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The New England Journal of Medicine Sep 2020
Review
Topics: Antigen-Presenting Cells; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Immunotherapy; Metabolic Networks and Pathways; Thymus Gland
PubMed: 32937048
DOI: 10.1056/NEJMra1911109 -
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 -
Science China. Life Sciences Jul 2023With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between... (Review)
Review
With the exception of an extremely small number of cases caused by single gene mutations, most autoimmune diseases result from the complex interplay between environmental and genetic factors. In a nutshell, etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage. In recent years, population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity, providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways. In this review, we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics. An overview of the genetic basis of autoimmunity is followed by 3 chapters detailing susceptibility genes involved in innate immunity, adaptive immunity and inflammatory cell death processes respectively. With such attempts, we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the 'usual suspects' of a limited subset of validated therapeutic targets.
Topics: Humans; Autoimmune Diseases; Immunity, Innate; Autoimmunity; Adaptive Immunity; Genetic Predisposition to Disease
PubMed: 36738430
DOI: 10.1007/s11427-021-2187-3 -
Nature Reviews. Immunology May 2024The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for... (Review)
Review
The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction.
Topics: Humans; Immune Tolerance; Animals; Antigens; Autoimmunity; Organ Transplantation; Autoimmune Diseases
PubMed: 38086932
DOI: 10.1038/s41577-023-00970-x -
Frontiers in Immunology 2021The distinguishing of the IgG4-related disease (IgG4-RD) from among other rheumatic diseases has brought attention to the IgG4 subclass of immunoglobulins. It is the... (Review)
Review
The distinguishing of the IgG4-related disease (IgG4-RD) from among other rheumatic diseases has brought attention to the IgG4 subclass of immunoglobulins. It is the least numerous subclass among immunoglobulins G. In general, IgG4 is considered to be non-inflammatory and tolerance inducing, due to its unique structure. However, in IgG4-RD this antibody plays a pathogenic role in activation of the fibrinogenesis and of the inflammatory process; there are also suggestions that it may be a marker of an abnormal inflammatory response. The importance of IgG4 for the pathogenesis of allergic diseases, with a vital role of its ratio to immunoglobulin E (IgE/IgG4 ratio), has been known for years. The role of IgG4 in the course and pathogenesis of rheumatic diseases is still being researched and is not yet fully understood. Increased IgG4 levels have been revealed in rheumatoid arthritis, although no clear link between this phenomenon and disease activity has been demonstrated. There are articles on the potential importance of IgG4 concentration (of both elevated and decreased serum levels) in Sjogren's syndrome. Additionally, anti-nuclear IgG4 antibody significant titers have been detected in SLE patients, and it has been suggested that the effect of these antibodies on complement consumption and the production of proinflammatory cytokines may play a role in inhibiting the progression of SLE. IgG4 plays a role in autoimmune diseases other than rheumatic diseases, such as pemphigus, bullous pemphigoid, idiopathic membranous glomerulonephritis, or myasthenia gravis, but also in helmints infections. Research shows the importance of IgG4 in malignancy of neoplasms. Melanoma cells are known to stimulate IgG4 production through a modified Th2-based inflammatory response. The role of this immunoglobulin in cholangiocarcinoma is also considered as possible. The aim of this review article is to discuss the current knowledge of IgG4 not only from the perspective of the IgG4-RD but also from a point of view of other autoimmune diseases with particular emphasis on rheumatic diseases.
Topics: Animals; Autoimmunity; Humans; Immunoglobulin G; Rheumatic Diseases
PubMed: 35145508
DOI: 10.3389/fimmu.2021.787422 -
Frontiers in Immunology 2018In addition to determining biological sex, sex hormones are known to influence health and disease regulation of immune cell activities and modulation of target-organ... (Review)
Review
In addition to determining biological sex, sex hormones are known to influence health and disease regulation of immune cell activities and modulation of target-organ susceptibility to immune-mediated damage. Systemic autoimmune disorders, such as systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis are more prevalent in females, while cancer shows the opposite pattern. Sex hormones have been repeatedly suggested to play a part in these biases. In this review, we will discuss how androgens and the expression of functional androgen receptor affect immune cells and how this may dampen or alter immune response(s) and affect autoimmune disease incidences and progression.
Topics: Androgens; Animals; Autoimmune Diseases; Autoimmunity; Female; Humans; Immune Tolerance; Male; Sex Characteristics
PubMed: 29755457
DOI: 10.3389/fimmu.2018.00794 -
Science (New York, N.Y.) Mar 2018Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut...
Despite multiple associations between the microbiota and immune diseases, their role in autoimmunity is poorly understood. We found that translocation of a gut pathobiont, , to the liver and other systemic tissues triggers autoimmune responses in a genetic background predisposing to autoimmunity. Antibiotic treatment prevented mortality in this model, suppressed growth of in tissues, and eliminated pathogenic autoantibodies and T cells. Hepatocyte- cocultures induced autoimmune-promoting factors. Pathobiont translocation in monocolonized and autoimmune-prone mice induced autoantibodies and caused mortality, which could be prevented by an intramuscular vaccine targeting the pathobiont. -specific DNA was recovered from liver biopsies of autoimmune patients, and cocultures with human hepatocytes replicated the murine findings; hence, similar processes apparently occur in susceptible humans. These discoveries show that a gut pathobiont can translocate and promote autoimmunity in genetically predisposed hosts.
