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Advanced Drug Delivery Reviews Dec 2023The high prevalence and rising incidence of autoimmune diseases have become a prominent public health issue. Autoimmune disorders result from the immune system... (Review)
Review
The high prevalence and rising incidence of autoimmune diseases have become a prominent public health issue. Autoimmune disorders result from the immune system erroneously attacking the body's own healthy cells and tissues, causing persistent inflammation, tissue injury, and impaired organ function. Existing treatments primarily rely on broad immunosuppression, leaving patients vulnerable to infections and necessitating lifelong treatments. To address these unmet needs, an emerging frontier of vaccine development aims to restore immune equilibrium by inducing immune tolerance to autoantigens, offering a potential avenue for a cure rather than mere symptom management. We discuss this burgeoning field of vaccine development against inflammation and autoimmune diseases, with a focus on common autoimmune disorders, including multiple sclerosis, type 1 diabetes, rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematosus. Vaccine-based strategies provide a new pathway for the future of autoimmune disease therapeutics, heralding a new era in the battle against inflammation and autoimmunity.
Topics: Humans; Autoimmune Diseases; Lupus Erythematosus, Systemic; Autoimmunity; Immune Tolerance; Inflammation; Vaccines
PubMed: 37980949
DOI: 10.1016/j.addr.2023.115140 -
Frontiers in Immunology 2023Laminin 332 is a heterotrimeric structural protein of the basal membrane zone (BMZ) of the skin and adjacent mucosal tissues. The importance of laminin 332 for the... (Review)
Review
Laminin 332 is a heterotrimeric structural protein of the basal membrane zone (BMZ) of the skin and adjacent mucosal tissues. The importance of laminin 332 for the structural integrity of the BMZ is demonstrated by mutations in any of the three genes encoding for its three chains causing variants of junctional epidermolysis bullosa. Autoimmunity against laminin 332 is observed in mucous membrane pemphigoid (MMP) and in the rare patients with orf-induced pemphigoid. MMP is an autoimmune blistering disease with predominant mucosal manifestations and autoantibodies against the BMZ of the skin and orifice-close mucous membranes. The main autoantigens of MMP are type XVII collagen (BP180) and laminin 332 targeted in about 80% and 10-20% of patients, respectively. An increasing number of studies has highlighted the association of anti-laminin 332 MMP and malignancies that can be revealed in about a quarter of these patients. This data has led to the recommendation of current guidelines to assay for anti-laminin 332 reactivity in all MMP patients. The present review focuses on anti-laminin 332 MMP describing clinical features, its pathophysiology, and detection of serum anti-laminin 332 IgG. In addition, the available data about the occurrence of malignancies in anti-laminin 332 MMP, the underlying tumor entities, and its biology are detailed.
Topics: Humans; Autoimmunity; Pemphigoid, Bullous; Autoantibodies; Skin; Biological Assay
PubMed: 37638011
DOI: 10.3389/fimmu.2023.1250115 -
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 -
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 -
Frontiers in Immunology 2022Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but... (Review)
Review
Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop , throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids. The most common autoimmune endocrinopathies in pregnant women are Hashimoto's disease, Graves' disease, and, more rarely, primary adrenal insufficiency in the form of Addison's disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women.
Topics: Autoimmune Diseases; Autoimmunity; Female; Graves Disease; Humans; Placenta; Pregnancy; Progesterone
PubMed: 35844617
DOI: 10.3389/fimmu.2022.907561 -
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 -
Frontiers in Immunology 2022The gut microbiota plays a major role in the developmental biology and homeostasis of cells belonging to the adaptive and innate arms of the immune system. Alterations... (Review)
Review
The gut microbiota plays a major role in the developmental biology and homeostasis of cells belonging to the adaptive and innate arms of the immune system. Alterations in its composition, which are known to be regulated by both genetic and environmental factors, can either promote or suppress the pathogenic processes underlying the development of various autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis, to just name a few. Cross-recognition of gut microbial antigens by autoreactive T cells as well as gut microbe-driven alterations in the activation and homeostasis of effector and regulatory T cells have been implicated in this process. Here, we summarize our current understanding of the positive and negative associations between alterations in the composition of the gut microbiota and the development of various autoimmune disorders, with a special emphasis on antigenic mimicry.
Topics: Autoimmune Diseases; Autoimmunity; Gastrointestinal Microbiome; Humans; Lupus Erythematosus, Systemic; Molecular Mimicry
PubMed: 35572569
DOI: 10.3389/fimmu.2022.873607