet, and the commensal microbiota, influence the development of multiple sclerosis through interactions with genetic variants of multiple sclerosis, thus leading to the dysregulation of immune responses. SUMMARY A better understanding of immune-mediated mechanisms in the pathogenesis of multiple sclerosis and the contribution of environmental risk factors toward the development of multiple sclerosis will help further improve therapeutic approaches to prevent disease progression.
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Wang J, Yang G, Dubrovsky AM, Choi J, Leung PSC. Xenobiotics and loss of tolerance in primary biliary cholangitis. World J Gastroenterol 2016; 22:338-348. [PMID: 26755880 PMCID: PMC4698496 DOI: 10.3748/wjg.v22.i1.338] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2015] [Revised: 08/15/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Data from genome wide association studies and geoepidemiological studies established that a combination of genetic predisposition and environmental stimulation is required for the loss of tolerance in primary biliary cholangitis (PBC). The serologic hallmark of PBC are the presence of high titer anti-mitochondrial autoantibodies (AMA) that recognize the lipoyl domain of the mitochondrial pyruvate dehydrogenase E2 (PDC-E2) subunit. Extensive efforts have been directed to investigate the molecular basis of AMA. Recently, experimental data has pointed to the thesis that the breaking of tolerance to PDC-E2 is a pivotal event in the initial etiology of PBC, including environmental xenobiotics including those commonly found in cosmetics and food additives, suggesting that chemical modification of the PDC-E2 epitope may render its vulnerable to become a neo-antigen and trigger an immune response in genetically susceptible hosts. Here, we will discuss the natural history, genetics and immunobiology of PBC and structural constraints of PDC-E2 in AMA recognition which makes it vulnerable to chemical modification.
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Abstract
The strategies employed in vaccinology have improved since the seminal work of Edward Jenner in the eighteenth century. Stimulated by failure to develop vaccines for cancers and chronic infectious diseases as well as an emergence of a multitude of new technologies not available earlier, vaccinology has moved from a largely experimental art to a new phase of innovation. Currently, immune reactions can be predicted and modeled before they occur and formulations can be optimized in advance for genetic background, age, sex, lifestyle, environmental factors, and microbiome. A multitude of scientific insights and technological advancements have led us to this current status, yet possibly none of the recent developments is individually more promising to achieve these goals than the interdisciplinary science of systems vaccinology. This review summarizes current trends and applications of systems vaccinology, including technically tangible areas of vaccine and immunology research which allow the transformative process into a truly broad understanding of vaccines, thereby effectively modeling interaction of vaccines with health and disease. It is becoming clear that a multitude of factors have to be considered to understand inter-patient variability of vaccine responses including those characterized from the interfaces between the immune system, microbiome, metabolome, and the nervous system.
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Boule LA, Burke CG, Fenton BM, Thevenet-Morrison K, Jusko TA, Lawrence BP. Developmental Activation of the AHR Increases Effector CD4+ T Cells and Exacerbates Symptoms in Autoimmune Disease-Prone Gnaq+/- Mice. Toxicol Sci 2015; 148:555-66. [PMID: 26363170 DOI: 10.1093/toxsci/kfv203] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Perinatal environmental exposures are potentially important contributors to the increase in autoimmune diseases. Yet, the mechanisms by which these exposures increase self-reactive immune responses later in life are poorly understood. Autoimmune diseases require CD4(+) T cells for initiation, progression, and/or clinical symptoms; thus, developmental exposures that cause durable changes in CD4(+) T cells may play a role. Early life activation of the aryl hydrocarbon receptor (AHR) causes persistent changes in the response of CD4(+) T cells to infection later in life but whether CD4(+) T cells are affected by developmental exposure in the context of an autoimmune disease is unknown. Gnaq(+/-) mice develop symptoms of autoimmune disease similar to those measured clinically, and therefore can be used to evaluate gene-environment interactions during development on disease progression. Herein, we examined the effect of AHR activation in utero and via lactation, or solely via lactation, on disease onset and severity in adult Gnaq(+/-) offspring. Developmental activation of the AHR-accelerated disease in Gnaq(+/-) mice, and this correlates with increases in effector CD4(+) T-cell populations. Increased symptom onset and cellular changes due to early life AHR activation were more evident in female Gnaq(+/-) mice compared with males. These observations suggest that developmental AHR activation by pollutants, and other exogenous ligands, may increase the likelihood that genetically predisposed individuals will develop clinical symptoms of autoimmune disease later in life.
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Affiliation(s)
| | | | | | | | - Todd A Jusko
- Department of Public Health Sciences, and Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York
| | - B Paige Lawrence
- *Department of Microbiology and Immunology, Department of Environmental Medicine, University of Rochester Medical Center, Rochester, New York
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Riley WT, Nilsen WJ, Manolio TA, Masys DR, Lauer M. News from the NIH: potential contributions of the behavioral and social sciences to the precision medicine initiative. Transl Behav Med 2015; 5:243-6. [PMID: 26327928 DOI: 10.1007/s13142-015-0320-5] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Affiliation(s)
- William T Riley
- Office of Behavioral and Social Sciences Research, National Institutes of Health, 30 Center Dr., Bethesda, MD USA
| | - Wendy J Nilsen
- Office of Behavioral and Social Sciences Research, National Institutes of Health, 30 Center Dr., Bethesda, MD USA
| | - Teri A Manolio
- Division of Genomic Medicine, National Human Genome Research Institute, 5635 Fishers Lane MSC 9305, Bethesda, MD 20892-9305 USA
| | - Daniel R Masys
- Department of Biomedical Informatics and Medical Education, University of Washington School of Medicine, Seattle, WA 98109-4714 USA
| | - Michael Lauer
- Division of Cardiovascular Sciences of the National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Room 8128, Bethesda, MD 20892 USA
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Epigenetic control of autoimmune diseases: From bench to bedside. Clin Immunol 2015; 157:1-15. [DOI: 10.1016/j.clim.2014.12.013] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Revised: 11/17/2014] [Accepted: 12/18/2014] [Indexed: 01/10/2023]
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Ngo ST, Steyn FJ, McCombe PA. Gender differences in autoimmune disease. Front Neuroendocrinol 2014; 35:347-69. [PMID: 24793874 DOI: 10.1016/j.yfrne.2014.04.004] [Citation(s) in RCA: 659] [Impact Index Per Article: 59.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2014] [Revised: 04/20/2014] [Accepted: 04/22/2014] [Indexed: 12/21/2022]
Abstract
Autoimmune diseases are a range of diseases in which the immune response to self-antigens results in damage or dysfunction of tissues. Autoimmune diseases can be systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence, whereby females are generally more frequently affected than males. In this review, we consider gender differences in systemic and organ-specific autoimmune diseases, and we summarize human data that outlines the prevalence of common autoimmune diseases specific to adult males and females in countries commonly surveyed. We discuss possible mechanisms for sex specific differences including gender differences in immune response and organ vulnerability, reproductive capacity including pregnancy, sex hormones, genetic predisposition, parental inheritance, and epigenetics. Evidence demonstrates that gender has a significant influence on the development of autoimmune disease. Thus, considerations of gender should be at the forefront of all studies that attempt to define mechanisms that underpin autoimmune disease.
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Affiliation(s)
- S T Ngo
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia; University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia
| | - F J Steyn
- School of Biomedical Sciences, University of Queensland, St Lucia, Queensland, Australia
| | - P A McCombe
- University of Queensland Centre for Clinical Research, University of Queensland, Herston, Queensland, Australia; Department of Neurology, Royal Brisbane & Women's Hospital, Herston, Queensland, Australia.
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