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The International Journal of... Jun 2022Autoimmune cytopenias are a consequence of autoantibodies that target blood cell lineages and mark them for their accelerated destruction, mostly through phagocytosis by... (Review)
Review
Autoimmune cytopenias are a consequence of autoantibodies that target blood cell lineages and mark them for their accelerated destruction, mostly through phagocytosis by monocytes and macrophages and complement activation. Neutrophils, although equipped with Fc and complement receptors and effector mechanisms that are critical in other autoimmune conditions, remained long overlooked. Recent reports, however, propose a new and possibly critical role of neutrophils. In this review, we gathered available evidence on the contribution of neutrophils to the development, onset, and consequences of autoantibody-dependent cytopenias.
Topics: Autoantibodies; Autoimmune Diseases; Humans; Macrophages; Neutrophils; Phagocytosis
PubMed: 35644471
DOI: 10.1016/j.biocel.2022.106231 -
Frontiers in Immunology 2023Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting... (Review)
Review
Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.
Topics: Humans; Inflammasomes; Autoimmune Diseases; Skin; Autoantibodies; Vitiligo
PubMed: 37325658
DOI: 10.3389/fimmu.2023.1190388 -
Trends in Molecular Medicine Jan 2023Autoantibodies targeting brain antigens can mediate a wide range of neurological symptoms ranging from epileptic seizures to psychosis to dementia. Although earlier... (Review)
Review
Autoantibodies targeting brain antigens can mediate a wide range of neurological symptoms ranging from epileptic seizures to psychosis to dementia. Although earlier experimental work indicated that autoantibodies can be directly pathogenic, detailed studies on disease mechanisms, biophysical autoantibody properties, and target interactions were hampered by the availability of human material and the paucity of monospecific disease-related autoantibodies. The emerging generation of patient-derived monoclonal autoantibodies (mAbs) provides a novel platform for the detailed characterization of immunobiology and autoantibody pathogenicity in vitro and in animal models. This Feature Review focuses on recent advances in mAb generation and discusses their potential as powerful scientific tools for high-resolution imaging, antigenic target identification, atomic-level structural analyses, and the development of antibody-selective immunotherapies.
Topics: Animals; Humans; Autoantibodies
PubMed: 36280535
DOI: 10.1016/j.molmed.2022.09.011 -
International Journal of Molecular... Jan 2023Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. To date, a lot of research has been conducted to investigate the underlying mechanisms of this... (Review)
Review
Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. To date, a lot of research has been conducted to investigate the underlying mechanisms of this disease at both molecular and cellular levels. There is increasing evidence suggesting that autoimmunity is an important factor in the initiation and perpetuation of AF. Autoantibodies are thought to play a pivotal role in the regulation of heart rhythm and the conduction system and, therefore, are associated with AF development. In this review, we have summarized current knowledge concerning the role of autoantibodies in AF development as well as their prognostic and predictive value in this disease. The establishment of the autoantibody profile of separate AF patient groups may appear to be crucial in terms of developing novel treatment approaches for those patients; however, the exact role of various autoantibodies in AF is still a matter of ongoing debate.
Topics: Humans; Atrial Fibrillation; Autoantibodies; Heart Conduction System; Autoimmunity; Cardiac Conduction System Disease
PubMed: 36768174
DOI: 10.3390/ijms24031852 -
Immunologic Research Aug 2023Autoimmune diseases are caused by the break-down in self-tolerance mechanisms and can result in the generation of autoantibodies specific to human antigens. Human... (Review)
Review
Autoimmune diseases are caused by the break-down in self-tolerance mechanisms and can result in the generation of autoantibodies specific to human antigens. Human autoantigen profiling technologies such as solid surface arrays and display technologies are powerful high-throughput technologies utilised to discover and map novel autoantigens associated with disease. This review compares human autoantigen profiling technologies including the application of these approaches in chronic and post-infectious autoimmune disease. Each technology has advantages and limitations that should be considered when designing new projects to profile autoantibodies. Recent studies that have utilised these technologies across a range of diseases have highlighted marked heterogeneity in autoantibody specificity between individuals as a frequent feature. This individual heterogeneity suggests that epitope spreading maybe an important mechanism in the pathogenesis of autoimmune disease in general and likely contributes to inflammatory tissue damage and symptoms. Studies focused on identifying autoantibody biomarkers for diagnosis should use targeted data analysis to identify the rarer public epitopes and antigens, common between individuals. Thus, utilisation of human autoantigen profiling technology, combined with different analysis approaches, can illuminate both pathogenesis and biomarker discovery.
