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International Journal of Molecular... May 2021Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this... (Review)
Review
Trillions of microorganisms inhabit the mucosal membranes maintaining a symbiotic relationship with the host's immune system. B cells are key players in this relationship because activated and differentiated B cells produce secretory immunoglobulin A (sIgA), which binds commensals to preserve a healthy microbial ecosystem. Mounting evidence shows that changes in the function and composition of the gut microbiota are associated with several autoimmune diseases suggesting that an imbalanced or dysbiotic microbiota contributes to autoimmune inflammation. Bacteria within the gut mucosa may modulate autoimmune inflammation through different mechanisms from commensals ability to induce B-cell clones that cross-react with host antigens or through regulation of B-cell subsets' capacity to produce cytokines. Commensal signals in the gut instigate the differentiation of IL-10 producing B cells and IL-10 producing IgA+ plasma cells that recirculate and exert regulatory functions. While the origin of the dysbiosis in autoimmunity is unclear, compelling evidence shows that specific species have a remarkable influence in shaping the inflammatory immune response. Further insight is necessary to dissect the complex interaction between microorganisms, genes, and the immune system. In this review, we will discuss the bidirectional interaction between commensals and B-cell responses in the context of autoimmune inflammation.
Topics: Autoimmunity; B-Lymphocytes; Cell Differentiation; Humans; Immunoglobulin A; Inflammation; Interleukin-10; Microbiota
PubMed: 34063669
DOI: 10.3390/ijms22094846 -
Frontiers in Immunology 2022Autoimmune disease, caused by unwanted immune responses to self-antigens, affects millions of people each year and poses a great social and economic burden to... (Review)
Review
Autoimmune disease, caused by unwanted immune responses to self-antigens, affects millions of people each year and poses a great social and economic burden to individuals and communities. In the course of autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and multiple sclerosis, disturbances in the balance between the immune response against harmful agents and tolerance towards self-antigens lead to an immune response against self-tissues. In recent years, various regulatory immune cells have been identified. Disruptions in the quality, quantity, and function of these cells have been implicated in autoimmune disease development. Therefore, targeting or engineering these cells is a promising therapeutic for different autoimmune diseases. Regulatory T cells, regulatory B cells, regulatory dendritic cells, myeloid suppressor cells, and some subsets of innate lymphoid cells are arising as important players among this class of cells. Here, we review the roles of each suppressive cell type in the immune system during homeostasis and in the development of autoimmunity. Moreover, we discuss the current and future therapeutic potential of each one of these cell types for autoimmune diseases.
Topics: Humans; Immunity, Innate; Lymphocytes; Autoimmune Diseases; Autoimmunity; Autoantigens
PubMed: 36591309
DOI: 10.3389/fimmu.2022.1075813 -
Current Opinion in Endocrinology,... Aug 2021Current therapies for autoimmune disorders often employ broad suppression of the immune system. Antigen-specific immunotherapy (ASI) seeks to overcome the side-effects... (Review)
Review
PURPOSE OF REVIEW
Current therapies for autoimmune disorders often employ broad suppression of the immune system. Antigen-specific immunotherapy (ASI) seeks to overcome the side-effects of immunosuppressive therapy by specifically targeting only disease-related autoreactive T and B cells. Although it has been in development for several decades, ASI still is not in use clinically to treat autoimmunity. Novel ways to deliver antigen may be effective in inducing ASI. Here we review recent innovations in antigen delivery.
RECENT FINDINGS
New ways to deliver antigen include particle and nonparticle approaches. One main focus has been the targeting of antigen-presenting cells in a tolerogenic context. This technique often results in the induction and/or expansion of regulatory T cells, which has the potential to be effective against a complex, polyclonal immune response.
SUMMARY
Whether novel delivery approaches can help bring ASI into general clinical use for therapy of autoimmune diseases remains to be seen. However, preclinical work and early results from clinical trials using these new techniques show promising signs.
