Elucidation of the Pathogenesis of Autoinflammatory Diseases Using iPS Cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Saito MK
PROVIDER: S-EPMC7912798 | biostudies-literature | 2021 Feb
REPOSITORIES: biostudies-literature
Publications
Elucidation of the Pathogenesis of Autoinflammatory Diseases Using iPS Cells.
Children (Basel, Switzerland) 20210201 2
Autoinflammatory diseases are a disease entity caused by the dysregulation of innate immune cells. Typical autoinflammatory diseases are monogenic disorders and often very rare. As a result, there is a relative lack of understanding of the pathogenesis, poor diagnosis and little available treatment. Induced pluripotent stem (iPS) cells are a new technology being applied to in vitro disease modeling. These models are especially useful for the analysis of rare and intractable diseases including au ...[more]
Similar Datasets
Project description:ObjectiveThe present manuscript aims to describe an international, electronic-based, user-friendly and interoperable patient registry for monogenic autoinflammatory diseases (mAIDs), developed in the contest of the Autoinflammatory Diseases Alliance (AIDA) Network.MethodsThis is an electronic platform, based on the Research Electronic Data Capture (REDCap) tool, used for real-world data collection of demographics, clinical, laboratory, instrumental and socioeconomic data of mAIDs patients. The instrument has flexibility, may change over time based on new scientific acquisitions, and communicate potentially with other similar registries; security, data quality and data governance are corner stones of the platform.ResultsAIDA project will share knowledge and expertise on mAIDs. Since its start, 118 centers from 24 countries and 4 continents have joined the AIDA project. Fifty-nine centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 337 users (122 Principal Investigators, 210 Site Investigators, 2 Lead Investigators, and 3 data managers). The Registry collects baseline and follow-up data using 3,748 fields organized into 21 instruments, which include demographics, patient history, symptoms, trigger/risk factors, therapies, and healthcare information for mAIDs patients.ConclusionsThe AIDA mAIDs Registry, acts both as a research tool for future collaborative real-life studies on mAIDs and as a service to connect all the figures called to participate. On this basis, the registry is expected to play a pivotal role in generating new scientific evidence on this group of rare diseases, substantially improving the management of patients, and optimizing the impact on the healthcare system. NCT05200715 available at https://clinicaltrials.gov.
| S-EPMC9500177 | biostudies-literature
Project description:Systemic autoinflammatory diseases (SAIDs) are a growing group of disorders caused by a dysregulation of the innate immune system leading to episodes of systemic inflammation. In 1997, MEFV was the first gene identified as disease causing for Familial Mediterranean Fever, the most common hereditary SAID. In most cases, autoinflammatory diseases have a strong genetic background with mutations in single genes. Since 1997 more than 30 new genes associated with autoinflammatory diseases have been identified, affecting different parts of the innate immune system. Nevertheless, for at least 40-60% of patients with phenotypes typical for SAIDs, a distinct diagnosis cannot be met, leading to undefined SAIDs (uSAIDs). However, SAIDs can also be of polygenic or multifactorial origin, with environmental influence modulating the phenotype. The implementation of a disease continuum model combining the adaptive and the innate immune system with autoinflammatory and autoimmune diseases shows the complexity of SAIDs and the importance of new methods to elucidate molecular changes and causative factors in SAIDs. Diagnosis is often based on clinical presentation and genetic testing. The timeline from onset to diagnosis takes up to 7.3 years, highlighting the indisputable need to identify new treatment and diagnostic targets. Recently, other factors are under investigation as additional contributors to the pathogenesis of SAIDs. This review gives an overview of pathogenesis and etiology of SAIDs, and summarizes recent diagnosis and treatment options.