Topics: Animals; Anti-Bacterial Agents; Autoantibodies; Autoimmune Diseases; Autoimmunity; Bacterial Translocation; Bacterial Vaccines; DNA, Bacterial; Enterococcus; Gastrointestinal Microbiome; Genetic Predisposition to Disease; Hepatocytes; Humans; Liver; Mice; T-Lymphocytes
PubMed: 29590047
DOI: 10.1126/science.aar7201 -
Cells Apr 2020Following fifteen years of research, neutrophil extracellular traps (NETs) are widely reported in a large range of inflammatory infectious and non-infectious diseases.... (Review)
Review
Following fifteen years of research, neutrophil extracellular traps (NETs) are widely reported in a large range of inflammatory infectious and non-infectious diseases. Cumulating evidences from in vitro, in vivo and clinical diagnostics suggest that NETs may play a crucial role in inflammation and autoimmunity in a variety of autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV). Most likely, NETs contribute to breaking self-tolerance in autoimmune diseases in several ways. During this review, we discuss the current knowledge on how NETs could drive autoimmune responses. NETs can break self-tolerance by being a source of autoantigens for autoantibodies found in autoimmune diseases, such as anti-citrullinated protein antibodies (ACPAs) in RA, anti-dsDNA in SLE and anti-myeloperoxidase and anti-protein 3 in AAV. Moreover, NET components could accelerate the inflammatory response by mediating complement activation, acting as danger-associated molecular patterns (DAMPs) and inflammasome activators, for example. NETs also can activate other immune cells, such as B cells, antigen-presenting cells and T cells. Additionally, impaired clearance of NETs in autoimmune diseases prolongs the presence of active NETs and their components and, in this way, accelerate immune responses. NETs have not only been implicated as drivers of inflammation, but also are linked to resolution of inflammation. Therefore, NETs may be central regulators of inflammation and autoimmunity, serve as biomarkers, as well as promising targets for future therapeutics of inflammatory autoimmune diseases.
Topics: Autoimmune Diseases; Autoimmunity; Extracellular Traps; Humans; Inflammation
PubMed: 32276504
DOI: 10.3390/cells9040915 -
Frontiers of Hormone Research 2017Pituitary autoimmunity, considered a synonym of autoimmune hypophysitis, defines a wide spectrum of conditions (neoplastic, functional, and iatrogenic pituitary... (Review)
Review
Pituitary autoimmunity, considered a synonym of autoimmune hypophysitis, defines a wide spectrum of conditions (neoplastic, functional, and iatrogenic pituitary disorders; and extra-pituitary autoimmune and non-autoimmune diseases), and is characterized by the presence of antipituitary antibodies (APAs) at various titer and prevalence. These conditions have been increasingly recognized not only in adults, but also in children. The autoimmune pathogenesis, histological features of the primary (i.e. lymphocytic, granulomatous, xanthomatous, IgG-4 related lymphoplasmacytic, and necrotizing) forms, and the pathognomonic association of lymphocytic hypophysitis with pregnancy and CTLA-4 antibody therapy, have been clearly demonstrated. Meanwhile, non-invasive differential diagnosis remains extremely challenging since none of the suggested clinical, radiological or laboratory criteria are pathognomonic. In this context, the demonstration of APA is not sufficient, because of the lack of specificity, and associated methodological and theoretical issues (i.e. disease marker vs. pathogen; antigen target(s); and diagnostic/prognostic significance). This chapter aims at providing a comprehensive overview of the pituitary autoimmunity panorama for epidemiological, clinical radiological, and histological aspects, while discussing the main diagnostic limitations and issues associated with disease management.
Topics: Autoimmune Diseases; Autoimmunity; Humans; Pituitary Diseases; Pituitary Gland
PubMed: 28245451
DOI: 10.1159/000452905 -
Clinical Immunology (Orlando, Fla.) Mar 2017Autophagy is a highly conserved protein degradation pathway from yeasts to humans that is essential for removing protein aggregates and misfolded proteins in healthy... (Review)
Review
Autophagy is a highly conserved protein degradation pathway from yeasts to humans that is essential for removing protein aggregates and misfolded proteins in healthy cells. Recently, autophagy-related genes polymorphisms have been implicated in several autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and multiple sclerosis. Numerous studies reveal autophagy and autophagy-related proteins also participate in immune regulation. Conditional deletions of autophagy-related proteins in mice have rendered protection from experimental autoimmune encephalomyelitis, and TNF-mediated joint destruction in animal models of multiple sclerosis and experimental arthritis respectively. As autophagy is strongly implicated in immune functions such as removal of intracellular bacteria, inflammatory cytokine secretion, antigen presentation, and lymphocyte development, in this review we summarized current understanding of the roles of autophagy and autophagy proteins in autoimmune diseases.
Topics: Animals; Antigen Presentation; Autoimmune Diseases; Autoimmunity; Autophagy; Humans
PubMed: 28095319
DOI: 10.1016/j.clim.2017.01.007