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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 -
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 2018Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of... (Review)
Review
Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches.
Topics: Autoantibodies; Autoantigens; Autoimmune Diseases; Epitopes; Humans; Skin Diseases, Vesiculobullous
PubMed: 29719538
DOI: 10.3389/fimmu.2018.00779 -
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 -
Current Opinion in Endocrinology,... Aug 2017Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin and other pancreatic β cells proteins including GAD65 (GADA),... (Review)
Review
PURPOSE OF REVIEW
Type 1 diabetes (T1D) is now predictable by measuring major islet autoantibodies (IAbs) against insulin and other pancreatic β cells proteins including GAD65 (GADA), islet antigen 2 (IA-2A), and zinc transporter 8 (ZnT8A). The assay technology for IAbs has made great progress; however, several important aspects still need to be addressed and improved.
RECENT FINDINGS
Currently a radio-binding assay has been well established as the 'gold' standard assay for all four IAbs. New generation of nonradioactive IAb assay with electrochemiluminescence technology has been shown to further improve sensitivity and disease specificity. Recently, multiplexed assays have opened the possibility of more efficient screening in large populations. Identification of potential new autoantibodies to neo-antigens or neo-epitopes posttranslational modification is a new important field to be explored.
SUMMARY
Individuals having a single positive autoantibody are at low risk for progression to T1D, whereas individuals expressing two or more positive autoantibodies, especially on multiple tests over time, have nearly 100% risk of developing clinical T1D when followed for over two decades. More efficient and cost effective IAb assays will hopefully lead to point-of-care screening in the general population.
Topics: Autoantibodies; Diabetes Mellitus, Type 1; Diagnostic Techniques, Endocrine; Disease Progression; Glutamate Decarboxylase; Humans; Insulin; Insulin-Secreting Cells; Quality Improvement; Sensitivity and Specificity; Zinc Transporter 8
PubMed: 28509692
DOI: 10.1097/MED.0000000000000348 -
Current Opinion in Hematology Nov 2023Warm autoimmune hemolytic anemia (wAIHA) is the most common of the immune hemolytic anemias. Although there are numerous case reports and reviews regarding this... (Review)
Review
PURPOSE OF REVIEW
Warm autoimmune hemolytic anemia (wAIHA) is the most common of the immune hemolytic anemias. Although there are numerous case reports and reviews regarding this condition, some of the unusual and more recent findings have not been fully defined and may be contentious. This review will provide insight into the common specificity of the warm autoantibodies and hypothesize a novel mechanism of wAIHA, that is proposed to be linked to the controversial subject of red blood cell senescence.
RECENT FINDINGS AND HYPOTHESES
It is now well established that band 3 on the red blood cell is the main target of autoantibodies in wAIHA. wAIHA targets the older red blood cells (RBCs) in about 80% of cases and, recently, it has been shown that the RBCs in these patients are aging faster than normal. It has been proposed that in these 80% of patients, that the autoantibody recognizes the senescent red blood cell antigen on band 3. It is further hypothesized that this autoantibody's production and potency has been exacerbated by hypersensitization to the RBC senescent antigen, which is processed through the adaptive immune system to create the pathogenic autoantibody. Recent publications have supported previous data that the senescent RBC antigen is exposed via a dynamic process, wherein oscillation of a band 3 internal loop flipping to the cell surface, creates a conformational neoantigen that is the RBC senescent antigen. It has also recently been shown that the cytokine profile in patients with wAIHA favors production of inflammatory cytokines/chemokines that includes interleukin-8 which can activate neutrophils to increase the oxidative stress on circulating RBCs to induce novel antigens, as has been postulated to favour exposure of the senescent RBC antigen.
SUMMARY
This manuscript reviews new findings and hypotheses regarding wAIHA and proposes a novel mechanism active in most wAIHA patients that is due to an exacerbation of normal RBC senescence.
Topics: Humans; Anemia, Hemolytic, Autoimmune; Immunoglobulin G; Erythrocytes; Autoantibodies
PubMed: 37497853
DOI: 10.1097/MOH.0000000000000779 -
Frontiers in Immunology 2023Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell...
BACKGROUND
Anti-IgLON5 disease is a rare neurological disorder characterized by autoantibodies against IgLON5, and pathological evidence of neurodegeneration. IgLON5 is a cell adhesion molecule but its physiological function is unknown. Our aim was to investigate the IgLON5 interactome and to determine if IgLON5 antibodies (IgLON5-abs) affect these protein interactions.
METHODS
IgLON5 interactome was investigated by mass spectrometry sequencing of proteins immunoprecipitated by IgLON5 autoantibodies using cultures of rat cerebellar granular neurons (CGNs). Shedding of IgLON5 was explored using HEK cells transfected with human IgLON5 plasmid and in CGNs. Interactions of IgLON5 with identified binding partners and IgLON5-abs effects were confirmed by immunofluorescence in transfected HEK cells and rat hippocampal neurons.
RESULTS
Patients' IgLON5 antibodies co-precipitated all members of the IgLON family and three 3 additional surface proteins. IgLON5 predominantly establishes homomeric and heteromeric (within the cell) and (between cells)-interactions with other IgLON family members and undergoes spontaneous ectodomain shedding. Antibodies from patients with anti-IgLON5 disease prevent trans-interactions in hippocampal neurons independently of the IgLON5 IgG subclass distribution.
CONCLUSIONS
We show a potentially novel pathogenic mechanism of IgLON5-abs that consists in blocking IgLON5 interactions with its binding partners. These findings extend our knowledge about the physiological role of IgLON5 and pave the way to future understanding of the pathological mechanisms of anti-IgLON5 disease.
Topics: Humans; Animals; Rats; Autoantibodies; Neurons; Hashimoto Disease; Encephalitis; Sleep Apnea, Obstructive; Cell Adhesion Molecules, Neuronal
PubMed: 37033996
DOI: 10.3389/fimmu.2023.1151574