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Frontiers in Immunology 2022Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that... (Review)
Review
Adequate control of autoimmune diseases with an unclear etiology resulting from autoreactivation of the immune system remains a major challenge. One of the factors that trigger autoimmunity is the abnormal induction of cell death and the inadequate clearance of dead cells that leads to the exposure or release of intracellular contents that activate the immune system. Different from other cell death subtypes, such as apoptosis, necroptosis, autophagy, and pyroptosis, ferroptosis has a unique association with the cellular iron load (but not the loads of other metals) and preserves its distinguishable morphological, biological, and genetic features. This review addresses how ferroptosis is initiated and how it contributes to the pathogenesis of autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel diseases. The mechanisms responsible for ferroptosis-associated events are discussed. We also cover the perspective of targeting ferroptosis as a potential therapeutic for patients with autoimmune diseases. Collectively, this review provides up-to-date knowledge regarding how ferroptosis occurs and its significance in autoimmune diseases.
Topics: Apoptosis; Autoimmune Diseases; Autoimmunity; Ferroptosis; Humans; Lupus Erythematosus, Systemic
PubMed: 35720308
DOI: 10.3389/fimmu.2022.916664 -
Nature Reviews. Disease Primers May 2019Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by... (Review)
Review
Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.
Topics: Autoimmunity; Cardiac Resynchronization Therapy; Cardiomyopathy, Dilated; Echocardiography; Electrocardiography; Heart Failure; Humans; Inflammation; Magnetic Resonance Imaging; Prognosis; Quality of Life; Sex Factors
PubMed: 31073128
DOI: 10.1038/s41572-019-0084-1 -
Nature Reviews. Nephrology Aug 2023Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur... (Review)
Review
Autoimmune diseases are a diverse group of conditions characterized by aberrant B cell and T cell reactivity to normal constituents of the host. These diseases occur widely and affect individuals of all ages, especially women. Among these diseases, the most prominent immunological manifestation is the production of autoantibodies, which provide valuable biomarkers for diagnosis, classification and disease activity. Although T cells have a key role in pathogenesis, they are technically more difficult to assay. In general, autoimmune disease results from an interplay between a genetic predisposition and environmental factors. Genetic predisposition to autoimmunity is complex and can involve multiple genes that regulate the function of immune cell populations. Less frequently, autoimmunity can result from single-gene mutations that affect key regulatory pathways. Infection seems to be a common trigger for autoimmune disease, although the microbiota can also influence pathogenesis. As shown in seminal studies, patients may express autoantibodies many years before the appearance of clinical or laboratory signs of disease - a period called pre-clinical autoimmunity. Monitoring autoantibody expression in at-risk populations may therefore enable early detection and the initiation of therapy to prevent or attenuate tissue damage. Autoimmunity may not be static, however, and remission can be achieved by some patients treated with current agents.
Topics: Humans; Female; Genetic Predisposition to Disease; Autoimmune Diseases; Autoimmunity; Autoantibodies; T-Lymphocytes
PubMed: 37165096
DOI: 10.1038/s41581-023-00720-1 -
Nature Genetics Oct 2020We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10)...
We report on the influence of ~22 million variants on 731 immune cell traits in a cohort of 3,757 Sardinians. We detected 122 significant (P < 1.28 × 10) independent association signals for 459 cell traits at 70 loci (53 of them novel) identifying several molecules and mechanisms involved in cell regulation. Furthermore, 53 signals at 36 loci overlapped with previously reported disease-associated signals, predominantly for autoimmune disorders, highlighting intermediate phenotypes in pathogenesis. Collectively, our findings illustrate complex genetic regulation of immune cells with highly selective effects on autoimmune disease risk at the cell-subtype level. These results identify drug-targetable pathways informing the design of more specific treatments for autoimmune diseases.
Topics: Autoimmune Diseases; Autoimmunity; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Italy; Phenotype; Polymorphism, Single Nucleotide
PubMed: 32929287
DOI: 10.1038/s41588-020-0684-4 -
Nature Reviews. Drug Discovery Jan 2021Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches... (Review)
Review
Despite recent advances in the treatment of autoimmune and inflammatory diseases, unmet medical needs in some areas still exist. One of the main therapeutic approaches to alleviate dysregulated inflammation has been to target the activity of kinases that regulate production of inflammatory mediators. Small-molecule kinase inhibitors have the potential for broad efficacy, convenience and tissue penetrance, and thus often offer important advantages over biologics. However, designing kinase inhibitors with target selectivity and minimal off-target effects can be challenging. Nevertheless, immense progress has been made in advancing kinase inhibitors with desirable drug-like properties into the clinic, including inhibitors of JAKs, IRAK4, RIPKs, BTK, SYK and TPL2. This Review will address the latest discoveries around kinase inhibitors with an emphasis on clinically validated autoimmunity and inflammatory pathways.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans; Inflammation; Protein Kinase Inhibitors; Protein Kinases
PubMed: 33077936
DOI: 10.1038/s41573-020-0082-8 -
Current Opinion in Immunology Feb 2023Autoimmunity is characterized by self-reactive immune components and autoimmune disease by autoimmunity plus pathology. Both autoimmunity and autoimmune diseases are... (Review)
Review
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.
