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Nature Communications Sep 2017Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon...
Cyclic GMP-AMP synthase is essential for innate immunity against infection and cellular damage, serving as a sensor of DNA from pathogens or mislocalized self-DNA. Upon binding double-stranded DNA, cyclic GMP-AMP synthase synthesizes a cyclic dinucleotide that initiates an inflammatory cellular response. Mouse studies that recapitulate causative mutations in the autoimmune disease Aicardi-Goutières syndrome demonstrate that ablating the cyclic GMP-AMP synthase gene abolishes the deleterious phenotype. Here, we report the discovery of a class of cyclic GMP-AMP synthase inhibitors identified by a high-throughput screen. These compounds possess defined structure-activity relationships and we present crystal structures of cyclic GMP-AMP synthase, double-stranded DNA, and inhibitors within the enzymatic active site. We find that a chemically improved member, RU.521, is active and selective in cellular assays of cyclic GMP-AMP synthase-mediated signaling and reduces constitutive expression of interferon in macrophages from a mouse model of Aicardi-Goutières syndrome. RU.521 will be useful toward understanding the biological roles of cyclic GMP-AMP synthase and can serve as a molecular scaffold for development of future autoimmune therapies.Upon DNA binding cyclic GMP-AMP synthase (cGAS) produces a cyclic dinucleotide, which leads to the upregulation of inflammatory genes. Here the authors develop small molecule cGAS inhibitors, functionally characterize them and present the inhibitor and DNA bound cGAS crystal structures, which will facilitate drug development.
Topics: Animals; Autoimmune Diseases; Autoimmune Diseases of the Nervous System; Autoimmunity; Benzofurans; DNA; Enzyme Inhibitors; High-Throughput Screening Assays; Immunity, Innate; Inflammation; Macrophages; Mass Spectrometry; Mice; Nervous System Malformations; Nucleotidyltransferases; Small Molecule Libraries; Structure-Activity Relationship
PubMed: 28963528
DOI: 10.1038/s41467-017-00833-9 -
Cells Feb 2023Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...].
Autoreactive B cells play a key role in the initiation or aggravation of many systemic and tissue-specific autoimmune disorders [...].
Topics: Humans; Autoimmunity; Autoimmune Diseases; B-Lymphocytes; Signal Transduction
PubMed: 36766841
DOI: 10.3390/cells12030499 -
Current Psychiatry Reports Aug 2019Here, we propose to review the immuno-inflammatory hypothesis in OCD given the concurrent incidence of autoimmune comorbidities, infectious stigma, and raised levels of... (Review)
Review
PURPOSE OF REVIEW
Here, we propose to review the immuno-inflammatory hypothesis in OCD given the concurrent incidence of autoimmune comorbidities, infectious stigma, and raised levels of inflammatory markers in a significant subset of patients. A better understanding of the immune dysfunction in OCD may allow stratifying the patients in order to design personalized pharmaco/psychotherapeutic strategies.
RECENT FINDINGS
A persistent low-grade inflammation involving both innate and adaptive immune system with coexisting autoimmune morbidities and stigma of infectious events has been prominently observed in OCD. Hence, specific treatments targeting inflammation/infection are a feasible alternative in OCD. This review highlights that OCD is associated with low-grade inflammation, neural antibodies, and neuro-inflammatory and auto-immune disorders. In some subset of OCD patients, autoimmunity is likely triggered by specific bacterial, viral, or parasitic agents with overlapping surface epitopes in CNS. Hence, subset-profiling in OCD is warranted to benefit from distinct immune-targeted treatment modalities.
Topics: Autoimmunity; Humans; Inflammation; Neurons; Obsessive-Compulsive Disorder
PubMed: 31367805
DOI: 10.1007/s11920-019-1062-8 -
Rheumatic Diseases Clinics of North... Aug 2020Clonal hematopoiesis has been linked with the development of hematologic malignancy and atherosclerotic cardiovascular disease; however, the association with autoimmune... (Review)
Review
Clonal hematopoiesis has been linked with the development of hematologic malignancy and atherosclerotic cardiovascular disease; however, the association with autoimmune diseases remains to be defined. The link between autoimmune diseases and myeloid neoplasms (MNs) is complex, often multifactorial, and seems bidirectional. The limited data suggest an increased risk of MNs in rheumatoid arthritis and systemic lupus erythematosus. Paraneoplastic manifestations of MN include arthritis, vasculitis, and connective tissue disease. Treatment options for autoimmune disease such as cyclophosphamide and azathioprine have been associated with MNs, whereas the data for methotrexate and tumor necrosis factor inhibitors are equivocal.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Clonal Hematopoiesis; Humans; Leukemia, Myeloid; Myelodysplastic Syndromes
PubMed: 32631598
DOI: 10.1016/j.rdc.2020.03.001 -
Current Alzheimer Research 2018Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language... (Review)
Review
BACKGROUND
Frontotemporal Dementia (FTD) is a neurodegenerative disorder which asymmetrically affects the frontotemporal lobe, characterized by behavioural abnormalities, language impairment, and deficits of executive functions. Genetic studies identified mutations causing the disease, namely Microtubule Associated Protein Tau (MAPT), Granulin (GRN) and chromosome 9 open reading frame 72 (C9orf72) mutations, which contributed to elucidate the molecular pathways involved in brain depositions of either Tau or TAR DNA-binding protein 43 (TDP43) inclusions. However, in the majority of sporadic FTD patients, the mechanisms triggering Tau or TDP43 protein deposition are still to be uncovered.
