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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 -
Cellular & Molecular Immunology Apr 2023Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development, activation and effector phases of T and B... (Review)
Review
Immune tolerance deletes or suppresses autoreactive lymphocytes and is established at multiple levels during the development, activation and effector phases of T and B cells. These mechanisms are cell-intrinsically programmed and critical in preventing autoimmune diseases. We have witnessed the existence of another type of immune tolerance mechanism that is shaped by lifestyle choices, such as diet, microbiome and microbial metabolites. Short-chain fatty acids (SCFAs) are the most abundant microbial metabolites in the colonic lumen and are mainly produced by the microbial fermentation of prebiotics, such as dietary fiber. This review focuses on the preventive and immunomodulatory effects of SCFAs on autoimmunity. The tissue- and disease-specific effects of dietary fiber, SCFAs and SCFA-producing microbes on major types of autoimmune diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis and lupus, are discussed. Additionally, their key regulatory mechanisms for lymphocyte development, tissue barrier function, host metabolism, immunity, autoantibody production, and inflammatory effector and regulatory lymphocytes are discussed. The shared and differential effects of SCFAs on different types and stages of autoimmune diseases are discussed.
Topics: Humans; Autoimmunity; Gastrointestinal Microbiome; Autoimmune Diseases; Dietary Fiber; Immune Tolerance; Fatty Acids, Volatile
PubMed: 36854801
DOI: 10.1038/s41423-023-00987-1 -
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 -
European Journal of Immunology Jan 2023Autoimmune diseases are characterized by the recognition of self-antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and... (Review)
Review
Autoimmune diseases are characterized by the recognition of self-antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and indirectly involved in the pathophysiology of autoimmunity, both via antigen-presentation to T cells and production of proinflammatory cytokines and/or autoantibodies. Consequently, B lineage cells have been identified as therapeutic targets in autoimmune diseases. B cell depleting strategies have proven beneficial in the treatment of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), ANCA-associated vasculitis (AAV), multiple sclerosis (MS), and a wide range of other immune-mediated inflammatory diseases (IMIDs). However, not all patients respond to treatment or may not reach (drug-free) remission. Moreover, B cell depleting therapies do not always target all B cell subsets, such as short-lived and long-lived plasma cells. These cells play an active role in autoimmunity and in certain diseases their depletion would be beneficial to achieve disease remission. In the current review article, we provide an overview of novel strategies to target B lineage cells in autoimmune diseases, with the focus on rheumatic diseases. Both advanced therapies that have recently become available and more experimental treatments that may reach the clinic in the near future are discussed.
Topics: Humans; Plasma Cells; Autoimmune Diseases; B-Lymphocytes; Autoimmunity; Arthritis, Rheumatoid; Autoantibodies
PubMed: 36314264
DOI: 10.1002/eji.202149675 -
Cell Metabolism Oct 2020Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under...
Regulatory T cells (Tregs) are vital for the maintenance of immune homeostasis, while their dysfunction constitutes a cardinal feature of autoimmunity. Under steady-state conditions, mitochondrial metabolism is critical for Treg function; however, the metabolic adaptations of Tregs during autoimmunity are ill-defined. Herein, we report that elevated mitochondrial oxidative stress and a robust DNA damage response (DDR) associated with cell death occur in Tregs in individuals with autoimmunity. In an experimental autoimmune encephalitis (EAE) mouse model of autoimmunity, we found a Treg dysfunction recapitulating the features of autoimmune Tregs with a prominent mtROS signature. Scavenging of mtROS in Tregs of EAE mice reversed the DDR and prevented Treg death, while attenuating the Th1 and Th17 autoimmune responses. These findings highlight an unrecognized role of mitochondrial oxidative stress in defining Treg fate during autoimmunity, which may facilitate the design of novel immunotherapies for diseases with disturbed immune tolerance.
Topics: Animals; Autoimmunity; Cell Line; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria; Oxidation-Reduction; T-Lymphocytes, Regulatory
PubMed: 32738205
DOI: 10.1016/j.cmet.2020.07.001 -
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 -
Nature Immunology Sep 2021The immunosuppressive function of regulatory T (T) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced...
The immunosuppressive function of regulatory T (T) cells is dependent on continuous expression of the transcription factor Foxp3. Foxp3 loss of function or induced ablation of T cells results in a fatal autoimmune disease featuring all known types of inflammatory responses with every manifestation stemming from T cell paucity, highlighting a vital function of T cells in preventing fatal autoimmune inflammation. However, a major question remains whether T cells can persist and effectively exert their function in a disease state, where a broad spectrum of inflammatory mediators can either inactivate T cells or render innate and adaptive pro-inflammatory effector cells insensitive to suppression. By reinstating Foxp3 protein expression and suppressor function in cells expressing a reversible Foxp3 null allele in severely diseased mice, we found that the resulting single pool of rescued T cells normalized immune activation, quelled severe tissue inflammation, reversed fatal autoimmune disease and provided long-term protection against them. Thus, T cells are functional in settings of established broad-spectrum systemic inflammation and are capable of affording sustained reset of immune homeostasis.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Differentiation; Female; Forkhead Transcription Factors; Gene Expression Regulation; Homeostasis; Inflammation Mediators; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Systemic Inflammatory Response Syndrome; T-Lymphocytes, Regulatory
PubMed: 34426690
DOI: 10.1038/s41590-021-01001-4