Search Results (268)

The COVID-19 pandemic, caused by SARS-CoV-2, has led to a wide range of acute and chronic disease manifestations. While most infections are mild, a significant number of patients develop severe illness marked by respiratory failure, thromboinflammation, and multi-organ dysfunction. In addition, post-acute sequelae—commonly known as long-COVID—can persist for months. Recent studies have identified the emergence of diverse autoantibodies in COVID-19, including those targeting nuclear antigens, phospholipids, type I interferons, cytokines, endothelial components, and G-protein-coupled receptors. These autoantibodies are more frequently detected in patients with moderate to severe disease and have been implicated in immune dysregulation, vascular injury, and persistent symptoms. This review examines the underlying immunological mechanisms driving autoantibody production during SARS-CoV-2 infection—including molecular mimicry, epitope spreading, and bystander activation—and discusses their functional roles in acute and post-acute disease. We further explore the relevance of autoantibodies in maternal–fetal immunity and comorbid conditions such as autoimmunity and cancer, and we summarize current and emerging therapeutic strategies. A comprehensive understanding of SARS-CoV-2-induced autoantibodies may improve risk stratification, inform clinical management, and guide the development of targeted immunomodulatory therapies. Full article

Background and Clinical Significance: Antisynthetase syndrome (ASyS) is a rare autoimmune entity defined by the presence of anti-aminoacyl-t ribonucleic acid (RNA) synthetase autoantibodies and classically associated with a triad of interstitial lung disease (ILD), inflammatory myopathy, and arthritis. Additional clinical features may include Raynaud’s phenomenon and “mechanic’s hands”. Among antisynthetase antibodies, anti-PL-12 is notably associated with predominant or isolated ILD and may occur in the absence of clinically evident myositis, thereby complicating timely diagnosis. Case Presentation: We are presenting a 45-year-old non-smoking female patient with a prior diagnosis of seronegative rheumatoid arthritis (RA) who developed progressive dyspnea, dry cough, and sicca symptoms. High-resolution computed tomography revealed a nonspecific interstitial pneumonia (NSIP) pattern. Despite normal creatine kinase and lactate dehydrogenase levels, serological work-up revealed positive anti-PL-12 and anti-Ro52 antibodies, supporting a diagnosis of antisynthetase syndrome without myositis, fulfilling the diagnostic criteria for ASyS per Connors and Solomon. Treatment with corticosteroids and cyclophosphamide induced clinical and functional respiratory improvement, while azathioprine was initiated for maintenance. Conclusions: This case underscores the clinical heterogeneity of antisynthetase syndrome and highlights the diagnostic challenge posed by anti-PL-12–associated ILD in the absence of myositis. Importantly, it demonstrates that in patients with pre-existing rheumatologic diagnoses, the emergence of atypical pulmonary manifestations warrants repeat serologic evaluation to assess ASyS and other autoimmune conditions. Early diagnosis and immunosuppressive treatment are essential to optimize outcomes. Full article

Background: Regulatory T cells (Tregs) are the main suppressor cells that maintain immune tolerance and prevent autoimmunity. Changes in Treg number or function are implicated in a wide range of autoimmune and inflammatory (AI/I) diseases, with or without underlying inborn errors of immunity (IEI). Understanding the phenotypic profiles of Treg subsets and their associations with immune dysregulation is crucial to identifying potential robust and holistic biomarkers for disease activity. Methods: We examined peripheral blood mononuclear cells from 40 patients diagnosed with various autoimmune/inflammatory diseases, including those with genetically confirmed inborn errors of immunity (IEIs), and compared these samples to those from 38 healthy controls of the same age. Utilizing multiparametric flow cytometry, we measured multiple Treg sub-populations and investigated their correlations with lymphocyte subset profiles and the diversity of autoantibodies. We applied advanced statistical and machine learning techniques, such as t-SNE, k-means clustering, and ROC analysis, to analyze immunophenotypic patterns in the patients. Results: Among all Treg sub-populations, only CD4⁺CD127^lowCD25^highFOXP3⁺ Tregs showed a significant decrease in patients compared to healthy controls (p < 0.05), while other Treg phenotypes did not differ. FOXP3 expression showed reduced intensity in patients and demonstrated diagnostic potential (AUC = 0.754). Notably, this Treg subset negatively correlated with CD19⁺ B cell percentages and positively correlated with the diversity of circulating autoantibodies. Unsupervised clustering revealed three distinct immunophenotypic profiles, highlighting heterogeneity among patients and underlining FOXP3-centered immune dysregulation. Conclusions: Our results presented that patients have an impairment in the CD4⁺CD127^lowCD25^highFOXP3⁺ regulatory T cell subset, which is identified by significantly decreased frequency and decreased expression of FOXP3. Immunological heterogeneity among patients was further uncovered by unsupervised clustering, highlighting the critical role that FOXP3-centered regulatory failure plays in the pathophysiology of illness. The combined evaluation of these three immunological factors, centered around FOXP3, holds promise as an integrative tool for monitoring disease progression across various autoimmune and immunodeficient contexts. Full article