| S-EPMC7610735 | biostudies-literature
Project description:Autoinflammatory diseases are hyperinflammatory, immune dysregulatory conditions that typically present in early childhood with fever and rashes and disease-specific patterns of organ inflammation. This review provides a historic background of autoinflammatory disease research, an overview of the currently genetically defined autoinflammatory diseases, and insights into treatment strategies derived from understanding of the disease pathogenesis. The integrative assessment of autoinflammatory conditions led to the identification of innate pro-inflammatory cytokine 'amplification loops' as the cause of the systemic and organ-specific disease manifestations, which initially centered around increased IL-1 production and signaling. More recently, additional innate pro-inflammatory cytokine amplification loops resulting in increased Type I IFN, IL-17, IL-18, or IL-36 signaling or production have led to the successful use of targeted therapies in some of these conditions. Clinical findings such as fever patterns, type of skin lesions, genetic mutation testing, and the prevalent cytokine abnormalities can be used to group autoinflammatory diseases.
| S-EPMC4970964 | biostudies-literature
Project description:For many decades, we have relied on immortalised retinal cell lines, histology of enucleated human eyes, animal models, clinical observation, genetic studies and human clinical trials to learn more about the pathogenesis of retinal diseases and explore treatment options. The recent availability of patient-specific induced pluripotent stem cells (iPSC) for deriving retinal lineages has added a powerful alternative tool for discovering new disease-causing mutations, studying genotype-phenotype relationships, performing therapeutics-toxicity screening and developing personalised cell therapy. This review article provides a clinical perspective on the current and potential benefits of iPSC for managing the most common blinding diseases of the eye: inherited retinal diseases and age-related macular degeneration.
| S-EPMC4470196 | biostudies-literature
Project description:Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. From apathogenetic point of view they are determined by a dys regulation of innate immunity, without involvement of specific immunity (auto reactive T cells and auto antibodies). Recently, the increased knowledge in the field of auto inflammation highlighted shared immune mechanisms in the pathogenesis of both classical monogenetic and multifactorial auto inflammatory diseases and a broad spectrum of chronic age-related inflammatory pathologies. The current increase in the prevalence of chronic inflammatory diseases makes this subject of topical interest. In the light of these considerations, we propose an update of auto inflammatory diseases and a new interpretation of auto inflammation with both theoretical and clinical implications.
| S-EPMC3905709 | biostudies-literature
Project description:Autoinflammatory syndromes are characterized by periodic febrile attacks in combination with increased inflammatory markers. The dysregulation of different cellular signaling pathways leads to an excessive immune response, which can in turn promote multisystemic inflammatory processes. Due to overlapping symptoms, variable expressivity and pleiotropy, a purely clinical diagnosis of autoinflammatory diseases is difficult in many cases. Because an early and definitive diagnosis can greatly improve the quality of life of many patients, molecular genetic methods have become an important part of the diagnostic process. With the development of next-generation sequencing (NGS), the genetic diagnosis of patients with autoinflammatory diseases has significantly improved. Considerable progress has not only been made in the genetic characterization of undiagnosed patients, but additionally in identifying numerous new disease-associated genes; however, the plethora of molecular genetic analytical methods makes it difficult to select the method with the highest diagnostic specificity and sensitivity. The NGS technologies have also led to a large increase in the number of identified variants, making the clinical evaluation of these variants more complex. Consensus-driven and standardized molecular diagnostic guidelines, both for the diagnostic process and for the interpretation of the obtained results, have therefore become essential.
| S-EPMC7484157 | biostudies-literature
Project description:Monogenic autoinflammatory disorders are a group of conditions defined by systemic or localized inflammation without identifiable causes, such as infection. In contrast to classical primary immunodeficiencies that manifest with impaired immune responses, these disorders are due to defects in genes that regulate innate immunity leading to constitutive activation of pro-inflammatory signaling. Through studying patients with rare autoinflammatory conditions, novel mechanisms of inflammation have been identified that bare on our understanding not only of basic signaling in inflammatory cells, but also of the pathogenesis of more common inflammatory diseases and have guided treatment modalities. Autoinflammation has further been implicated as an important component of cardiovascular, neurodegenerative, and metabolic syndromes. In this review, we will focus on a subset of inherited enzymatic deficiencies that lead to constitutive inflammation, and how these rare diseases have provided insights into diverse areas of cell biology not restricted to immune cells. In this way, Mendelian disorders of the innate immune system, and in particular loss of catalytic activity of enzymes in distinct pathways, have expanded our understanding of the interplay between many seemingly disparate cellular processes. We also explore the overlap between autoinflammation, autoimmunity, and immunodeficiency, which has been increasingly recognized in patients with dysregulated immune responses.