Topics: Antigens; Autoimmune Diseases; Autoimmunity; Humans; Immune Tolerance; Immunosuppressive Agents; Immunotherapy; T-Lymphocytes, Regulatory
PubMed: 34101653
DOI: 10.1097/MED.0000000000000649 -
Journal of Radiation Research Apr 2018The thyroid gland is vulnerable not only to external radiation but also to internal radiation, because the thyroid cells can incorporate radioactive iodine when... (Review)
Review
The thyroid gland is vulnerable not only to external radiation but also to internal radiation, because the thyroid cells can incorporate radioactive iodine when synthesizing thyroid hormones. Since radiation-induction of thyroid neoplasia, including thyroid cancer, is well recognized, the data on radiation-related thyroid autoimmunity and dysfunction are summarized and reviewed. High-dose irradiation, irrespective of being external or internal, is strongly associated with a risk of hypothyroidism (with the prevalence ranging from 2.4% to 31%) and of Graves' hyperthyroidism (with the prevalence being up to 5%). It is easy to understand that high-dose irradiation induces hypothyroidism with some frequency, because high-dose irradiation destroys the thyroid gland. On the other hand, the basis for development of hyperthyroidism is mechanistically unclear, and it is merely speculative that autoantigens may be released from damaged thyroid glands and recognized by the immune system, leading to the development of anti-thyrotropin receptor antibodies and Graves' hyperthyroidism in subjects who are immunologically predisposed to this ailment. In contrast, the data on moderate to low-dose irradiation on thyroid autoimmunity and dysfunction are inconsistent. Although it is difficult to draw a definitive conclusion, some data may suggest a transient effect of moderate- to low-dose irradiation on hypothyroidism and autoimmune thyroiditis, implying that the effect, if it exists, is reversible. Finally, no report has shown a statistically significant increase in the prevalence of moderate- to low-dose irradiation-induced Graves' hyperthyroidism.
Topics: Autoimmunity; Dose-Response Relationship, Radiation; Humans; Radiation; Thyroid Gland
PubMed: 29069397
DOI: 10.1093/jrr/rrx054 -
Clinical and Experimental Immunology Jul 2022The human immune system safeguards against pathogens through a multitude of cellular and molecular signals, involving different components of the innate and adaptive... (Review)
Review
The human immune system safeguards against pathogens through a multitude of cellular and molecular signals, involving different components of the innate and adaptive response. Contrastingly, autoimmune diseases, allergic conditions, and cancer evoke different aspects of these otherwise protective processes. Understanding the immunological hallmarks for each pathological setting is essential for improving prevention, diagnosis, prognosis, and treatment. The activatory states of immune effector cells, especially in relation to their direct or indirect interactions with antibodies, are important determinants of an efficient, protective response that results in target clearance and improved clinical outcomes. Dysregulation of effector cells and their functions alongside alternatively activated humoral immune responses may contribute to several chronic diseases including allergic inflammation, autoimmune disorders and cancer. This Review Series brings to the forefront several key activation and regulatory features of immune effector cells in different diseases including cancer, infection allergy, and autoimmunity. Specific attention is drawn on how antibodies can impact effector cell states, and their pro-inflammatory and immune protective functions. Articles in this Series discuss different effector cells and antibody isotypes in infection, inflammation, tolerance and cancer immune surveillance, covering basic and translational mechanisms, clinical and epidemiological insights into these immune responses. Understanding the critical attributes of immune cells, especially those needed to effectively engage antibodies, will undoubtedly help better exploit their potential for disease management and therapy.
Topics: Autoimmune Diseases; Autoimmunity; Humans; Hypersensitivity; Immune Tolerance; Inflammation
PubMed: 35752999
DOI: 10.1093/cei/uxac065 -
Neurotherapeutics : the Journal of the... Jan 2021Associations between sleep disorders and neurological autoimmunity have been notably expanding recently. Potential immune-mediated etiopathogenesis has been proposed for... (Review)
Review
Associations between sleep disorders and neurological autoimmunity have been notably expanding recently. Potential immune-mediated etiopathogenesis has been proposed for various sleep disorders including narcolepsy, Kleine-Levin syndrome, and Morvan syndrome. Sleep manifestations are also common in various autoimmune neurological syndromes, but may be underestimated as overriding presenting (and potentially dangerous) neurological symptoms often require more urgent attention. Even so, sleep dysfunction has been described with various neural-specific antibody biomarkers, including IgLON5; leucine-rich, glioma-inactivated protein 1 (LGI1); contactin-associated protein 2 (CASPR2); N-methyl-D-aspartate (NMDA)-receptor; Ma2; dipeptidyl-peptidase-like protein-6 (DPPX); alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R); anti-neuronal nuclear antibody type-1 (ANNA-1, i.e., Hu); anti-neuronal nuclear antibody type-2 (ANNA-2, i.e., Ri); gamma-aminobutyric acid (GABA)-B-receptor (GABA-B-R); metabotropic glutamate receptor 5 (mGluR5); and aquaporin-4 (AQP-4). Given potentially distinctive findings, it is possible that sleep testing could potentially provide objective biomarkers (polysomnography, quantitative muscle activity during REM sleep, cerebrospinal fluid hypocretin-1) to support an autoimmune diagnosis, monitor therapeutic response, or disease progression/relapse. However, more comprehensive characterization of sleep manifestations is needed to better understand the underlying sleep disruption with neurological autoimmunity.