Anticytokine autoantibodies (AAbs), particularly anti-interferon-gamma (anti-IFN-γ) AAbs, disrupt cytokine functions, leading to infections, autoimmune-like diseases, and conditions resembling interleukin-12 (IL-12)/IFN-γ pathway defects. Advances in genetic testing have clarified overlaps between autoinflammatory, autoimmune disorders, and primary immunodeficiencies but reveal complex phenotypes and pathways. While these insights deepen our understanding of immune mechanisms, they also complicate diagnosis and treatment, with limited options for IFN-γ deficiencies caused by genetic mutations. The adult-onset immunodeficiency with disseminated lymphadenitis due to nontuberculous mycobacteria (NTM) and other opportunistic infections has been linked to high levels of anti-IFN-γ AAbs. This syndrome, initially identified in HIV-negative Asian patients, frequently affects individuals of Asian descent and may be associated with specific human leukocyte antigen (HLA) alleles. The presence of neutralizing anti-IFN-γ AAbs impairs the IFN-γ-dependent immune response, likely contributing to the persistent NTM infection. This study underscores the potential for late-onset anti-IFN-γ AAb syndrome to manifest with disseminated NTM (dNTM) infections, highlights the importance of timely diagnosis and considers rituximab as a potential therapeutic option. Full article

Long-COVID (LC) is characterized by diverse and persistent symptoms, potentially mirroring different molecular pathways. Recent data might offer that one of them is mediated by functional autoantibodies (fAAb) targeting G protein-coupled receptors (GPCR). Thus, the aim of this study was to investigate the clinical phenotype of patients with LC in relation to their GPCR-fAAb seropositivity. The present study recruited 194 patients with LC and profiled them based on self-reported symptoms. GPCR-fAAb seropositivity was identified by using a cardiomyocyte bioassay, testing the presence and functionality of the AAbs. Logistic regression, clustering, and decision tree analyses were applied to examine associations between GPCR-fAAb profiles and self-reported symptoms considering age and gender. The most prevalent GPCR-fAAbs in patients with LC were fAAB targeting the β2 adrenergic receptor (β2-fAAb, 92.8%), the muscarinergic M2 receptor (M2-fAAb, 87.1%), the Angiotensin II type 1 receptor (AT1-fAAb, 85.6%), and angiotensin (1–7) Mas receptor (MAS-fAAb, 85.6%). β2-fAAb showed a significant relation with dizziness, lack of concentration, and POTS, while Endothelin Type A receptor functional autoantibody (ET-A-fAAb) was significantly related to deterioration of pre-existing neurological disorders. Statistical analysis indicated a strong positive correlation between M2- and β2-fAAb; as in addition, an association of β2-fAAb and gender was observed to one of the major clinical symptoms (fatigue/PEM), a critical impact of GPCR-fAAb on LC-pathogenesis can be assumed. Summing up, the present data show that specific GPCR-fAAb are associated with distinct clinical phenotypes. Especially, the combination of M2- and β2-fAAb seemed to be essential for the LC-phenotype with a combination of fatigue/PEM and lack of concentration as major clinical symptoms. Full article

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic “windows of opportunity” offered by TPE. We conclude that TPE is underutilized in both preventative and precision medicine, and that next generation TPE therapies will involve personalized plasma biomarker and modulation feedback, with synergistic plasma infusion therapies to mitigate age associated disease and promote tissue rejuvenation. Full article