OBJECTIVE
We aimed to present an extensive evaluation of literature data on immune homeostasis in FTD, in order to provide potentially evidence-based approaches for a disease still orphan of any treatment.
METHODS
A structured search of bibliographic databases from peer-reviewed literature was pursued focusing on autoimmunity in the brain and FTD.
RESULTS
One-hundred-fourteen papers were included in this review. The majority of studies (32) were represented by extensive literature revision on immunity, central nervous system (CNS) and autoimmunity; neuroimaging papers (11) in autoimmune diseases were evaluated, and immunomodulatory approaches (25) were revised. Six papers were found specifically related to FTD and autoimmune hypothesis, the other papers referring to current state of art on FTD.
CONCLUSION
Overall this review contribute to expand the knowledge of a possible immune hypothesis in FTD, suggesting therapeutic perspectives in autoimmune related neurodegeneration, to reduce or revert the disease.
Topics: Animals; Autoimmunity; Brain; Frontotemporal Dementia; Humans
PubMed: 29357796
DOI: 10.2174/1567205015666180119104825 -
Cells Aug 2021Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in... (Review)
Review
Autoimmune diseases are among the most common chronic illness caused by a dysregulated immune response against self-antigens. Close to 5% of the general population in Western countries develops some form of autoimmunity, yet its underlying causes, although intensively studied, are still not fully known, and no curative therapies exist. It is well established that autoimmune diseases have common mechanisms and are caused by both genetic and non-genetic risk factors. One novel risk factor that can contribute to autoimmunity is somatic mutations, in a role parallel to their role in cancer. Somatic mutations are stochastic, , non-inherited mutations. In this hypothesis, the persistent proliferation of self-reactive lymphocytes (that is usually hindered by a series of checkpoints) is permitted, due to somatic mutations in these expanding cells, allowing them to bypass multiple regulatory checkpoints, causing autoimmunity. This novel concept of the contribution of these mutations in non-malignant diseases has recently started to be explored. It proposes a novel paradigm for autoimmunity etiology and could be the missing piece of the autoimmunity puzzle.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Proliferation; Humans; Lymphocytes; Mutation
PubMed: 34440825
DOI: 10.3390/cells10082056 -
Frontiers in Immunology 2023MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression in ubiquitous biological processes, including immune-related pathways. This review... (Review)
Review
MicroRNAs (miRNAs) are crucial post-transcriptional regulators of gene expression in ubiquitous biological processes, including immune-related pathways. This review focuses on the miR-183/96/182 cluster (miR-183C), which contains three miRNAs, miR-183, -96, and -182, having almost identical seed sequences with minor differences. The similarity among seed sequences allows these three miRNAs to act cooperatively. In addition, their minor differences permit them to target distinct genes and regulate unique pathways. The expression of miR-183C was initially identified in sensory organs. Subsequently, abnormal expression of miR-183C miRNAs in various cancers and autoimmune diseases has been reported, implying their potential role in human diseases. The regulatory effects of miR-183C miRNAs on the differentiation and function of both innate and adaptive immune cells have now been documented. In this review, we have discussed the complex role of miR-183C in the immune cells in both normal and autoimmune backgrounds. We highlighted the dysregulation of miR-183C miRNAs in several autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and ocular autoimmune disorders, and discussed the potential for utilizing miR-183C as biomarkers and therapeutic targets of specific autoimmune diseases.
Topics: Humans; Autoimmunity; Gene Expression Regulation; Autoimmune Diseases; MicroRNAs; Lupus Erythematosus, Systemic
PubMed: 36891312
DOI: 10.3389/fimmu.2023.1134634 -
Current Opinion in Rheumatology Jan 2019To give an overview of recently published articles addressing the mechanisms underlying sex bias in autoimmune disease. (Review)
Review
PURPOSE OF REVIEW
To give an overview of recently published articles addressing the mechanisms underlying sex bias in autoimmune disease.