Topics: Humans; Autoimmune Diseases; Autoantibodies; Autoantigens; Epitopes
PubMed: 36690876
DOI: 10.1007/s12026-023-09362-8 -
Scientific Reports Aug 2023Hashimoto thyroiditis is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. It has shown to negatively impact female...
Hashimoto thyroiditis is an autoimmune disease characterized by hypothyroidism and a high level of anti-thyroid autoantibodies. It has shown to negatively impact female fertility; however, the mechanisms are unclear. Ovarian follicular fluid appears to be the key to understanding how Hashimoto thyroiditis affecst fertility. Thus, we aimed to evaluated the metabolic profile of follicular fluid and antithyroid autoantibody levels in the context of Hashimoto thyroiditis. We collected follicular fluid from 61 patients, namely 38 women with thyroid autoantibody positivity and 23 women as negative controls, undergoing in vitro fertilization treatment. Follicular fluid samples were analyzed using metabolomics, and thyroid autoantibodies were measured. Fifteen metabolites with higher concentrations in the follicular fluid samples from Hashimoto thyroiditis were identified, comprising five possible affected pathways: the glycerophospholipid, arachidonic acid, linoleic acid, alpha-linolenic acid, and sphingolipid metabolism pathways. These pathways are known to regulate ovarian functions. In addition, antithyroglobulin antibody concentrations in both serum and follicular fluid were more than tenfold higher in women with Hashimoto thyroiditis than in controls. Our data showed that the metabolic profile of follicular fluid is altered in women with Hashimoto thyroiditis, suggesting a potential mechanistic explanation for the association of this disease with female infertility.
Topics: Humans; Female; Hashimoto Disease; Follicular Fluid; Autoantibodies; Autoimmune Diseases; Metabolomics
PubMed: 37532758
DOI: 10.1038/s41598-023-39514-7 -
Frontiers in Immunology 2022Autoimmune diseases are often associated with autoantibodies that abnormally target self-antigens (autoantigens). An intuitive therapeutic strategy for diseases caused... (Review)
Review
Autoimmune diseases are often associated with autoantibodies that abnormally target self-antigens (autoantigens). An intuitive therapeutic strategy for diseases caused by aAbs is to design decoys, or soluble molecules that target the antigen combining site of these aAbs, thereby blocking binding of aAb to self-antigen and subsequent tissue damage. Here, we review the known decoy molecules of these types, discuss newer technological opportunities afforded by monoclonal antibody and structural biology advances, and discuss the challenges to this approach. Recent opportunities relevant to this approach for cardiac phenotypes, specifically Ro-associated long QT syndrome, are discussed.
Topics: Antibodies, Monoclonal; Autoantibodies; Autoantigens; Autoimmune Diseases; Cardiomyopathies; Humans; Immunoassay; Phenotype
PubMed: 35154130
DOI: 10.3389/fimmu.2022.812649 -
The Quarterly Journal of Nuclear... Jun 2021Hyperthyroidism is a clinical condition characterized by inappropriately high synthesis and secretion of thyroid hormones by the thyroid gland. It has multiple... (Review)
Review
Hyperthyroidism is a clinical condition characterized by inappropriately high synthesis and secretion of thyroid hormones by the thyroid gland. It has multiple aetiologies, manifestations and potential therapies. Graves' disease is the most common form of hyperthyroidism, due to the production of autoantibodies against thyrotropin receptor, capable of over-stimulating thyroid function. A reliable diagnosis of hyperthyroidism can be established on clinical grounds, followed by the evaluation of serum thyroid function tests (thyrotropin first and then free thyroxine, adding the measurement of free triiodothyronine in selected specific situations). The recent guidelines of both the American and European Thyroid Associations have strongly recommended the measurement of thyrotropin receptor autoantibodies for the accurate diagnosis and management of Graves' disease. If autoantibody test is negative, a radioiodine uptake should be performed. Considering the most recent laboratory improvements, binding assays can be considered the best first solution for the measurement of thyrotropin receptor autoantibodies in diagnosis and management of overt cases of Graves' disease. In fact, they have a satisfactory clinical sensitivity and specificity (97.4% and 99.2%, respectively) being performed in clinical laboratories on automated platforms together with the other thyroid function tests. In this setting, the bioassays should be reserved for fine and complex diagnoses and for particular clinical conditions where it is essential to document the transition from stimulating to blocking activity or vice versa (e.g. pregnancy and post-partum, related thyroid eye disease, Hashimoto's thyroiditis with extrathyroidal manifestations, unusual cases after LT4 therapy for hypothyroidism or after antithyroid drug treatment for Graves' disease). Undoubtedly, technological advances will help improve laboratory diagnostics of hyperthyroidism. Nevertheless, despite future progress, the dialogue between clinicians and laboratory will continue to be crucial for an adequate knowledge and interpretation of the laboratory tests and, therefore, for an accurate diagnosis and correct management of the patient.
