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Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions. [ABSTRACT FROM AUTHOR]

Plain language summary: The thyroid is a gland located in the neck and is important for many processes in the body. Problems with the thyroid gland are common in women of reproductive age. It is essential to have a normal working thyroid gland in order to achieve a successful pregnancy. One of the most common problems with the thyroid is underactivity (known as hypothyroidism). An early, mild form of an underactive thyroid is called subclinical hypothyroidism. Often people with this condition do not have any symptoms. Another common problem is thyroid autoimmunity. Here, the immune system attacks the thyroid gland, sometimes leading to the development of abnormal thyroid function. This can be diagnosed by the presence of proteins in the bloodstream called antibodies. Mild thyroid problems and the presence of high levels of thyroid antibodies have been linked to miscarriage and premature birth. There is debate in medicine about whether there should be routine testing of thyroid function both in the general population and in individuals who are trying for a baby. In addition, the strategies used to manage certain thyroid problems are questioned. Discussions around testing and subsequent management particularly relate to women with a history of subfertility or repeated miscarriages. This Scientific Impact Paper provides information on thyroid testing and the management of mild thyroid problems and thyroid antibodies in women with a history of subfertility or recurrent miscarriages, using the latest evidence and guidelines. It concludes that there may be a role for treating these women with thyroxine tablets (the hormone produced by the thyroid gland) when subclinical hypothyroidism is present, and gives guidance on the cut‐off levels for treatment. [ABSTRACT FROM AUTHOR]

Objective: The long-lasting persistence of autoantibodies stands as one of the hypotheses explaining the multisystemic manifestations seen in individuals with post-COVID-19 condition. The current review offers restricted insights into the persistence of autoantibodies in plasma/serum in people with post-COVID symptoms. Methods: PubMed/MEDLINE, CINAHL, EMBASE, and Web of Science databases, as well as on medRxiv and bioRxiv preprint servers were searched up to January 5th, 2024. Papers investigating the presence of autoantibodies in plasma/serum samples in people with post-COVID symptoms were included. The Newcastle-Ottawa Scale (NOS) was used to assess methodological quality. Results: From 162 identified records, five articles met all inclusion criteria; four studies included infected controls with no post-COVID symptoms whereas all five studies included non-infected controls (410 COVID-19 survivors with post-COVID symptoms, 223 COVID-19 survivors with no post-COVID symptoms as controls and 266 non-infected healthy controls). Four studies concluded that the presence of autoantibodies had a potential (but small) role in post-COVID-19 condition whereas one study concluded that autoantibodies were not associated. Quality assessment showed all studies had high methodological quality. Conclusion: Although evidence suggests that persistent autoantibodies can be associated with post-COVID symptoms, the clinical relevance of their presence seems modest at this stage. Current results highlight further research to clarify the role of autoantibodies in the development of post-COVID symptoms, guiding the development of tailored diagnostic and treatment approaches to enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Autoimmune Limbic Encephalitis is a rare disease occurring with a frequency of approximately 13.7/100,000 people, mainly among middle-aged women. The disease is caused by autoantibodies, either synthesised due to the presence of a tumour or having an idiopathic nature. Depending on the type of autoantibodies detected, the disease is divided into subtypes, which differ in the frequency of specific clinical symptoms (most commonly psychosis, mood changes, memory problems, cognitive impairment and seizures) and can direct to detection of a specific type of cancer. Making a prompt diagnosis and initiating treatment is crucial as it ensures a reduction in clinical symptoms and improves survival rate. Broad immunotherapy is used - intravenous immunoglobulin, corticosteroids, azathioprine, rituximab, cyclophosphamide, anti-epileptic drugs and plasmapheresis. The efficacy is high - 80% of patients recover, and relapses occur in only 10% of cases. If a patient is diagnosed with cancer, effective oncological treatment is necessary to achieve complete remission. Materials and methods: In order to select articles, the literature available in PubMed and Google Scholar was reviewed, using the keywords: autoimmune limbic encephalitis, autoantibodies, immunotherapy. From the available papers, those from 2000-2023 that best described the topic were selected. Among the selected articles, retrospective descriptions, clinical cases and descriptive articles were taken into account. This paper describes the epidemiology, pathophysiology, clinical manifestations, diagnosis and treatment of the disease. [ABSTRACT FROM AUTHOR]

Autoantibodies are immune system‐produced antibodies that wrongly target the body's cells and tissues for attack. The COVID‐19 pandemic has made it possible to link autoantibodies to both the severity of pathogenic infection and the emergence of several autoimmune diseases after recovery from the infection. An overview of autoimmune disorders and the function of autoantibodies in COVID‐19 and other infectious diseases are discussed in this review article. We also investigated the different categories of autoantibodies found in COVID‐19 and other infectious diseases including the potential pathways by which they contribute to the severity of the illness. Additionally, it also highlights the probable connection between vaccine‐induced autoantibodies and their adverse outcomes. The review also discusses the therapeutic perspectives of autoantibodies. This paper advances our knowledge about the intricate interaction between autoantibodies and COVID‐19 by thoroughly assessing the most recent findings. [ABSTRACT FROM AUTHOR]

Thrombopoietin, the primary regulator of blood platelet production, was postulated to exist in 1958, but was only proven to exist when the cDNA for the hormone was cloned in 1994. Since its initial cloning and characterization, the hormone has revealed many surprises. For example, instead of acting as the postulated differentiation factor for platelet precursors, megakaryocytes, it is the most potent stimulator of megakaryocyte progenitor expansion known. Moreover, it also stimulates the survival, and in combination with stem cell factor leads to the expansion of hematopoietic stem cells. All of these growth-promoting activities have resulted in its clinical use in patients with thrombocytopenia and aplastic anemia, although the clinical development of the native molecule illustrated that "it's not wise to mess with mother nature", as a highly engineered version of the native hormone led to autoantibody formation and severe thrombocytopenia. Finally, another unexpected finding was the role of the thrombopoietin receptor in stem cell biology, including the development of myeloproliferative neoplasms, an important disorder of hematopoietic stem cells. Overall, the past 30 years of clinical and basic research has yielded many important insights, which are reviewed in this paper. [ABSTRACT FROM AUTHOR]

The rising prevalence of paediatric type 2 diabetes (T2D) is concerning, particularly with limited medical intervention despite evidence of accelerated disease progression. This study of a Barts Health NHS Trust cohort from 2008 to 2022 aims to elucidate the incidence, clinical outcomes, and complications associated with paediatric T2D. A retrospective analysis utilising electronic and paper records identified 40 patients with T2D. The incidence doubled from 2.6/year in 2008–2013 to 5.4/year in 2014–2018. Sixty-eight percent exhibited co-morbidities, notably learning disabilities. At diagnosis, the mean BMI was 32.4 ± 6.71 kg/m2, with no gender-based disparity and no significant change over a two-year follow-up. The initial HbA1c was 75.2 ± 21.0 mmol/mol, decreasing to 55.0 ± 17.4 mmol/mol after three months (p = 0.001) and then rising to 63.0 ± 25.5 mmol/mol at one year (p = 0.07). While 22/37 patients achieved HbA1c < 48 mmol/mol, only 9 maintained this for a year. Several metabolic and cardiovascular complications were observed at diagnosis and follow-up, with no significant change in frequency. In 2022, 15 patients transitioned to adult services. HbA1c at transition was 74.7 ± 27.6 mmol/mol, showing no change one year post-transition (71.9 ± 26.9 mmol/mol, p = 0.34). This study highlights substantial therapeutic failure, with current management falling short in achieving a sustained reduction in BMI or HbA1c. Novel treatment approaches are needed to improve clinical outcomes and address the high burden of co-morbidities and complications. [ABSTRACT FROM AUTHOR]

The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous human suffering and a monumental financial burden. The autoantibodies formed in most ADs have been identified, allowing the development of novel anti-idiotypic antibodies to mute the autoantibodies using vaccines. Nucleoside vaccines have been successfully tested as antigen-specific immunotherapies (ASI), with mRNA technology offering multi-epitope targeting to mute multiple autoantibodies. This paper proposes using mRNA technology to produce anti-idiotypic antibodies with broad effectiveness in preventing and treating them. This paper delves into the state-of-the-art mRNA design strategies used to develop novel ASIs by selecting appropriate T cell and B cell epitopes to generate anti-idiotypic antibodies. The low cost and fast development of mRNA vaccines make this technology the most affordable for the global control of ADs. [ABSTRACT FROM AUTHOR]

