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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 -
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 -
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 -
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 -
Cellular & Molecular Immunology May 2011The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose... (Review)
Review
The etiology of autoimmune diseases remains largely unknown. Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients. These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity. Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases. In recent years, several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation. More specifically, data support the impact of epigenetic changes in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis and other autoimmune diseases, in some cases based on mechanistical observations. We herein discuss what we currently know and what we expect will come in the next future. Ultimately, epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Histones; Humans; Protein Processing, Post-Translational
PubMed: 21278766
DOI: 10.1038/cmi.2010.78 -
International Journal of... 2013Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the... (Review)
Review
Vaccines have eradicated or controlled many infectious diseases, saving each year millions of lives and quality of life of many other millions of people. In spite of the success of vaccines over the last two centuries, parents (and also some health care workers) gloss over the devastating consequences of diseases, which are now avoided thanks to vaccines, and direct their attention to possible negative effects of immunization. Three immunological objections are raised: vaccines cause antigenic overload, natural immunity is safer and better than vaccine-induced immunity, and vaccines induce autoimmunity. The last point is examined in this review. Theoretically, vaccines could trigger autoimmunity by means of cytokine production, anti-idiotypic network, expression of human histocompatibility leukocyte antigens, modification of surface antigens and induction of novel antigens, molecular mimicry, bystander activation, epitope spreading, and polyclonal activation of B cells. There is strong evidence that none of these mechanisms is really effective in causing autoimmune diseases. Vaccines are not a source of autoimmune diseases. By contrast, absolute evidence exists that infectious agents can trigger autoimmune mechanisms and that they do cause autoimmune diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Communicable Disease Control; Humans; Immunization Schedule; Patient Selection; Risk Factors; Vaccines
PubMed: 23755743
DOI: 10.1177/039463201302600201 -
Frontiers in Immunology 2022A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to... (Review)
Review
A dysregulated immune response toward self-antigens characterizes autoimmune and autoinflammatory (AIF) disorders. Autoantibodies or autoreactive T cells contribute to autoimmune diseases, while autoinflammation results from a hyper-functional innate immune system. Aside from their differences, many studies suggest that monocytes and macrophages (Mo/Ma) significantly contribute to the development of both types of disease. Mo/Ma are innate immune cells that promote an immune-modulatory, pro-inflammatory, or repair response depending on the microenvironment. However, understanding the contribution of these cells to different immune disorders has been difficult due to their high functional and phenotypic plasticity. Several factors can influence the function of Mo/Ma under the landscape of autoimmune/autoinflammatory diseases, such as genetic predisposition, epigenetic changes, or infections. For instance, some vaccines and microorganisms can induce epigenetic changes in Mo/Ma, modifying their functional responses. This phenomenon is known as trained immunity. Trained immunity can be mediated by Mo/Ma and NK cells independently of T and B cell function. It is defined as the altered innate immune response to the same or different microorganisms during a second encounter. The improvement in cell function is related to epigenetic and metabolic changes that modify gene expression. Although the benefits of immune training have been highlighted in a vaccination context, the effects of this type of immune response on autoimmunity and chronic inflammation still remain controversial. Induction of trained immunity reprograms cellular metabolism in hematopoietic stem cells (HSCs), transmitting a memory-like phenotype to the cells. Thus, trained Mo/Ma derived from HSCs typically present a metabolic shift toward glycolysis, which leads to the modification of the chromatin architecture. During trained immunity, the epigenetic changes facilitate the specific gene expression after secondary challenge with other stimuli. Consequently, the enhanced pro-inflammatory response could contribute to developing or maintaining autoimmune/autoinflammatory diseases. However, the prediction of the outcome is not simple, and other studies propose that trained immunity can induce a beneficial response both in AIF and autoimmune conditions by inducing anti-inflammatory responses. This article describes the metabolic and epigenetic mechanisms involved in trained immunity that affect Mo/Ma, contraposing the controversial evidence on how it may impact autoimmune/autoinflammation conditions.
Topics: Autoimmune Diseases; Autoimmunity; Hereditary Autoinflammatory Diseases; Humans; Immunity, Innate; Killer Cells, Natural
PubMed: 35464438
DOI: 10.3389/fimmu.2022.868343 -
Nature Reviews. Immunology Feb 2023Self-reactive immune responses occur in autoimmune diseases and also in chronic inflammatory and metabolic diseases that are not generally considered as autoimmune...
Self-reactive immune responses occur in autoimmune diseases and also in chronic inflammatory and metabolic diseases that are not generally considered as autoimmune diseases. How do the mechanisms of autoreactivity in the different settings overlap and how are they distinguished? Evidence indicates that while autoimmune diseases rely on both a supportive genetic background and a cooperative environment, chronic inflammatory and metabolic diseases strongly hinge on a conducive milieu for the activation of pathogenic autoreactive cells even in the absence of facilitating polygenic factors.
Topics: Humans; Autoimmunity; Autoantibodies
PubMed: 36418434
DOI: 10.1038/s41577-022-00812-2 -
Rheumatic Diseases Clinics of North... Feb 2018Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from... (Review)
Review
Autoimmune liver diseases coexist with rheumatic disorders in approximately 30% of cases and may also share pathogenic mechanisms. Autoimmune liver diseases result from an immune-mediated injury of different tissues, with autoimmune hepatitis (AIH) targeting hepatocytes, and primary biliary cholangitis (PBC) and primary sclerosing cholangitis targeting cholangiocytes. Sjogren syndrome is diagnosed in 7% of AIH cases and serologic autoimmunity profiles are a common laboratory abnormality, particularly in the case of serum antimitochondrial (PBC) or anti-liver kidney microsomal antibodies (AIH). Therapeutic strategies may overlap between rheumatic and autoimmune liver diseases and practitioners should be vigilant in managing bone loss.
Topics: Autoimmunity; Diagnosis, Differential; Genetic Predisposition to Disease; Hepatitis, Autoimmune; Humans; Precision Medicine; Rheumatic Diseases
PubMed: 29149928
DOI: 10.1016/j.rdc.2017.09.008 -
BMC Medicine Mar 2014Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to... (Review)
Review
Immunologic research into pathogenic mechanisms operating in autoimmune-mediated atherosclerosis initially focused on adaptive immunity. Current interest is directed to more basic inflammatory mechanisms. Chronic inflammation (innate immunity-associated) may trigger initial events that can lead to atherosclerotic cardiovascular disease. This chronic inflammation may start early in life and be perpetuated by classic atherosclerosis risk factors. Lipid peroxidation of low-density lipoprotein seems to be a key event in the initiation and progression of atherosclerosis. Oxidized low-density lipoprotein triggers inflammatory and immunogenic events that promote endothelial dysfunction and the synthesis and secretion of pro-inflammatory cytokines, leading to an autoimmune response capable of accelerating the intracellular accumulation of lipids within atherosclerotic plaques. Oxidized low-density lipoprotein binds β2-glycoprotein I to form circulating complexes found in both autoimmune and non-autoimmune atherosclerosis. It is likely that β2-glycoprotein I and/or these complexes contribute to early atherogenesis by stimulating pro-inflammatory innate immunity through endogenous sensors and inflammasome/interleukin-1 pathways. We discuss the chronic inflammatory (innate) and autoimmune (adaptive) responses operating in atherosclerosis to discern the role of autoimmunity in atherosclerotic cardiovascular disease.
Topics: Adaptive Immunity; Animals; Atherosclerosis; Autoimmune Diseases; Autoimmunity; Humans; Immunity, Innate
PubMed: 24642015
DOI: 10.1186/1741-7015-12-47