Topics: Humans; Autoimmunity; Prevalence; Autoimmune Diseases; Air Pollution
PubMed: 36446151
DOI: 10.1016/j.coi.2022.102266 -
Pharmacological Research Oct 2015Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time.... (Review)
Review
Vaccines and autoimmunity are linked fields. Vaccine efficacy is based on whether host immune response against an antigen can elicit a memory T-cell response over time. Although the described side effects thus far have been mostly transient and acute, vaccines are able to elicit the immune system towards an autoimmune reaction. The diagnosis of a definite autoimmune disease and the occurrence of fatal outcome post-vaccination have been less frequently reported. Since vaccines are given to previously healthy hosts, who may have never developed the disease had they not been immunized, adverse events should be carefully accessed and evaluated even if they represent a limited number of occurrences. In this review of the literature, there is evidence of vaccine-induced autoimmunity and adjuvant-induced autoimmunity in both experimental models as well as human patients. Adjuvants and infectious agents may exert their immune-enhancing effects through various functional activities, encompassed by the adjuvant effect. These mechanisms are shared by different conditions triggered by adjuvants leading to the autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In conclusion, there are several case reports of autoimmune diseases following vaccines, however, due to the limited number of cases, the different classifications of symptoms and the long latency period of the diseases, every attempt for an epidemiological study has so far failed to deliver a connection. Despite this, efforts to unveil the connection between the triggering of the immune system by adjuvants and the development of autoimmune conditions should be undertaken. Vaccinomics is a field that may bring to light novel customized, personalized treatment approaches in the future.
Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Autoimmunity; Humans; Vaccination; Vaccines
PubMed: 26275795
DOI: 10.1016/j.phrs.2015.08.003 -
Clinical Immunology (Orlando, Fla.) Nov 2018Aging of the immune system in humans and animals is characterized by a decline in both adaptive and innate immune responses. Paradoxically, aging is also associated with... (Review)
Review
Aging of the immune system in humans and animals is characterized by a decline in both adaptive and innate immune responses. Paradoxically, aging is also associated with a state of chronic inflammation ("inflammaging") and an increased likelihood of developing autoimmune diseases. Epigenetic changes in non-dividing and dividing cells, including immune cells, due to environmental factors contribute to the inflammation and autoimmunity that characterize both the state and diseases of aging. Here, we review the epigenetic mechanisms involved in the development of immune senescence and autoimmunity in old age.
Topics: Adaptive Immunity; Aging; Autoimmune Diseases; Autoimmunity; Epigenesis, Genetic; Humans; Immunity, Innate; Immunosenescence; Inflammation
PubMed: 29654845
DOI: 10.1016/j.clim.2018.04.002 -
Seminars in Cancer Biology Aug 2020Immune checkpoint inhibitors have emerged as a remarkable treatment option for diverse cancer types. However, a significant number of patients on checkpoint inhibitors... (Review)
Review
Immune checkpoint inhibitors have emerged as a remarkable treatment option for diverse cancer types. However, a significant number of patients on checkpoint inhibitors develop immune-related adverse events (irAEs) affecting a wide variety of organs. These events, which may reflect enhanced T cell activation, are unpredictable, heterogeneous, and in some instances permanent or life-threatening. It is not clear whether these toxicities are distinct from conventional autoimmune diseases or whether the manifestation of irAEs is associated with therapeutic efficacy. Studies across the spectrum of basic, preclinical and clinical research deciphering the role of genetics, epigenetics, gut microbiota and underlying immune status of patients who develop irAEs are required to gain a deeper mechanistic understanding. Insights gained from such studies will facilitate identification of biomarkers for optimal treatment and clinical management of patients. In this Review, we provide basic and clinical understanding of immune checkpoint inhibitors and irAEs. We discuss the connection between immune system, autoimmunity and cancer; immune checkpoint inhibitors and associated autoimmune toxicities; insights into potential underlying mechanisms of irAEs; impact of autoimmune diagnosis on cancer outcome; and management of irAEs.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Biomarkers, Tumor; Humans; Immunologic Factors; Immunotherapy; Neoplasms
PubMed: 31330185
DOI: 10.1016/j.semcancer.2019.06.012 -
Schizophrenia Research Sep 2016Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain,... (Review)
Review
Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis is a recently-discovered synaptic autoimmune disorder in which auto-antibodies target NMDARs in the brain, leading to their removal from the synapse. Patients manifest with prominent psychiatric symptoms - and in particular psychosis - early in the disease course. This presentation converges with long-standing evidence on multiple fronts supporting the glutamatergic model of schizophrenia. We review mechanisms underlying disease in anti-NMDAR encephalitis, and discuss its role in furthering our understanding of neural circuit dysfunction in schizophrenia.
Topics: Anti-N-Methyl-D-Aspartate Receptor Encephalitis; Autoimmunity; Humans; Psychotic Disorders; Schizophrenia
PubMed: 25458857
DOI: 10.1016/j.schres.2014.10.007