This article explores the role of T helper cells in autoimmune diseases and the need for more effective treatment strategies. The authors specifically focus on autoreactive CD4+ T helper cells, particularly the T follicular helper subset, which promote the production of autoantibodies. They also discuss the imbalance between pathogenic peripheral T helper cells and tissue-resident Tregs in autoimmune diseases. The article highlights the importance of further research to develop targeted therapies for controlling autoimmune diseases. Additionally, the document provides a summary of various studies and reviews on the role of T helper cells in specific autoimmune diseases, aiming to contribute to the understanding of T cell involvement and potential therapeutic targets. [Extracted from the article]

In order to understand autoimmune phenomena contributing to the pathophysiology of COVID-19 and post-COVID syndrome, we have been profiling autoantigens (autoAgs) from various cell types. Although cells share numerous autoAgs, each cell type gives rise to unique COVID-altered autoAg candidates, which may explain the wide range of symptoms experienced by patients with autoimmune sequelae of SARS-CoV-2 infection. Based on the unifying property of affinity between autoAgs and the glycosaminoglycan dermatan sulfate (DS), this paper reports 140 candidate autoAgs identified from proteome extracts of human Jurkat T-cells, of which at least 105 (75%) are known targets of autoantibodies. Comparison with currently available multi-omic COVID-19 data shows that 125 (89%) DS-affinity proteins are altered at protein and/or RNA levels in SARS-CoV-2-infected cells or patients, with at least 94 being known autoAgs in a wide spectrum of autoimmune diseases and cancer. Protein alterations by ubiquitination and phosphorylation during the viral infection are major contributors of autoAgs. The autoAg protein network is significantly associated with cellular response to stress, apoptosis, RNA metabolism, mRNA processing and translation, protein folding and processing, chromosome organization, cell cycle, and muscle contraction. The autoAgs include clusters of histones, CCT/TriC chaperonin, DNA replication licensing factors, proteasome and ribosome proteins, heat shock proteins, serine/arginine-rich splicing factors, 14-3-3 proteins, and cytoskeletal proteins. AutoAgs, such as LCP1 and NACA, that are altered in the T cells of COVID patients may provide insight into T-cell responses to viral infection and merit further study. The autoantigen-ome from this study contributes to a comprehensive molecular map for investigating acute, subacute, and chronic autoimmune disorders caused by SARS-CoV-2. Based on the unique affinity between autoantigens (autoAgs) and dermatan sulfate (DS), this paper reports 140 candidate autoAgs identified from proteome extracts of Jurkat T-cells, with at least 105 (75%) being known targets of autoantibodies in various autoimmune diseases and cancer. Comparison with currently available multi-omic COVID-19 data shows that 125 (89%) DS-affinity proteins are altered in SARS-CoV-2-infected cells or patients. AutoAgs, such as LCP1 and NACA, that are altered in the T cells of COVID-19 patients may provide insight into T-cell responses during viral infection. [ABSTRACT FROM AUTHOR]

To understand how COVID-19 may induce autoimmune diseases, we have been compiling an atlas of COVID autoantigens (autoAgs). Using dermatan sulfate (DS) affinity enrichment of autoantigenic proteins extracted from HS-Sultan lymphoblasts, we identified 362 DS-affinity proteins, of which at least 201 (56%) are confirmed autoAgs. Comparison with available multi-omic COVID data shows that 315 (87%) of the 362 proteins are affected in SARS-CoV-2 infection via altered expression, interaction with viral components, or modification by phosphorylation or ubiquitination, at least 186 (59%) of which are known autoAgs. These proteins are associated with gene expression, mRNA processing, mRNA splicing, translation, protein folding, vesicles, and chromosome organization. Numerous nuclear autoAgs were identified, including both classical antinuclear antibodies (ANAs) and extractable nuclear antigens (ENAs) of systemic autoimmune diseases and unique autoAgs involved in the DNA replication fork, mitotic cell cycle, or telomerase maintenance. We also identified many uncommon autoAgs involved in nucleic acid and peptide biosynthesis and nucleocytoplasmic transport, such as aminoacyl-tRNA synthetases. In addition, this study found autoAgs that potentially interact with multiple SARS-CoV-2 Nsp and Orf components, including CCT/TriC chaperonin, insulin degrading enzyme, platelet-activating factor acetylhydrolase, and the ezrin-moesin-radixin family. Furthermore, B-cell-specific IgM-associated endoplasmic reticulum (ER) complex (including MBZ1, BiP, heat shock proteins, and protein disulfide-isomerases) is enriched by DS-affinity and up-regulated in B-cells of COVID-19 patients, and a similar IgH-associated ER complex was also identified in autoreactive pre-B1 cells in our previous study, which suggests a role of autoreactive B1 cells in COVID-19 that merits further investigation. In summary, this study demonstrates that virally infected cells are characterized by alterations of proteins with propensity to become autoAgs, thereby providing a possible explanation for infection-induced autoimmunity. The COVID autoantigen-ome provides a valuable molecular resource and map for investigation of COVID-related autoimmune sequelae and considerations for vaccine design. This paper investigates the autoantigenic proteome ('autoantigen-ome') of human B cells and shows that a large fraction of these DS-binding autoantigens is affected during SARS-CoV-2 infection, giving rise to a diverse pool of autoAgs that may lead to infection-induced autoimmune diseases. The COVID autoantigen-ome provided in this paper may serve as a molecular map and resource for investigating autoimmune phenomena of SARS-CoV-2 infection and its long-term sequelae. Understanding immunogenic proteins of COVID may also enhance vaccine target design. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is the most common autoimmune bullous disease: it most commonly affects individuals over 70 years old and impacts severely on their quality of life. BP represents a paradigm for an organ-specific autoimmune disease and is characterized by circulating IgG autoantibodies to hemidesmosomal components: BP180 and BP230. While the crucial role of these autoantibodies in triggering BP inflammatory cascade is fully acknowledged, many ancillary etiologicalmechanisms need to be elucidated yet. Cutaneous melanoma is due to a malignant transformation of skin melanocytes, that produce and distribute pigments to surrounding keratinocytes. Melanoma is the most fatal skin cancer because of its increasing incidence and its propensity to metastasize. Several data such as: i) reported cases of concomitant melanoma and BP; ii) results from association studies; iii) BP onset following immune check-point inhibitors therapy; iv) expression of BP antigens in transformed melanocytes; and vi) circulating autoantibodies to BP antigens in melanoma patients suggest an intriguing, although unproven, possible association between melanoma and BP. However, a possible causative link is still debated and the putative pathogenetic mechanism underlying this association is unclear. This review aims to describe and discuss the possible relationship between BP and melanoma and give an overview of the speculations for or against this association. Of note, if demonstrated, this association could unwrap considerations of clinical relevance that represent new research frontiers. [ABSTRACT FROM AUTHOR]

We report two unrelated adults with homozygous (P1) or compound heterozygous (P2) private loss-of-function variants of V-Rel Reticuloendotheliosis Viral Oncogene Homolog B (RELB). The resulting deficiency of functional RelB impairs the induction of NFKB2 mRNA and NF-κB2 (p100/p52) protein by lymphotoxin in the fibroblasts of the patients. These defects are rescued by transduction with wild-type RELB complementary DNA (cDNA). By contrast, the response of RelB-deficient fibroblasts to Tumor Necrosis Factor (TNF) or IL-1β via the canonical NF-κB pathway remains intact. P1 and P2 have low proportions of naïve CD4+ and CD8+ T cells and of memory B cells. Moreover, their naïve B cells cannot differentiate into immunoglobulin G (IgG)- or immunoglobulin A (IgA)-secreting cells in response to CD40L/IL-21, and the development of IL-17A/F-producing T cells is strongly impaired in vitro. Finally, the patients produce neutralizing autoantibodies against type I interferons (IFNs), even after hematopoietic stem cell transplantation, attesting to a persistent dysfunction of thymic epithelial cells in T cell selection and central tolerance to some autoantigens. Thus, inherited human RelB deficiency disrupts the alternative NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs, confers a predisposition to viral, bacterial, and fungal infections. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Adult‐onset immunodeficiency (AOID) is an emerging acquired immunodeficiency, characterized by multiple opportunistic infections including non‐tuberculous mycobacterium (NTM) due to the presence of anti‐IFN‐γ autoantibody (AIGA). This case highlights the challenges of accurate diagnosis of monoclonal gammaglobulinemia with NTM infection and favorable outcomes of anti‐plasma cell therapy in AOID. Adult‐onset immunodeficiency (AOID) is an emerging acquired immunodeficiency due to anti‐IFN‐γ autoantibody (AIGA) with low morbidity, frequent disseminated infections, a prolonged course, difficult diagnosis and treatment, and a poor prognosis. Here, we report a patient with positive AIGA and monoclonal gammaglobulinemia who was mimicking symptomatic multiple myeloma and resulting in a non‐tuberculous mycobacterial (NTM) infection. While he achieved an excellent therapeutic effect with anti‐plasma cell therapy, it also serves as a warning that monoclonal gammaglobulinemia with NTM infection is easily misdiagnosed as symptomatic multiple myeloma, and the screening for AIGA should not be ignored in patients with NTM infection. [ABSTRACT FROM AUTHOR]