Topics: Animals; Antithyroid Agents; Autoantibodies; Biosensing Techniques; Cell Line; Humans; Hyperthyroidism; Iodine Radioisotopes; Protein Binding; Receptors, Thyrotropin; Sensitivity and Specificity; Thyroid Gland
PubMed: 33565846
DOI: 10.23736/S1824-4785.21.03344-6 -
Frontiers in Immunology 2022Type I interferon (IFN) plays a vital role in the pathogenesis of systemic lupus erythematosus. Cyclic GMP AMP synthase (cGAS) is a cytosolic DNA sensor that recognizes...
INTRODUCTION
Type I interferon (IFN) plays a vital role in the pathogenesis of systemic lupus erythematosus. Cyclic GMP AMP synthase (cGAS) is a cytosolic DNA sensor that recognizes dsDNA and creates cGAMP to activate STING-mediated type I IFN production. The activation of STING induces lupus disease in Fcgr2b deficient mice through the differentiation of dendritic cells. In contrast, Cgas-deficient mice could be generated more autoantibody production and proteinuria in pristane-induced lupus (PIL). These data suggested that the other dsDNA sensors could be involved in lupus development mechanisms.
METHODS
This study aimed to identify the cGAS-mediated mechanisms contributing to lupus pathogenesis in PIL. The Cgas-deficient and WT mice were induced lupus disease with pristane and subsequently analyzed autoantibody, histopathology, and immunophenotypes. The lung tissues were analyzed with the expression profiles by RT-PCR and western blot. The bone marrow-derived macrophages were stimulated with inflammasome activators and observed pyroptosis.
RESULTS
The Cgas-/- mice developed more severe pulmonary hemorrhage and autoantibody production than WT mice. The activated dendritic cells, IFN-g-, and IL-17a-producing T helper cells, and infiltrated macrophages in the lung were detected in Cgas-/- mice higher than in WT mice. We observed an increase in expression of Aim2, Casp11, and Ifi16 in the lung and serum IL-1a but IL-1b in pristane-injected Cgas-/- mice. The rise of Caspase-11 in the lung of pristane-injected Cgas-/- mice suggested noncanonical inflammasome activation. The activation of AIM2 and NLRP3 inflammasomes in bone marrow-derived macrophages (BMDMs) enhanced the number of dead cells in Cgas-/- mice compared with WT mice. Activation of the inflammasome significantly induced pyroptosis in Cgas-/- BMDMs. The dsDNA level, but not mitochondrial DNA, increased dramatically in pristane-injected Cgas-/- mice suggesting the dsDNA could be a ligand activating inflammasomes. The cGAS agonist-induced BMDM activation in the Cgas-/- mice indicated that the activation of DNA sensors other than cGAS enhanced activated macrophages.
CONCLUSION
These findings suggested that cGAS hampers the unusual noncanonical inflammasome activation through other DNA sensors.
Topics: Animals; Mice; Autoantibodies; Disease Models, Animal; DNA; Inflammasomes; Inflammation; Lupus Erythematosus, Systemic; Macrophages; Nucleotidyltransferases
PubMed: 36591278
DOI: 10.3389/fimmu.2022.1010764 -
The Journal of Investigative Dermatology Mar 2022T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing... (Review)
Review
T cells are key drivers of autoimmunity in numerous noncommunicable inflammatory skin diseases by directly harming host tissue or through helping B cells in producing autoantibodies. Technological advances have contributed to identifying autoantigens, the Holy Grail of autoimmunity, in many inflammatory disorders of the skin. Novel therapeutic approaches such as chimeric (auto)antibody receptor T cells are a milestone on the way to finding individualized, well-tolerated, targeted therapies. This review summarizes the current knowledge on pathogenesis, immune response pattern‒related ontology, diagnostic approaches, and treatment options of autoimmune skin diseases.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Humans; T-Lymphocytes
PubMed: 34538423
DOI: 10.1016/j.jid.2021.04.032