Topics: Autoimmune Diseases; Autoimmunity; Central Nervous System Diseases; Humans; Sleep Wake Disorders
PubMed: 33786802
DOI: 10.1007/s13311-021-01020-x -
Clinical and Experimental Rheumatology 2016The type I interferon (IFN) system is our main defense against viral infections and consists of a large number of sensors of nucleic acid that can trigger the production... (Review)
Review
The type I interferon (IFN) system is our main defense against viral infections and consists of a large number of sensors of nucleic acid that can trigger the production of more than 15 different proteins with antiviral and immunostimulatory capacity. There are several observations suggesting an important role for this system in the etiopathogenesis of systemic lupus erythematosus (SLE) and other autoimmune diseases. Among these are the development of autoimmune diseases during IFN-α treatment, a prominent increase in the expression of type I IFN regulated genes (an IFN signature) in a number of rheumatic diseases, the existence of endogenous IFN inducers in SLE patients and a genetic association between autoimmune diseases and gene variants within the type I IFN signalling pathway. Collectively, these observations suggests that inhibition of the type I IFN system could be beneficial in SLE and possible also other autoimmune diseases. Many different therapeutic targets exist and several studies are in progress aiming to block or down-regulate the activated type I IFN system. A number of studies with monoclonal anti-IFN-α antibodies in SLE patients have been reported, and a small study investigating vaccination with an interferon-α-kinoid against IFN-α has been published. Trials targeting the type I IFN receptor are under way, and other possibilities include elimination of the endogenous IFN inducers and inhibition of key molecules in the type I IFN signalling pathway. Results so far show that it is possible to partially suppress the IFN signature, improve several biomarkers and ameliorate clinical manifestations by some of these new treatment strategies.
Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Autoimmunity; Humans; Interferon Type I; Molecular Targeted Therapy; Signal Transduction
PubMed: 27586799
DOI: No ID Found -
Nature Reviews. Rheumatology Mar 2023The human genome project led to the advancement of genetic technologies and genomic medicine for a variety of human diseases, including monogenic autoimmune and... (Review)
Review
The human genome project led to the advancement of genetic technologies and genomic medicine for a variety of human diseases, including monogenic autoimmune and autoinflammatory diseases. As a result, the genome of an individual can now be rapidly sequenced at a low cost, and this technology is beginning to change the practice of rheumatology. In this Perspective, we describe how new sequencing technologies combined with careful clinical phenotyping have led to the discovery of rare rheumatic diseases and their corresponding disease-causing mutations. Additionally, we explore ways in which single-gene mutations, including somatic mutations, are creating opportunities to develop personalized medicines. To illustrate this idea, we focus on diseases affecting the TREX1-cGAS-STING pathway, which is associated with monogenic autoinflammatory diseases and vasculopathies. For many of the affected patients and families, there is an urgent, unmet need for the development of personalized therapies. New innovations related to small molecular inhibitors and gene therapies have the potential to benefit these families, and might help drive further innovations that could prove useful for patients with more common forms of autoimmunity and autoinflammation.
Topics: Humans; Inflammation; Precision Medicine; Autoimmunity; Hereditary Autoinflammatory Diseases; Autoimmune Diseases
PubMed: 36750685
DOI: 10.1038/s41584-022-00904-2 -
The Journal of Clinical Investigation Jun 2015Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting... (Review)
Review
Autoimmune diseases affect up to approximately 10% of the population. While rare Mendelian autoimmunity syndromes can result from monogenic mutations disrupting essential mechanisms of central and peripheral tolerance, more common human autoimmune diseases are complex disorders that arise from the interaction between polygenic risk factors and environmental factors. Although the risk attributable to most individual nucleotide variants is modest, genome-wide association studies (GWAS) have the potential to provide an unbiased view of biological pathways that drive human autoimmune diseases. Interpretation of GWAS requires integration of multiple genomic datasets including dense genotyping, cis-regulatory maps of primary immune cells, and genotyped studies of gene expression in relevant cell types and cellular conditions. Improved understanding of the genetic basis of autoimmunity may lead to a more sophisticated understanding of underlying cellular phenotypes and, eventually, novel diagnostics and targeted therapies.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Databases, Genetic; Gene Expression Regulation; Gene-Environment Interaction; Genome-Wide Association Study; Humans
PubMed: 26030227
DOI: 10.1172/JCI78086 -
Current Opinion in Immunology Dec 2014
Topics: Animals; Autoimmune Diseases; Autoimmunity; Humans
PubMed: 25456769
DOI: 10.1016/j.coi.2014.10.010