Autoimmune diseases of the liver and biliary tract require timely and accurate diagnosis. This study evaluates the D-tek panel (D-Tek, Mons, Belgium) of 10 immunodot antigens for its effectiveness in diagnosing autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). We retrospectively analysed serum samples from 111 patients who had undergone routine testing, including indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assays (ELISA), to confirm or exclude autoimmune liver or biliary tract disease. The panel tested for M2/nPDC, M2/OGDC-E2, M2/BCOADC-E2, M2/PDC-E2, gp210, sp100, LKM1, LC1, SLA, and F-actin antigens. Results showed that all positive IIF+ELISA results were confirmed by the immunodot panel, except for two samples from patients who had never been diagnosed with AIH. The immunodot test identified over 20 additional autoantibodies in samples initially negative by IIF, corroborated by laboratory imaging and medical history. The immunodot technique proved to be a quick, sensitive, and specific method with high overall accuracy. This study suggests that the immunodot technique may be an effective screening and confirmatory method for autoimmune liver diseases, potentially improving diagnostic efficiency and accuracy in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) is a major cause of mortality worldwide. It is preceded by the progressive development of lesions of the gastric mucosa, namely atrophic gastritis, intestinal metaplasia, and dysplasia, collectively referred to preneoplasia. Periodic monitoring has been proposed for the surveillance of intestinal metaplasia and dysplasia. However, endoscopy, the current gold standard in GC diagnosis, has a limited ability to detect gastric preneoplasia, especially in early stages. In order to overcome the limitations of endoscopy screening, the potential of blood biomarkers has been investigated, and some biomarkers have been identified consistently across different studies. Nevertheless, validation studies in specific populations must be conducted before these results can allow the design of non-invasive tests to be translated into clinical practice for the early detection of patients at risk of developing GC. Gastric cancer (GC) is a major cause of cancer-related mortality worldwide. It is often associated with a bad prognosis because of its asymptomatic phenotype until advanced stages, highlighting the need for its prevention and early detection. GC development is preceded by the emergence of gastric preneoplasia lesions (GPNLs), namely atrophic gastritis (AG), intestinal metaplasia (IM), and dysplasia (DYS). GC is currently diagnosed by endoscopy, which is invasive and costly and has limited effectiveness for the detection of GPNLs. Therefore, the discovery of non-invasive biomarkers in liquid biopsies, such as blood samples, in order to identify the presence of gastric preneoplasia and/or cancer lesions at asymptomatic stages is of paramount interest. This comprehensive review provides an overview of recently identified plasma/serum proteins and their diagnostic performance for the prediction of GPNLs and early cancer lesions. Autoantibodies appear to be promising biomarkers for AG, IM and early gastric cancer detection, along with inflammation and immunity-related proteins and antibodies against H. pylori virulence factors. There is a lack of specific protein biomarkers with which to detect DYS. Despite the need for further investigation and validation, some emerging candidates could pave the way for the development of reliable, non-invasive diagnostic tests for the detection and prevention of GC. [ABSTRACT FROM AUTHOR]

The spectrum of pediatric rheumatological disorders is diverse and they are important differential diagnoses in a variety of clinical scenarios. Basic investigations not only provide supporting evidence for the diagnosis of a rheumatological illness but also help in exclusion of other diseases as well as for monitoring the activity of disease. Among these, complete blood count, biochemical assays including tests for inflammatory response, urine analysis, and various autoantibodies are often used. In addition, depending on the clinical features, imaging and tissue biopsies are used to confirm the diagnosis. [ABSTRACT FROM AUTHOR]

Wilson's disease (WD) is a rare, autosomal recessive disorder of copper metabolism caused by pathogenic mutations in the ATP7B gene. Cellular copper overload is associated with impaired iron metabolism. Oxidative stress, cuproptosis, and ferroptosis are involved in cell death in WD. The clinical picture of WD is variable. Hepatic/neuropsychiatric/other symptoms may manifest in childhood/adulthood and even old age. It has been shown that phenotypic variability may be determined by the type of ATP7B genetic variants as well as the influence of various genetic/epigenetic, environmental, and lifestyle modifiers. In 1976, immunological abnormalities were first described in patients with WD. These included an increase in IgG and IgM levels and a decrease in the percentage of T lymphocytes, as well as a weakening of their bactericidal effect. Over the following years, it was shown that there is a bidirectional relationship between copper and inflammation. Changes in serum cytokine concentrations and the relationship between cytokine gene variants and the clinical course of the disease have been described in WD patients, as well as in animal models of this disease. Data have also been published on the occurrence of antinuclear antibodies (ANAs), antineutrophil cytoplasmic antibodies (ANCAs), anti-muscle-specific tyrosine kinase antibodies, and anti-acetylcholine receptor antibodies, as well as various autoimmune diseases, including systemic lupus erythematosus (SLE), myasthenic syndrome, ulcerative colitis, multiple sclerosis (MS), polyarthritis, and psoriasis after treatment with d-penicillamine (DPA). The occurrence of autoantibodies was also described, the presence of which was not related to the type of treatment or the form of the disease (hepatic vs. neuropsychiatric). The mechanisms responsible for the occurrence of autoantibodies in patients with WD are not known. It has also not been clarified whether they have clinical significance. In some patients, WD was differentiated or coexisted with an autoimmune disease, including autoimmune hepatitis or multiple sclerosis. Various molecular mechanisms may be responsible for immunological abnormalities and/or the inflammatory processes in WD. Their better understanding may be important for explaining the reasons for the diversity of symptoms and the varied course and response to therapy, as well as for the development of new treatment regimens for WD. [ABSTRACT FROM AUTHOR]

Parietal cell autoantibodies (PCAs), which recognize the enzyme H+/K+-ATPase as a target, are considered to be a diagnostic marker of autoimmune gastritis and pernicious anemia; these conditions are characterized by the presence of corpus atrophic gastritis. Circulating PCAs can be detected using several analytical methods that are commonly available in the clinical laboratory. Traditionally, indirect immunofluorescence (IIF) on rodent or primate stomach tissue is used as a screening test for the detection of PCAs. However, IIF suffers from a high inter-observer variability and lacks standardization. In addition, like immunoblotting, results are expressed only in a qualitative or semi-quantitative manner. Based on the few available studies that are reviewed herein, quantitative enzyme-linked immunosorbent assays (ELISAs) and fluorescence enzyme immunoassays (FEIAs) using purified H+/K+-ATPase perform better than IIF in the detection of PCAs, displaying higher sensitivity and utility in monitoring the disease. In light of their higher diagnostic accuracy, these solid-phase methods should be preferred to IIF in the screening of autoimmune atrophic gastritis. The use of methods to detect antibodies versus a specific subunit of H+/K+-ATPase (α or β) is currently confined to the world of research. Further investigation is required to define the clinical utility of H+/K+-ATPase subunit detection. [ABSTRACT FROM AUTHOR]

Cells exposed to stressors of various origin activate protective mechanisms that include the expression of heat shock proteins (Hsps)/molecular chaperones belonging to several families. Well-characterized inducible Hsp70 is present in all human cell-types and biological fluids, including blood, urine, and saliva. The presence of anti-Hsp70 autoantibodies in the serum of healthy individuals has already been confirmed, and their elevated titers positively correlated with the severity of several pathological conditions, including coeliac disease and dermatitis herpetiformis - a cutaneous manifestation of coeliac disease. Here, using an indirect enzyme-linked immunosorbent assay, we demonstrate, for the first time, that anti-Hsp70 autoantibodies are present in the saliva and urine of healthy individuals. Although the occurrence of anti-Hsp70 autoantibodies in the biological fluids of healthy individuals is intriguing, their physiological role is currently unknown. It is believed that antibodies reacting with self-molecules present in the serum of healthy individuals are part of natural autoantibody pool with multiple regulatory functions. On the other hand, some autoantibodies (e.g., typical of autoimmune bullous skin diseases or systemic lupus erythematosus) may be present before the onset of the disease and serve as specific predictive biomarkers. Therefore, we would like to initiate a discussion or future research direction on the use of anti-Hsp70 autoantibodies as a potential "biomarker" in the diagnosis or prediction of autoimmune diseases. Our findings can be considered in biomedical research to develop noninvasive, inexpensive and easy-to-use tests. Nevertheless, large-scale comparative studies should be initiated, involving the collection and analysis of biological samples such as saliva or urine from patients suffering from autoimmune diseases or other inflammatory or neoplastic diseases, to determine whether the levels of anti-Hsp70 autoantibodies are indeed elevated and whether they correlate with the clinical picture of any disease or established biomarkers. [ABSTRACT FROM AUTHOR]