Background/Objectives: Neutralizing autoantibodies against type I interferons, particularly interferon-alpha (IFN-α), have been implicated in severe COVID-19 outcomes. This study investigated the prevalence and functional significance of anti-IFN-α autoantibodies (AAbs) in hospitalized unvaccinated COVID-19 patients and their association with COVID-19 disease severity. Methods: We retrospectively analyzed serum samples from 122 hospitalized COVID-19 patients (asymptomatic/mild: n = 69, moderate: n = 35, severe/critical: n = 18) and 32 healthy uninfected controls. Anti-IFN-α AAbs were quantified using a commercial enzyme-linked immunosorbent assay (ELISA) kit, with functional neutralization assessed via competitive ELISA and STAT1 phosphorylation inhibition. Statistical comparisons were performed using one-way ANOVA for parametric data and the Kruskal–Wallis test for non-parametric variables. Results: Anti-IFN-α AAbs were detected in 24.6% of COVID-19 patients, with all clinical subgroups showing significantly higher titers compared to healthy controls (p < 0.05). Although no significant differences in anti-IFN-α AAb levels were found between mild, moderate, and severe cases, patients with severe or critical COVID-19 had markedly higher mean titers (10,511.3 ng/mL) compared to non-severe (mild + moderate) cases (375.2 ng/mL, p < 0.001). Strongly neutralizing anti-IFN-α AAbs, with high titers (>20,000 ng/mL) and the ability to inhibit STAT1 phosphorylation, were identified in three severe COVID-19 cases. Anti-IFN-α AAb levels correlated positively with CRP (r = 0.80, p < 0.0001), LDH (r = 0.80, p = 0.001), and neutrophil count (r = 0.52, p = 0.003), and negatively with lymphocyte count (r = −0.59, p = 0.0006). Conclusions: Elevated and functionally neutralizing anti-IFN-α AAbs were associated with severe COVID-19. These findings support their role as a risk factor for poor outcomes and emphasize the importance of early COVID-19 vaccination. Screening may help identify high-risk individuals, particularly those unvaccinated or with immune vulnerabilities. Full article

Background/Objectives: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disorder caused by mutations in the AIRE gene. Approximately 60% of affected females develop premature ovarian insufficiency (POI) by age 30, often most commonly due to steroidogenic autoantibodies. Although APECED is typically diagnosed in childhood, its reproductive implications are underrecognized. This study reports a case of successful fertility preservation in an adult woman with APECED and reviews the relevant literature. Methods: We describe the clinical course of a 37-year-old woman with genetically confirmed APECED who underwent ovarian stimulation for fertility preservation. A comprehensive PubMed search was also conducted to identify English-language case reports on fertility preservation in APECED-associated POI. Results: The patient experienced menarche at age 13, adrenal insufficiency at 14, and menstrual irregularities from age 18. Genetic analysis confirmed an AIRE mutation (NM_000383: exon 11: c.1400+1G>A). Given her relatively high anti-Müllerian hormone level, she opted for fertility preservation and underwent six cycles of ovarian stimulation, resulting in the cryopreservation of 17 mature oocytes. During ovarian stimulation, multiple follicular developments were observed, but serum E2 levels remained low. The literature review identified fewer than 20 reported cases addressing fertility preservation in APECED, highlighting its rarity and the lack of standardized management. Conclusions: Although APECED frequently leads to early POI due to impaired steroidogenesis, residual ovarian function may persist. Early assessment of ovarian reserve and timely fertility counseling are crucial, even in asymptomatic patients or those diagnosed in childhood. Reproductive planning should be integrated into the long-term care of women with APECED. Full article

Primary Sjögren’s syndrome (pSS) exhibits considerable clinical and immunological heterogeneity, complicating personalized management. We aimed to delineate the demographic, functional, serological, histopathological, and therapeutic features of a Romanian pSS cohort and to identify biomarker–treatment correlations that could inform patient-oriented strategies. Thirty-two patients meeting the 2016 ACR/EULAR classification criteria for pSS were retrospectively analyzed. Data collected included demographics, autoantibody profiles (Anti-Ro/SSA, Anti-La/SSB, ANA, RF, Anti-CCP), immunoglobulin levels, complement consumption (C3/C4), minor salivary gland biopsy (focus score), salivary flow tests, and systemic inflammation markers (CRP). Pearson correlation matrices were constructed to explore the associations between serological markers and prescribed therapies. The cohort was predominantly female (87.5%) with a mean age of 52.8 ± 9.9 years. Seropositivity rates were 50% for Anti-Ro/SSA, 77% for Anti-La/SSB, and 40% for ANA. Clinically significant glandular dysfunction was evident in 65% of patients (unstimulated flow ≤ 0.1 mL/min), and all biopsies demonstrated focus scores > 1. Methotrexate use correlated strongly with Anti-Ro/SSA and Anti-La/SSB positivity (p ≤ 0.05), indicating its targeted application in seropositive sub-phenotypes. Conclusion: These findings underscore the immunologic and clinical diversity of pSS and support a biomarker-driven, multidisciplinary framework for personalized treatment. Larger prospective and multicenter studies are warranted to validate these correlations and to refine precision medicine approaches in pSS. Full article