| S-EPMC6365650 | biostudies-literature
Project description:The systemic autoinflammatory diseases are disorders of the innate immune system distinguished by severe inflammation resulting from dysregulation of the innate immune system. Hereditary fever syndromes, such as FMF, TNF receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes and mevalonate kinase deficiency, were the first group of systemic autoinflammatory diseases for which a genetic basis was established, between 1999 and 2001. Currently according to the latest report of the international union of immunological societies, 37 separate monogenic disorders were classified as autoinflammatory. In addition to the abovementioned monogenic conditions, we describe Schnitzler's syndrome, a well-defined, acquired autoinflammatory condition without a clear genetic basis. For the purposes of this review, we discuss several conditions defined by the latest consensus process as systemic autoinflammatory diseases. We focus on those disorders where recent studies have contributed to further phenotypic characterization or had an impact on clinical management.
| S-EPMC6878846 | biostudies-literature
Project description:The objective of this review is to describe the clinical manifestations of the growing spectrum of monogenic autoinflammatory diseases including recently described syndromes. The autoinflammatory diseases can be grouped based on clinical findings: 1. the three classic hereditary "periodic fever syndromes", familial Mediterranean Fever (FMF); TNF receptor associated periodic syndrome (TRAPS); and mevalonate kinase deficiency/hyperimmunoglobulinemia D and periodic fever syndrome (HIDS); 2. the cryopyrin associated periodic syndromes (CAPS), comprising familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID) or CINCA, and; 3. pediatric granulomatous arthritis (PGA); 4. disorders presenting with skin pustules, including deficiency of interleukin 1 receptor antagonist (DIRA); Majeed syndrome; pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome; deficiency of interleukin 36 receptor antagonist (DITRA); CARD14 mediated psoriasis (CAMPS), and early-onset inflammatory bowel diseases (EO-IBD); 5. inflammatory disorders caused by mutations in proteasome components, the proteasome associated autoinflammatory syndromes (PRAAS) and 6. very rare conditions presenting with autoinflammation and immunodeficiency.
| S-EPMC3769788 | biostudies-literature
Project description:Translating pathogenic insights gained from monogenic defects that cause autoinflammatory diseases into novel therapies has dramatically improved the lives of patients with these syndromes. The last 15 years have focused on the central role of IL-1 in driving autoinflammatory phenotypes and on therapies blocking IL-1 signaling. Recent discoveries from patients unresponsive to IL-1 blockade have highlighted other key inflammatory mediators and pathways. New genetic discoveries have confirmed unifying mechanisms of autoinflammation, including dysregulation of danger sensing, cell stress, and immune-receptor signaling. Recent gene discovery in novel diseases has demonstrated new concepts. First, several complex clinical syndromes, caused by mutations leading to chronic type I interferon (IFN) production present with organ manifestations different from IL-1 mediated diseases including cerebral calcifications, myositis, and interstitial lung disease and the frequent occurrence of autoantibodies. These disorders introduce type I IFN's as inflammatory mediators that cause autoinflammatory phenotypes. Second, conditions associated with high IL-18 production may provide a direct link between autoinflammation and macrophage activation syndrome. Third, dysregulation of inflammatory and cell differentiation pathways in nonhematopoietic cells, such as aberrant calcium signaling and impaired endothelial or keratinocyte development, provide an understanding of organ specificity in autoinflammatory disorders. Many of these discoveries highlight the intricate interconnections between autoinflammation, autoimmunity, immunodeficiency, and lymphoproliferation and suggest ways in which we may better diagnose and treat autoinflammatory diseases.
| S-EPMC4556430 | biostudies-literature