Background: Production of anti-phosphatidylserine (anti-PS) antibodies has been associated with malaria and can aggravate pathology. How these autoantibodies develop during early childhood in a malaria context is not known. We examined levels of anti-PS IgG and IgM antibodies in a longitudinal cohort of mother-baby pairs during birth, in the infants at 2.5, 6 months, and in mothers and their babies at 9 months postpartum. Results: There was no difference between levels of anti-PS IgG in cord blood and the mothers' peripheral blood at birth. However, anti-PS IgM levels were significantly higher in the mothers compared to the infants' cord blood, and IgM levels were steadily increasing during the first 9 months of the infants' life. In infants that had the highest anti-PS IgM levels at birth, there was a decline until 6 months with a rise at 9 months. Infants that possessed high anti-PS IgG at birth also exhibited a progressive decline in levels. When anti-PS were correlated to different fractions of B-cells, there were several correlations with P. falciparum specific atypical B cells both at birth and at 2.5 months for the infants, especially for anti-PS IgM. Anti-PS also correlated strongly to C1q-fixing antibodies at birth. Conclusion: These results show that anti-PS IgG acquired by mothers could be transferred transplacentally and that IgM antibodies targeting PS are acquired during the first year of life. These results have increased the knowledge about autoimmune responses associated with infections in early life and is critical for a comprehensive understanding of malaria vaccine functionality in endemic areas. [ABSTRACT FROM AUTHOR]

Fetal autoimmune atrioventricular block (AVB) is a rare but potentially lifethreatening condition. It results from the passage of maternal anti-SSA/Ro or Anti SSB/La auto-antibodies into the fetal circulation, leading to inflammation and fibrosis of the AV node and often to irreversible damage. Besides AVB, these antibodies can also cause cardiomyopathies, but there is no evidence linking them to tachyarrhythmias. We present the case of a patient with significant risk factors for fetal AVB: a prior history of hydrops fetalis, high anti-SSA/Ro antibody levels and hypothyroidism. In this case, the use of dexamethasone and intravenous immunoglobulin may have contributed to reversing the first degree atrioventricular block detected at 19 weeks of gestation. Additionally, at 21 weeks, the fetus developed a tachyarrhythmia that needed treatment with flecainide. Soon after the birth, the newborn underwent ECG Holter and Wolff-Parkinson-White Syndrome (WPWS) was diagnosed. To our knowledge, the coexistence of fetal AVB and WPWS has never been described. [ABSTRACT FROM AUTHOR]

B-1 cells have intricate biology, with distinct function, phenotype and developmental origin from conventional B cells. They generate a B cell receptor with conserved germline characteristics and biased V(D)J recombination, allowing this innate-like lymphocyte to spontaneously produce self-reactive natural antibodies (NAbs) and become activated by immune stimuli in a T cell-independent manner. NAbs were suggested as "rheostats" for the chronic diseases in advanced age. In fact, age-dependent loss of function of NAbs has been associated with clinically-relevant diseases in the elderly, such as atherosclerosis and neurodegenerative disorders. Here, we analyzed comprehensively the ontogeny, phenotypic characteristics, functional properties and emerging roles of B-1 cells and NAbs in health and disease. Additionally, after navigating through the complexities of B-1 cell biology from development to aging, therapeutic opportunities in the field are discussed. Highlights: • B-1 cell development is regulated by specific transcription factors and this innate-like B cell bypasses selection phases during lymphopoiesis to generate polyreactive BCRs. • B-1 cell-derived cytokines have immunoregulatory effects during homeostasis and diseases. • Natural antibodies act as "eat-me" signals for the phagocytosis of cellular debris and invading pathogens. • Impairment in natural antibody function is correlated with onset and progression of chronic diseases in the elderly. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigated a new blood test (9G testTM Cancer/Lung) for early lung cancer detection. This test measures complexes of autoantibodies with specific lung cancer antigens for CYFRA 21-1 and p53. This study found that the diagnostic performances were significantly better than traditional methods at identifying LC, especially in early stages. The test showed good overall accuracy (AUC of 0.945) and detected early-stage lung cancer with high sensitivity (87.5%). This suggests it could be a valuable tool alongside existing scans like X-rays and LDCT for improving early LC detection. The early detection of lung cancer (LC) improves patient outcomes, but current methods have limitations. Autoantibodies against tumor-associated antigens have potential as early biomarkers. This study evaluated the 9G testTM Cancer/Lung, measuring circulating complexes of two antigen–autoantibody immune complexes (AIC) against their respective free antigens (CYFRA 21-1 and p53) for LC diagnosis. We analyzed 100 LC patients and 119 healthy controls using the 9G testTM Cancer/Lung, quantifying the levels of AICs (CYFRA 21-1-Anti-CYFRA 21-1 autoantibody immune complex (CIC) and p53-Anti-p53 autoantibody immune complex (PIC)), free antigens (CYFRA 21-1 and p53), and ratios of AICs/antigens (LC index). The levels of the CICs and PICs were significantly elevated in LC compared to the controls (p < 0.0062 and p < 0.0026), while free antigens showed no significant difference. The CIC/CYFRA 21-1 and PIC/p53 ratios were also significantly higher in LC (all, p < 0.0001). The LC index, when combining both ratios, exhibited the best diagnostic performance with an area under the curve (AUC) of 0.945, exceeding individual CICs, PICs, and free antigens (AUCs ≤ 0.887). At a cut-off of 3.60, the LC index achieved 81% sensitivity and 95% specificity for LC diagnosis. It detected early-stage (Stage I–II) LC with 87.5% sensitivity, exceeding its performance in advanced stages (72.7%). The LC index showed no significant differences based on age, gender, smoking status (former, current, or never smoker), or pack years smoked. The LC index demonstrates promising potential for early LC diagnosis, exceeding conventional free antigen markers. [ABSTRACT FROM AUTHOR]

Background: Given the catastrophic results of antiphospholipid syndrome (APS) left untreated, the possible role of non-criteria antiphospholipid (aPL) in the diagnosis of seronegative (SN)-APS patients, and its impact on the timely treatment of people with SNAPS, the present review aimed to gather the available literature up to 2022 focusing on the role of non-criteria aPL in the diagnosis of SN cases suspected of APS using non-criteria aPL. Methods: All published papers focusing mainly on the diagnosis of the SN-APS patients by non-criteria aPL were searched in four databases of PubMed, Scopus, Medline, and Web of Sciences, followed by manual search up to 20 February 2022 using such keywords as "Antiphospholipid Syndrome", "Seronegative", and "Non-Criteria". Finally, 15 studies were selected after the detailed evaluation of the full-text versions. Results: Based on the obtained results of our study, 24% to 81.9% of the SN-APS cases were positive for at least one isotype of non-criteria aPL. Thrombophilia events were more frequent in the APS population, compared to SN-APS; however, obstetric manifestations were more frequent in the SN-APS population, compared to seropositive-APS. Antivimentin/cardiolipin and antiphosphatidylserine/prothrombin IgG/IgM were introduced as the best non-criteria aPL to detect seronegative cases that were correlated with clinical manifestations. Conclusion: It seems that a combination of testing for non-criteria aPL should be performed for cases suspected of APS with negative criteria markers. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterised by pathological processes involving autoimmunity, vasculopathy and resultant extensive skin and organ fibrosis. Recent studies have demonstrated activation and aberrant wound healing responses in the epithelial layer of the skin in this disease, implicating the epithelial keratinocytes as a source of pro-fibrotic and inflammatory mediators. In this paper, we investigated the role of Immunoglobulin G (IgG) autoantibodies directed against epithelial cells, as potential initiators and propagators of pathological keratocyte activation and the ensuing SSc fibrotic cascade. A keratinocyte cell-based ELISA is used to evaluate the binding of SSc IgG. SSc skin biopsies were stained by immunofluorescence for the presence of IgG in the keratinocyte layer. Moreover, IgG purified from SSc sera was evaluated for the potential to activate keratinocytes in tissue culture and to induce TLR2 and 3 signalling in reporter cell lines. We demonstrate enhanced binding of SSc IgG to keratinocytes and the activation of these cells leading to the release of IL-1α, representing a potential initiating pathway in this disease. [ABSTRACT FROM AUTHOR]