Bone metabolism is a dynamic process involving continuous bone formation and resorption, orchestrated by the interplay between osteoblasts and osteoclasts. Osteoporosis (Op), the most prevalent osteo-metabolic disorder globally, results from an imbalance in this remodeling cycle. Hashimoto’s thyroiditis (HT), a chronic autoimmune thyroid disorder, has been increasingly recognized as a contributor to bone loss, even in euthyroid individuals. HT is marked by immune dysregulation, autoantibody production, and chronic inflammation, factors that can alter bone remodeling. Furthermore, both thyroid-stimulating hormone (TSH) and thyroid hormones (THs) independently influence bone health. Low TSH and elevated TH levels, including in subclinical states, have been linked to reduced bone mineral density (BMD) and increased fracture risk. Nutritional factors, particularly selenium and iodine intake, modulate both thyroid and bone function, and can be considered as a link between HT and Op. In particular, antioxidant-rich diets such as the Mediterranean diet may confer protective effects. This review integrates current clinical and experimental evidence linking HT with bone metabolism disorders, emphasizing the multifactorial nature of bone fragility in autoimmune thyroid disease and the potential role of diet in mitigating its impact. Full article

IgA nephropathy (IgAN) is an inflammatory glomerular disease caused by the production of galactose-deficient IgA1 (Gd-IgA1), which induces the formation of autoantibodies and IgA immune complexes (IgAICs) that are ultimately deposited in the mesangium. This event triggers mesangial cell proliferation, cytokine release and complement activation, and both glomerular and interstitial damage, eventually leading to kidney function decline. Persisting proteinuria is the most relevant marker of disease progression. Systemic corticosteroids (CSs), a powerful anti-inflammatory approach, have shown kidney protective effects in early trials involving patients with IgAN at risk of progression with persistent proteinuria. However, later studies raised concerns regarding severe adverse events associated with high doses of methylprednisolone and questioned the long-term benefits. As a result, the KDIGO 2021 guidelines recommended limiting CS therapy to selected patients who accepted the high risk of adverse events. The treatment landscape shifted when reduced doses of methylprednisolone, combined with Pneumocystis pneumonia prophylaxis, demonstrated similar kidney protection compared to full methylprednisolone doses with fewer adverse events. An innovative approach involves a targeted budesonide formulation acting on Peyer’s patches, the main site of Gd-IgA1 production. This treatment showed benefits comparable to systemic CSs, with valuable limitations of adverse events. Several new drugs targeting key pathogenetic events of IgAN are under investigation, with promising results published in recent months. These new therapies target B cell activation (and subsequent Gd-IgA1 production), the complement cascade triggered by IgAIC deposition and the endothelin system, a key amplifier of kidney damage that contributes to the chronicity of IgAN. Full article

Natural autoantibodies (nAAbs) recognize self-antigens and are an important component of the immune system, having evolved from invertebrates to vertebrates, and are viewed as stable byproducts of immune function and essential players in health and disease. Initially characterized by their conserved nature and multi-reactivity, primarily as IgM isotypes, nAAbs are now recognized for their adaptability in response to infections and vaccinations, bridging innate and adaptive immunity. The nAAbs and the cellular elements, such as γδ T, iNKT, and MAIT cells, of the natural immune system perform a primary defense network with moderate antigen-specificity. This comprehensive literature review was conducted to analyze the role of natural autoantibodies (nAAbs) in health and disease. The review focused on research published over the past 40 years, emphasizing studies related to infectious diseases, vaccinations, and autoimmune disorders. Recent studies suggest that nAAbs engage in complex interactions in autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, and type 1 diabetes. Their roles in immunological processes, such as maternal tolerance during pregnancy, further underscore their complexity. Emerging evidence indicates that nAAbs and the cellular elements of the natural immune system may contribute to both disease pathogenesis and protective mechanisms, highlighting their dual nature. Continued research on nAAbs is vital for improving our understanding of immune responses and developing therapeutic strategies for autoimmune disorders and infectious diseases. Full article