RECENT FINDINGS
Recent studies investigating the origins of sex bias in autoimmune disease have revealed an extensive and interconnected network of genetic, hormonal, microbial, and environmental influences. Investigation of sex hormones has moved beyond profiling the effects of hormones on activity and prevalence of immune cell types to defining the specific immunity-related genes driving these changes. Deeper examination of the genetic content of the X and Y chromosomes and genetic escapees of X chromosome inactivation has revealed some key drivers of female-biased autoimmunity. Animal studies are offering further insights into the connections among microbiota, particularly that of the gut, and the immune system.
SUMMARY
Sex bias in autoimmune disease is the manifestation of a complex interplay of the sex chromosomes, sex hormones, the microbiota, and additional environmental and sociological factors.
Topics: Autoimmune Diseases; Autoimmunity; Female; Humans; Male; Microbiota; Sex Characteristics; Sex Factors
PubMed: 30394940
DOI: 10.1097/BOR.0000000000000564 -
Expert Opinion on Drug Safety Mar 2015Drug-induced lupus (DIL) refers to an idiosyncratic side effect of numerous, apparently unrelated, medications, in which symptoms overlap with those of systemic lupus... (Review)
Review
INTRODUCTION
Drug-induced lupus (DIL) refers to an idiosyncratic side effect of numerous, apparently unrelated, medications, in which symptoms overlap with those of systemic lupus erythematosus. DIL is reversible by discontinuation of the medication. The etiological mechanism underlying DIL is linked to the inherent susceptibility of the adaptive immune system to lapse into auto-reactivity.
AREAS COVERED
Clinical and laboratory features of DIL will be compared with those of idiopathic systemic lupus and with other types of drug reactions with overlapping features. Formerly commonly-used drugs conferred very high risk of developing DIL, although the probability of developing DIL has not been established with most lupus-inducing drugs. Pharmacological or physiochemical properties of the parent compounds are uninformative, but the importance of reactive drug metabolites in initiating autoimmunity will be discussed. As with most systemic autoimmune diseases, the pathogenesis of DIL is complex and obscure. The role of complement and human leukocyte allotypes as well as drug acetylator phenotype inform the underlying mechanism, and several of these non-mutually exclusive concepts will be described.
EXPERT OPINION
The pros and cons of proposed mechanisms for DIL will be discussed in the context of current understanding of autoimmunity and immune tolerance to self.
Topics: Animals; Autoimmunity; Drug-Related Side Effects and Adverse Reactions; HLA Antigens; Humans; Immune Tolerance; Lupus Erythematosus, Systemic
PubMed: 25554102
DOI: 10.1517/14740338.2015.995089 -
Jornal de Pediatria 2021Classical immunodeficiencies are mainly characterized by infectious conditions. In recent years, manifestations related to allergy, inflammation, autoimmunity,... (Review)
Review
OBJECTIVES
Classical immunodeficiencies are mainly characterized by infectious conditions. In recent years, manifestations related to allergy, inflammation, autoimmunity, lymphoproliferation, and malignancies related to this group of diseases have been described. The text intends to make an update on the non-infectious manifestations of the primary defects of the immune system.
SOURCE OF DATA
Searches were carried out in the PubMed database for review articles published in the last five years, in English, French, or Spanish, using the terms "allergy," "inflammation," "autoimmunity," "lymphoproliferation," "cancer," AND "immunodeficiency" or "primary immunodeficiency" or "inborn errors of immunity" NOT "HIV".
SYNTHESIS OF DATA
Non-infectious manifestations characterize the primary defects in which there is dysregulation of the immune system. The most common manifestations of autoimmunity in this group of diseases are autoimmune cytopenias. Exacerbated inflammatory processes, benign lymphoproliferation, and propensity to malignancy of the lymphoreticular system are related to several diseases in this group. Severe manifestations of atopy or food allergy characterize some immunodeficiencies. Disorders of inborn immunity of the autoinflammatory type are characterized by an aseptic inflammatory process in the absence of autoimmunity, with fever and recurrent manifestations in different organs.
CONCLUSIONS
Not only infectious conditions should raise the suspicion of immunodeficiencies, but also manifestations of allergy, inflammation, autoimmunity, lymphoproliferation, or cancer, especially if they are recurrent, associated to each other, affecting young patients, or in severe and/or difficult to treat conditions.
Topics: Autoimmunity; Humans; Immunologic Deficiency Syndromes; Inflammation; Neoplasms
PubMed: 33176164
DOI: 10.1016/j.jped.2020.10.004