An increased risk of atherosclerotic and thrombotic complications characterizes connective tissue diseases. Endothelial dysfunction is the basis for the initiation and progression of atherosclerosis and thrombosis. We present systemic lupus erythematosus (SLE) as a model rheumatic disease with endothelial dysfunction and discuss its mechanisms, factors that influence the early onset and rapid progression of atherosclerosis, and the increased risk of thromboembolic events. We focus on established methods to improve endothelium function, including statins, antiplatelet, and antithrombotic therapy. Hypercoagulable and hypofibrinolitic states and a hyperinflammatory response characterize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Several pathogenic mechanisms are typical for an acute phase of Covid-19 post-Covid syndrome and connective tissue diseases: endothelial dysfunction, elevated antiphospholipid antibody titer, activation of the complement system, and formation of extracellular neutrophil traps (NET). The current review discusses the mechanisms underlying SLE and the COVID-19 in the context of endothelial function, atherosclerosis, and thrombosis (Graphical abstract). Key Points • The pathophysiology of systemic lupus erythematosus (SLE) and Covid-19 shows some similarities, such as endothelial cell activation and dysfunction, the activation of complementary systems, the presence of antiphospholipid antibodies, and the formation of extracellular neutrophil traps. • Autoimmunity in both diseases creates the basis for hyperinflammatory, hypercoagulable, and hypofibrinolitic states and their thromboembolic complications. • This paper presents our perspective on the mechanisms behind the cardiovascular manifestations of SLE and COVID-19, with a particular emphasis on endothelial dysfunction. Covid-19 and systemic lupus erythematosus—potential similarities in pathophysiology. Figures of the panel illustrate the clinical manifestations of endothelial dysfunction, atherosclerosis, and thromboembolism, including coronary artery disease ([A] coronary angiography with left anterior descending artery stenosis and [B] scintigraphy with reduced perfusion in the myocardial apical segments), stroke ([C] carotid angiography, left carotid artery occlusion) and pulmonary embolism ([D]computed tomography with thrombus in the right pulmonary artery). [ABSTRACT FROM AUTHOR]

Objective: Sudden sensorineural hearing loss is considered idiopathic in up to 90 per cent of cases. This study explored the role of blood tests as biomarkers for the diagnosis and prognosis of sudden sensorineural hearing loss. Method: Two researchers filtered 34 papers into the final review. This review was pre-registered on the Prospero database and conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines. Results: Raised inflammatory markers are almost universal in sudden sensorineural hearing loss, suggesting an inflammatory or autoimmune process. The most useful biomarkers are neutrophil-lymphocyte ratio, platelet-lymphocyte ratio and fibrinogen level. Focused investigations should be deployed on a case-by-case basis to identify underlying metabolic, infective and autoimmune conditions. Conclusion: A full blood count and coagulation screen (fibrinogen) is recommended in all cases of sudden sensorineural hearing loss. These are inexpensive, accessible and offer as much diagnostic and prognostic information as any other biomarker. There is emerging evidence regarding specific biomarkers for sudden sensorineural hearing loss prognosis, with heat shock protein-70, anti-endothelial cell antibody and prestin demonstrating potential; investigation of their validity through prospective, controlled research is recommended. [ABSTRACT FROM AUTHOR]

The amyloid hypothesis has so far been at the forefront of explaining the pathogenesis of Alzheimer's Disease (AD), a progressive neurodegenerative disorder that leads to cognitive decline and eventual death. Recent evidence, however, points to additional factors that contribute to the pathogenesis of this disease. These include the neurovascular hypothesis, the mitochondrial cascade hypothesis, the inflammatory hypothesis, the prion hypothesis, the mutational accumulation hypothesis, and the autoimmunity hypothesis. The purpose of this review was to briefly discuss the factors that are associated with autoimmunity in humans, including sex, the gut and lung microbiomes, age, genetics, and environmental factors. Subsequently, it was to examine the rise of autoimmune phenomena in AD, which can be instigated by a blood-brain barrier breakdown, pathogen infections, and dysfunction of the glymphatic system. Lastly, it was to discuss the various ways by which immune system dysregulation leads to AD, immunomodulating therapies, and future directions in the field of autoimmunity and neurodegeneration. A comprehensive account of the recent research done in the field was extracted from PubMed on 31 January 2022, with the keywords "Alzheimer's disease" and "autoantibodies" for the first search input, and "Alzheimer's disease" with "IgG" for the second. From the first search, 19 papers were selected, because they contained recent research on the autoantibodies found in the biofluids of patients with AD. From the second search, four papers were selected. The analysis of the literature has led to support the autoimmune hypothesis in AD. Autoantibodies were found in biofluids (serum/plasma, cerebrospinal fluid) of patients with AD with multiple methods, including ELISA, Mass Spectrometry, and microarray analysis. Through continuous research, the understanding of the synergistic effects of the various components that lead to AD will pave the way for better therapeutic methods and a deeper understanding of the disease. [ABSTRACT FROM AUTHOR]

Anticytokine autoantibodies (ACAAs) can cause adult onset immunodeficiencies which mimic primary immunodeficiencies and can present as refractory and severe fungal infections. This paper provides an overview of the role of innate immunity, including key cytokines, in fungal infections and then describes four clinical scenarios where ACAAs are associated with severe presentations of a fungal infection: (1) Talaromyces marneffei infection and anti-interferon-γ, (2) histoplasmosis and anti-interferon-γ, (3) Cryptococcus gattii infection and anti-GM-CSF, and (4) mucocutaneous candidiasis and anti-IL-17A/F (IL-22). Testing for ACAAs and potential therapeutic options are discussed. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to provide a comprehensive review of recent literature data for autoimmune encephalitis (AIE). AIE refers to inflammatory, non-infectious, immune-mediated encephalitis characterised by neuroinflammation, synthesis of neuronal autoantibodies (NAAs), directed against surface, synaptic and intracellular antigens, with subsequent neuronal dysfunction. It is characterised by heterogeneous anatomic-clinical syndromes and prominent neuropsychiatric symptoms. Due to overlapping of different clinical and diagnostic biomarkers, AIE is often considered diagnosis of exclusion and requires an extensive work-up. Systematic search of the term «autoimmune encephalitis» in the PubMed database was performed, with limitation set for systematic review in papers English, published from 2004-2022. Further analysis was performed by the search of the author's reference list and Autoimmune Encephalitis Alliance (AEA) website. The analysis was conducted according to PRISMA (The Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Outcomes that were sought included: AIE classification and presentation; diagnostic processing; treatment. Preset search of published systematic reviews in PubMed database, derived eighty six papers. Further screening of derived data, author's reference list and AEA website was performed, according to previously defined outcomes. Finally, sixteen papers were independently selected and thoroughly analysed, with relevant conclusions presented in this paper. AIE is a severe inflammatory central nervous system (CNS) disorder with a complex differential diagnosis that often remains unrecognised. AIE research has established a wide range of new autoimmune antibodies syndromes, clinical and diagnostic biomarkers, which have improved diagnostic approach and treatment. Initial application of immunotherapy improves the outcome of disease. [ABSTRACT FROM AUTHOR]

Background: The association between autoantibodies and the risk of type 1 diabetes mellitus (T1DM) is well known. However, a quantitative overview of all associated autoantibodies and their effectiveness in diagnosing T1DM is still lacking. Purpose: To perform a meta-analysis concerning the association between autoantibodies and the risk of T1DM Methods: Published papers from PubMed, Embase, Cochrane, and Google Scholar were collected and analyzed using a fixed or random-effect model. Results: Seven papers on 1266 T1DM patients and 982 controls relevant to our study were included in the analysis. Our pooled analysis found that autoantibody expression in children with T1DM was associated with age at diagnosis [mean diff: 4.35 (95% CI: 1.10-7.60) p = 0.009) and the number of autoantibodies detected [OR: 2.13 (95% CI: 1.65-2.76) p < 0.00001]. However, duration of disease [mean diff: 33.36 (95% CI: 8.78-75.50), p = 0.12] and HbA1c [mean diff: 21.63 (95% CI: 5.43-48.48), p = 0.12] did not differ significantly between the single and multiple autoantibody detection groups. We also found that the expression of anti-ZnT8, anti-glutamic acid decarboxylase (GAD), and IAA was associated with a higher risk of T1DM development in children [OR: 35.26 (23.28-53.41), p < 0.00001; OR: 25.59 (18.29-35.79), p < 0.00001; OR: 23.62 (15.79-35.36), p < 0.0000, respectively]. Conclusion: ZnT8 has a better predictive value than other single autoantibodies, but two or more autoantibodies give superior predictive power. [ABSTRACT FROM AUTHOR]

Objective: Ghrelin is an orexigenic peptide that becomes post-translationally modified. Natural autoantibodies to ghrelin (ghrelin-aAb) have been described in healthy subjects, in eating disorders and rheumatic diseases, with potential clinical relevance. Despite these important reports, the data base on the prevalence and physiological role is small and technical approaches for assessing ghrelin-aAb are few, encouraging respective research for improving knowledge on the potential endocrine significance. Methods: A novel immunoprecipitation assay was generated based on a fusion protein of human ghrelin with a reporter gene. Assay quality was verified with commercial antibodies. Assay characteristics and matrix effects were determined, including stability of natural ghrelin-aAb to freezing, signal linearity in dilution experiments, and comparison of different matrices. Three groups of serum samples were analyzed for ghrelin-aAb, comprising commercial sera from healthy subjects and patients with type 1 or type 2 diabetes mellitus. Results: The newly generated ghrelin-aAb assay proved sensitive, robust and reliable over a broad concentration range. Results from serum and plasma differed slightly. The signals from serum remained stable towards freezing and thawing, and in dilution experiments. Applying a mathematical criterion for outliers (P75 + 1.5-times IQR), an average prevalence of 11%–12% of positive samples was identified in the different human cohorts, with no significant sexor disease-related difference. General significance: A novel diagnostic autoantibody assay detected ghrelinaAb with a similar prevalence in diabetic patients and controls, suggesting that autoimmunity to ghrelin plays little role in diabetes mellitus, but may be of relevance in other diseases where ghrelin signaling is essential. [ABSTRACT FROM AUTHOR]

Autoantibodies to nuclear antigens are hallmarks of systemic lupus erythematosus (SLE) where they contribute to pathogenesis. However, there remains a gap in our knowledge regarding how different isotypes of autoantibodies contribute to this autoimmune disease, including the production of the critical type I interferon (IFN) cytokines by plasmacytoid dendritic cells (pDCs) in response to immune complexes (ICs). We focused on IgA, which is the second-most prevalent isotype in serum and, along with IgG, is deposited in glomeruli in individuals with lupus nephritis. We show that individuals with SLE have serum IgA autoantibodies against most nuclear antigens, correlating with IgG against the same antigen. We investigated whether IgA autoantibodies against a major SLE autoantigen, Smith ribonucleoprotein (Sm/RNP), played a role in IC activation of pDCs. We found that pDCs expressed the IgA-specific Fc receptor, FcαR, and IgA1 autoantibodies synergized with IgG in RNA-containing ICs to generate robust primary blood pDC IFN-α responses in vitro. pDC responses to these ICs required both FcαR and FcγRIIa, showing synergy between these Fc receptors. Sm/RNP IC binding to and internalization by pDCs were greater when ICs contained both IgA1 and IgG. Circulating pDCs from individuals with SLE had higher binding of IgA1-containing ICs and higher expression of FcαR than pDCs from healthy control individuals. Although pDC FcαR expression correlated with the blood IFN-stimulated gene signature in SLE, Toll-like receptor 7 agonists, but not IFN-α, up-regulated pDC FcαR expression in vitro. Together, we show a mechanism by which IgA1 autoantibodies contribute to SLE pathogenesis. Editor's summary: Autoantibodies to nuclear antigens contribute to pathology in systemic lupus erythematosus (SLE). However, it is not understood how different isotypes of these antibodies contribute to disease. Here, Waterman et al. characterized circulating immunoglobulin A1 (IgA1) autoantibodies in individuals with SLE, showing that they reacted against many of the same self-antigens as their immunoglobulin G (IgG) counterparts, including against Smith ribonuclear proteins. The authors further showed that interferon-α (IFN-α)–producing plasmacytoid dendritic cells expressed the IgA1 receptor, Fc α receptor (FcαR), and that IgA1-containing immune complexes could drive IFN-α production by these cells in vitro. The authors showed that these responses required the presence of both IgA1 and IgG. Last, the authors showed that, in 18 individuals with SLE, interferon-stimulated gene expression positively correlated with the amount of FcαR in whole blood. Together, these results suggest that targeting FcαR could be a potential therapeutic for SLE treatment. —Brandon Berry [ABSTRACT FROM AUTHOR]

Context The 2 peaks of type 1 diabetes incidence occur during early childhood and puberty. Objective We sought to better understand the relationship between puberty, islet autoimmunity, and type 1 diabetes. Methods The relationships between puberty, islet autoimmunity, and progression to type 1 diabetes were investigated prospectively in children followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Onset of puberty was determined by subject self-assessment of Tanner stages. Associations between speed of pubertal progression, pubertal growth, weight gain, homeostasis model assessment of insulin resistance (HOMA-IR), islet autoimmunity, and progression to type 1 diabetes were assessed. The influence of individual factors was analyzed using Cox proportional hazard ratios. Results Out of 5677 children who were still in the study at age 8 years, 95% reported at least 1 Tanner Stage score and were included in the study. Children at puberty (Tanner Stage ≥2) had a lower risk (HR 0.65, 95% CI 0.45-0.93; P =.019) for incident autoimmunity than prepubertal children (Tanner Stage 1). An increase of body mass index Z-score was associated with a higher risk (HR 2.88, 95% CI 1.61-5.15; P <.001) of incident insulin autoantibodies. In children with multiple autoantibodies, neither HOMA-IR nor rate of progression to Tanner Stage 4 were associated with progression to type 1 diabetes. Conclusion Rapid weight gain during puberty is associated with development of islet autoimmunity. Puberty itself had no significant influence on the appearance of autoantibodies or type 1 diabetes. Further studies are needed to better understand the underlying mechanisms. [ABSTRACT FROM AUTHOR]

Interstitial lung disease is a common complication of anti-synthetase syndrome (ASS), and lymphocytic infiltration is often observed in the lesion. We have recently reported that disease-specific autoantibodies are produced by infiltrating lymphocytes in some autoimmune diseases. Here, we investigate the antigen specificity of B cells in the lung lesions of ASS patients. A total of 177 antibodies were produced from antibody-secreting cells in bronchoalveolar fluid (BALF) of three each of serum anti-Jo-1 and serum anti-EJ antibody-positive patients. Twelve to 30% and 50 to 62% of these antibodies were diseasespecific autoantibodies, respectively. These autoantibodies recognized conformational epitopes of the whole self-antigen and had affinity maturations, indicating that self-antigens themselves are the target of humoral immunity. In addition, 100 antibodies were produced from two salivary gland tissues, obtained by chance, of ASS patients. Salivary glands are not generally recognized as lesions of ASS, but unexpectedly, ASS-related autoantibody production was also observed similar to that of BALF. Immunostaining confirmed the presence of ASS-related autoantibody-producing cells in salivary glands. Our results suggest that disease-specific autoantibody production at lesion sites is a common pathogenesis of autoimmune diseases, and that tissue-specific production of autoantibodies can provide insights regarding the distribution of organ manifestations in autoimmune diseases. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with an unpredictable course of recurrent exacerbations alternating with more stable disease. SLE is characterized by broad immune activation and autoantibodies against double-stranded DNA and numerous proteins that exist in cells as aggregates with nucleic acids, such as Ro60, MOV10, and the L1 retrotransposon-encoded ORF1p. Results: Here we report that these 3 proteins are co-expressed and co-localized in a subset of SLE granulocytes and are concentrated in cytosolic dots that also contain DNA: RNA heteroduplexes and the DNA sensor ZBP1, but not cGAS. The DNA: RNA heteroduplexes vanished from the neutrophils when they were treated with a selective inhibitor of the L1 reverse transcriptase. We also report that ORF1p granules escape neutrophils during the extrusion of neutrophil extracellular traps (NETs) and, to a lesser degree, from neutrophils dying by pyroptosis, but not apoptosis. Conclusions: These results bring new insights into the composition of ORF1p granules in SLE neutrophils and may explain, in part, why proteins in these granules become targeted by autoantibodies in this disease. [ABSTRACT FROM AUTHOR]

Reactive pustular eruptions (RPEs) can manifest in a variety of conditions, including pustular psoriasis (PP) and adult-onset immunodeficiency syndrome due to anti-interferon-γ autoantibody (AOID). These RPEs can be attributed to different causes, one of which is genetic factors. However, the genetic basis for pustular skin diseases remains poorly understood. In our study, we conducted whole-exome sequencing on a cohort of 17 AOID patients with pustular reactions (AOID-PR) and 24 PP patients. We found that 76% and 58% of the AOID-PR and PP patients, respectively, carried rare genetic variations within the filaggrin (FLG) gene family. A total of 12 out of 21 SNPs on FLG had previously received clinical classifications, with only p.Ser2706Ter classified as pathogenic. In contrast, none of the FLG3 SNPs identified in this study had prior clinical classifications. Overall, these variations had not been previously documented in cases of pustular disorders, and two of them were entirely novel discoveries. Immunohistochemical analysis of skin biopsies revealed that FLG variants like p.Ser860Trp, p.Gly3903Ter, p.Gly2440Glu, and p.Glu2133Asp caused reductions in FLG levels similar to the pathogenic FLG p.Ser2706Ter. These results highlight rare FLG variants as potential novel genetic risk factors contributing to pustule formation in both AOID and PP. [ABSTRACT FROM AUTHOR]

Introduction: Systemic lupus erythematosus (SLE) is a multidimensional disease; however, the association of another systemic autoimmune disease further complicates its clinical presentation. Aim: We decided to investigate whether the association of overlap syndromes is linked with a different clinical picture compared to pure lupus and whether this association changes the sensitivity of the following commonly used criteria: the 2019 European League Against Rheumatism/American College of Rheumatology (EULAR/ACR), the ACR-1997 and the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Method: We performed a retrospective observational study among 382 patients afflicted with lupus: we measured as much of the full clinical and laboratory picture as possible in an unselected cohort. The diagnosis of SLE and other systemic autoimmune diseases was established by the rheumatologist in routine care and then the authors compared the characteristics of patients with pure lupus and those with overlapping pathologies. The diagnosis rates were compared to those that were determined based on the three classification criteria in order to identify various sensitivities and whether the existence of an overlap affects their rates. The fulfillment of each set of criteria was calculated using an Excel-based automatic calculation. Results: Among the patients, the ACR 1997′s sensitivity was 81.2% (310 patients), and the SLICC 2012 criteria achieved 94.5% sensitivity (361 patients). The 2019 EULAR/ACR classification criteria resulted in a slightly lower sensitivity (90.3%—345 patients) when compared to the original publication (96%) due to the lower sensitivity of our anti-nuclear antibody (ANA) test (measured via enzyme-linked immunosorbent assay (ELISA)). Nearly all ANA-negative (21/22—95%) patients showed a positive lupus-associated antibody test. The proportion of ANA-negative cases showed no significant difference among pure and overlap patients. No significant difference was found between patients with overlap (138 patients—36%) and pure SLE (244 patients—64%) through the use of these criteria, with the exception of the SLICC criteria (ACR: 80.4% vs. 81.6%; SLICC: 97.4% vs. 92.6%, p = 0.035; EULAR/ACR 2019: 91.4% vs. 89.6%). Patients with an overlap syndrome were significantly older (55 vs. 50 years, p = 0.001), more likely to suffer from interstitial lung disease (ILD: 20% vs. 11%, p = 0.0343) and less frequently showed class III/IV lupus nephritis (7% vs. 14%, p = 0.029) when compared with their pure lupus counterparts. Conclusion: All investigated criteria regarding sensitivity were similar to the original publication's findings. The sensitivity of the EULAR/ACR 2019 classification criterion in cases with overlap syndrome proved excellent, with results very similar to patients afflicted with pure SLE. In the presence of an overlap syndrome, we found significantly fewer patients with lupus nephritis III/IV but no differences in other typical lupus organ manifestation beyond the kidney, whereas we found a higher proportion of ILD in patients with an overlap, indicating that the presence of an overlap syndrome significantly influences the observed clinical picture in real-world conditions. [ABSTRACT FROM AUTHOR]

Judicious use of autoantibodies in paediatrics can be challenging. Autoimmune conditions can present with a wide range of signs and symptoms, many of which are non-specific. In combination with clinical features and laboratory findings, autoantibodies can facilitate diagnosis and in certain cases inform prognosis. Evidence for use of autoantibodies to guide and monitor treatment is limited. Caution is necessary when interpreting adult studies. We summarise the use of autoantibodies in paediatric practice with a guide on how they may be used. [ABSTRACT FROM AUTHOR]

Migrasomes represent a recently uncovered category of extracellular microvesicles, spanning a diameter range of 500 to 3000 nm. They are emitted by migrating cells and harbour a diverse array of RNAs and proteins. Migrasomes can be readily identified in bodily fluids like serum and urine, rendering them a valuable non‐invasive source for disease diagnosis through liquid biopsy. In this investigation, we introduce a streamlined and effective approach for the capture and quantitative assessment of migrasomes, employing wheat germ agglutinin (WGA)‐coated magnetic beads and flow cytometry (referred to as WBFC). Subsequently, we examined the levels of migrasomes in the urine of kidney disease (KD) patients with podocyte injury and healthy volunteers using WBFC. The outcomes unveiled a substantial increase in urinary podocyte‐derived migrasome concentrations among individuals with KD with podocyte injury compared to the healthy counterparts. Notably, the urinary podocyte‐derived migrasomes were found to express an abundant quantity of phospholipase A2 receptor (PLA2R) proteins. The presence of PLA2R proteins in these migrasomes holds promise for serving as a natural antigen for the quantification of autoantibodies against PLA2R in the serum of patients afflicted by membranous nephropathy. Consequently, our study not only pioneers a novel technique for the isolation and quantification of migrasomes but also underscores the potential of urinary migrasomes as a promising biomarker for the early diagnosis of KD with podocyte injury. [ABSTRACT FROM AUTHOR]

Anti-mitochondrial antibody (AMA) is not always present in patients with primary biliary cholangitis (PBC). We aimed to determine the additional value of anti-hexokinase 1 (anti-HK1) and anti-kelch-like 12 (anti-KLHL12) antibody in PBC and analyzed the biochemical and immunological parameters of 212 subjects, including PBC patients and healthy controls. Serum anti-gp210 and sp100 antibodies were determined by an immunoblotting test (IBT). Enzyme-linked immunosorbent assay (ELISA) was employed to evaluate anti-HK1 and anti-KLHL12. The diagnostic value of anti-HK1 and anti-KLHL12 to PBC was analyzed by constructing a receiver operating characteristic (ROC) curve. ROC analyses didn't show a very good performance of serum anti-HK1 for PBC diagnosis; the AUC was 0.664 with a sensitivity of 53.3 % and a specificity of 79.2 %. Regarding anti-KLHL12, ROC analysis yielded an AUC of 0.626, with a sensitivity of 45.7 % and a specificity of 93.8 %. For AMA-negative PBC patients, the AUC increased to 0.790 for KLHL12, and 0.708 for HK1. AMA combined with anti-HK1 or anti-KLHL12 antibody significantly improved the diagnostic sensitivity of PBC from 82 to about 95 %, respectively. In AMA-negative PBC patients, the sensitivities for anti-HK1 (62.50 %) and anti-KLHL12 (75 %) antibodies were higher than for anti-gp210 (37.5 %) and anti-sp100 antibody (43.75 %). When these four antibodies were combined, the overall sensitivity increased to 87.5 %. The determination of anti-HK1 and anti-KLHL12 facilitates the diagnosis of PBC, particularly in AMA-negative patients. Adding anti-HK1 and anti-KLHL12 antibodies to clinical detection enables early diagnosis and timely treatment, potentially improving patient prognosis. [ABSTRACT FROM AUTHOR]

Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to investigate the first involved joints and associated factors in Turkish patients with rheumatoid arthritis (RA). Patients and methods: This retrospective cross-sectional study included 300 newly diagnosed and disease-modifying antirheumatic drug-naïve RA patients (240 females, 60 males; mean age: 54±1.2 years; range, 18 to 82 years). Baseline demographic, clinical, and laboratory data were evaluated between January 2022 and December 2022. The patients were divided into four groups according to autoantibody profile: antibody-negative patients (Group 1; both RF and anti-CCP were negative in this group of patients), RF-positive patients (Group 2), anti-CCP-positive patients (Group 3), and patients with dual seropositivity with RF and anti- CCP (Group 4). The patients were also divided into two groups according to the size of the first affected joint: patients with SJI at diagnosis and patients without SJI involvement at diagnosis. Results: Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibody positivity rates were 40.3% and 35.6%, respectively. The mean lag time to diagnosis was 25±36 months. At the disease onset, 20% of patients did not have small joint involvement (SJI). Seronegative patients tended to be female (p=0.001), had longer lag time (p=0.001), and had lower levels of C-reactive protein (p=0.025), white blood count (p=0.005), and neutrophil/lymphocyte ratio (p=0.001) compared to the dual seropositive group. Patients presenting with SJI had a younger age (p=0.002), tended to be female (p=0.001), and had lower RF (p=0.034) and anti-CCP (p=0.031) positivity. Only age (p=0.005) and dual seronegativity (RF and anti-CCP; p=0.035) were the independent predictors of SJI in multivariate analysis. Conclusion: The decreasing age and seronegative status were defined as independent risk factors of SJI at the onset of RA. Population-based, prospective studies are needed for earlier diagnosis. [ABSTRACT FROM AUTHOR]

Simple Summary: COVID-19, with persistent and new onset of symptoms, such as fatigue, post-exertional malaise, and cognitive dysfunction that impact everyday functioning, is referred to as long-COVID under the general category of post-acute sequelae of the SARS-CoV-2 infection (PASC). It includes a wide range of signs and symptoms that can last weeks, months, or even years after infection, most of which are attributable to dysfunctions of the neurovegetative system. The causative mechanisms are still unknown, but autoimmunity and the production of autoantibodies targeting self-antigens via the molecular mimicry phenomenon seem to have a role. Here we evaluated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein in sera from ongoing symptomatic COVID-19 patients (long-COVID) with cardiorespiratory symptoms, subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2. Putative autoantibodies are present in both long-COVID-19 and vaccinated groups, suggesting that both viral infection and vaccination may trigger autoreactivity. However, the presence of autoantibodies is not sufficient for triggering autoimmunity, and other predisposing conditions must co-occur. Therefore, it is necessary to run further investigations to clarify the complex mechanisms involved in the development of long-COVID, providing knowledge which may offer further information for the prevention and treatment of the disease. As reported by the World Health Organization (WHO), about 10–20% of people have experienced mid- to long-term effects following SARS-CoV-2 infection, collectively referred to as post-COVID-19 condition or long-COVID, including some neurovegetative symptoms. Numerous findings have suggested that the onset of these neurovegetative symptoms upon viral infection may be caused by the production of autoantibodies through molecular mimicry phenomena. Accordingly, we had previously demonstrated that 22 of the human proteins sharing putatively immunogenic peptides with SARS-CoV-2 proteins are expressed in the dorsal motor nucleus and nucleus ambiguous. Therefore, if molecular mimicry occurs following severe forms of COVID-19, there could be transitory or permanent damage in some vagal structures, resulting in a lower vagal tone and all the related clinical signs. We investigated the presence of autoantibodies against two proteins of vagal nuclei sharing a peptide with SARS-CoV-2 spike glycoprotein using an immunoassay test on blood obtained from patients with cardiorespiratory symptoms in patients affected by ongoing symptomatic COVID-19 (long-COVID), subjects vaccinated without a history of SARS-CoV-2 infection, and subjects not vaccinated without a history of SARS-CoV-2 infection. Interestingly, putative autoantibodies were present in both long-COVID-19 and vaccinated groups, opening interesting questions about pathogenic mechanisms of the disease. [ABSTRACT FROM AUTHOR]

Background: The early reliable detection and quantification of autoantibodies play an important role in autoimmune disease diagnosis and in disease-course monitoring. New technologies, such as the multiplexed determination of autoantibodies, have recently been introduced and are being adopted more frequently. The aim of this study was to evaluate the ability of a new microdot array-based multiparametric assay (ZENIT AMiDot CTD panel, A. Menarini Diagnostics, Firenze, Italy) to correctly classify patients with autoimmune rheumatic diseases (ARDs) and compare it to a fluorescence enzyme immunoassay (FEIA) for the detection of anti-ENAs. Methods: The study included 69 consecutive samples from patients with ARDs that were analyzed using two different methods (FEIA and AMiDot) to detect anti-CENP B and six anti-ENA antibodies: anti-Scl-70, anti-SSB/La, anti-Jo-1, anti-U1-RNP, anti-Ro52, and anti-Ro60. The control group sera came from sixty-eight blood donors. Tests were run on the automated slide processor ZENIT FLOW, and then the slides were imaged and analyzed using ZENIT fast. Results: Since the samples were selected for at least one antibody positivity with an ARD diagnosis, we did not calculate clinical sensitivity but only specificity, which was 98.53%, ranging from 90% for anti-SSB/La antibodies to 100% for anti-CENP B ones. Mean agreement among the methods assessed by Cohen's kappa was 0.816 ± 0.240. Conclusions: The assay demonstrated good clinical performance and may be considered a valuable aid in detecting ARD patients, offering an alternative to methods such as FEIA which are largely in use today. [ABSTRACT FROM AUTHOR]

The role of spirituality in health and disease is a complex and emerging area of research. Incorporating spirituality into the bio-psycho-social model of health and disease leading to the bio-psycho-social-spiritual model provides a more comprehensive framework. In this context, chronic disorders like primary Sjögren's syndrome (pSS) are of interest due to their intricate interactions between biological, psychological, and spiritual factors. This study explored the relationship between spirituality, immune parameters, and disease activity in pSS patients. Data from 108 patients were analyzed, including self-assessed spirituality (answering to direct questions and completing the Spiritual Transcendence Scale), immunological parameters and disease activity scores. The findings revealed several associations. Individuals with spiritual attitudes or engaged in regular prayer/meditation showed lower serum levels of autoantibodies specific to pSS and lower disease activity scores. Spiritual engagement was also linked to decreased perceived skin and tracheal dryness, suggesting potential benefits for physical symptoms. These findings suggest that spirituality may play a significant role in modulating immune responses and disease activity in pSS patients. The study underscores the importance of considering spirituality as an integral part of the holistic approach to health and disease, further expanding the understanding of the interconnectedness of biological, psychological, and spiritual dimensions. [ABSTRACT FROM AUTHOR]

Pemphigus is a rare autoimmune bullous disease, with pemphigus vulgaris (PV) and pemphigus foliaceous (PF) being its most common forms. This report presents a case of PF triggered by vaccinations. A previously healthy 38-year-old Caucasian man developed skin lesions six months after receiving vaccinations for hepatitis A, rabies, cholera, typhoid fever, and yellow fever before travelling to Sudan. Exami- nation revealed pruritic erosions, crusts, and flaccid blisters primarily on the trunk and limbs. Histopathology was nonspecific, but direct immunofluorescence showed intercellular IgG, C3c, and C1q deposits. Elevated autoantibodies against desmoglein 1 (DSG1) confirmed the PF diagnosis. The patient responded well to oral prednisone and topical treatments, with complete resolution of symptoms within six months. The aetiology of pemphigus remains unclear, but vaccines can nonspecifically activate the immune system, potentially triggering pemphigus in predisposed individuals. This case highlights the need to consider pemphigus as a potential adverse effect of vaccination. [ABSTRACT FROM AUTHOR]

Inflammation is closely associated with cerebrovascular diseases, cardiovascular diseases, diabetes, and cancers, and it is accompanied by the development of autoantibodies in the early stage of inflammation-related diseases. Hence, it is meaningful to discover novel antibody biomarkers targeting inflammation-related diseases. In this study, Jumonji C-domain-containing 6 (JMJD6) was identified by the serological identification of antigens through recombinant cDNA expression cloning. In particular, JMJD6 is an antigen recognized in serum IgG from patients with unstable angina pectoris (a cardiovascular disease). Then, the serum antibody levels were examined using an amplified luminescent proximity homogeneous assay-linked immunosorbent assay and a purified recombinant JMJD6 protein as an antigen. We observed elevated levels of serum anti-JMJD6 antibodies (s-JMJD6-Abs) in patients with inflammation-related diseases such as ischemic stroke, acute myocardial infarction (AMI), diabetes mellitus (DM), and cancers (including esophageal cancer, EC; gastric cancer; lung cancer; and mammary cancer), compared with the levels in healthy donors. The s-JMJD6-Ab levels were closely associated with some inflammation indicators, such as C-reactive protein and intima–media thickness (an atherosclerosis index). A better postoperative survival status of patients with EC was observed in the JMJD6-Ab-positive group than in the negative group. An immunohistochemical analysis showed that JMJD6 was highly expressed in the inflamed mucosa of esophageal tissues, esophageal carcinoma tissues, and atherosclerotic plaques. Hence, JMJD6 autoantibodies may reflect inflammation, thereby serving as a potential biomarker for diagnosing specific inflammation-related diseases, including stroke, AMI, DM, and cancers, and for prediction of the prognosis in patients with EC. [ABSTRACT FROM AUTHOR]

Background: Antineutrophil cytoplasmatic antibodies (ANCA) have been detected in patients with systemic lupus erythematosus (SLE). In this study, we investigated the presence of ANCA in a sample of Brazilian SLE patients and its possible associations with clinical and serological outcomes. Additionally, we reviewed the literature of on ANCA in SLE. Results: The presence of ANCA was detected in 130 patients using indirect immunofluorescence (IIF). The test was positive in 29.9% of the cases (17.6% pANCA and 11.5% cANCA). Male sex and peripheral vasculitis were more prevalent in the ANCA-positive sample. cANCA was associated with lupus anticoagulant and pANCA had a positive association with peripheral vasculitis and a negative association with anti- SSB/La antibodies. In the 22 studies included in the literature review, a wide range of ANCA positivity was found (13% to 81.1% by IIF and 0 to 22.2% by ELISA). ANCA was associated with renal damage in the Asian population. Although other associations have been found in isolated studies, they were not consistently reported. Conclusions: The ANCA prevalence found in this Brazilian sample was within the range reported in the literature and these autoantibodies were more frequent in males and in patients with vasculitis. The literature showed controversial results on the association between ANCA and SLE disease activity or clinical characteristics. [ABSTRACT FROM AUTHOR]