Background: Systemic sclerosis (SSc) is a rare connective tissue disease characterized by vasculopathy, autoimmunity, and fibrosis. Due to its low prevalence and heterogeneous clinical presentation, early diagnosis remains challenging, often delaying appropriate treatment. The disease progresses from microvascular dysfunction, manifesting as Raynaud’s phenomenon, to systemic fibrosis affecting multiple organs, including the lungs, gastrointestinal tract, heart, and kidneys. There have been considerable advancements in understanding the pathophysiology of the disease during the last few years and this has already resulted in the improvement of the therapeutic approaches used to control organ-specific manifestations. However, the underlying cause of the disease still remains incompletely elucidated. Methods: Here, we summarize the current knowledge on the SSc pathogenesis. Results: The pathophysiology involves an interplay of chronic inflammation, impaired vascular function, and excessive extracellular matrix deposition, leading to progressive organ damage. Endothelial dysfunction in SSc is driven by immune-mediated injury, oxidative stress, and the imbalance of vasoconstrictors and vasodilators, leading to capillary loss and chronic hypoxia. Autoantibodies against endothelial cells or other toxic factors induce apoptosis and impair angiogenesis, further exacerbating vascular damage. Despite increased angiogenic factor levels, capillary repair mechanisms are defective, resulting in progressive ischemic damage. Dysregulated immune responses involving Th2 cytokines, B cells, and macrophages contribute to fibroblast activation and excessive collagen deposition. Transforming growth factor-beta (TGF-β) plays a central role in fibrotic progression, while fibroblasts resist apoptosis, perpetuating tissue scarring. The extracellular matrix in SSc is abnormally stiff, reinforcing fibroblast activation and creating a self-perpetuating fibrotic cycle. Conclusions: Advances in molecular and cellular understanding have facilitated targeted therapies, yet effective disease-modifying treatments remain limited. Future research should focus on precision medicine approaches, integrating biomarkers and novel therapeutics to improve patient outcomes. Full article

Background/Objectives: Hashimoto’s thyroiditis (HT) is an autoimmune disease influenced by genetic factors and environmental triggers that affect immune system function. Data suggest that vitamin D may also play a role in the etiopathogenesis of HT. Methods: This retrospective study included patients admitted to the Endocrinology and Metabolic Diseases Outpatient Clinic. Data from individuals aged 18 years and older were analyzed, including serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), free thyroxine (fT4), anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG), and vitamin D. HT was diagnosed based on the presence of anti-TPO and/or anti-TG antibodies, while individuals with negative results for both were classified as non-HT. Thyroid function was categorized as euthyroid if TSH levels were between 0.55 mU/L and 4.78 mU/L and fT4 levels were between 0.89 ng/dL and 1.76 ng/dL; hypothyroid status was defined as TSH > 4.78 mU/L. Vitamin D levels were classified as deficient (<50 nmol/L), insufficient (50–74.9 nmol/L), or sufficient (≥75 nmol/L). Results: Of the total participants, 25,018 did not have HT, while 27,800 were diagnosed with HT. Vitamin D level was significantly higher in the HT group than the non-HT group (41.43 nmol/L and 39.44 nmol/L, p < 0.001). Vitamin D deficiency was present in 65.5% of the non-HT group and 62.1% of the HT group (p < 0.001). Subgroup analyses based on thyroid function showed that vitamin D levels were highest in the euthyroid HT group and similar in the euthyroid non-HT, hypothyroid non-HT, and hypothyroid HT groups (p < 0.001). Conclusions: In conclusion, while vitamin D levels were higher in the HT group compared to the non-HT group, no clinically significant association between vitamin D levels and HT or autoantibody positivity was observed. Vitamin D deficiency was more prevalent in the hypothyroid group compared to the euthyroid group. This study suggests that although vitamin D deficiency may not be directly involved in the pathogenesis of HT, it may still play a role in modulating immune activity or influencing the disease phenotype.. Full article

Polycystic ovary syndrome (PCOS) is a common female endocrinopathy associated with reproductive and metabolic abnormalities. PCOS is characterized by complex pathogenesis and pathophysiology. Its multifactorial etiology and heterogeneous presentation make effective treatment difficult. Endocrine abnormalities in PCOS create a vicious cycle of overriding dysfunction involving the hypothalamic-pituitary-ovarian (HPO) axis. Most research has primarily focused on identifying genetic, epigenetic, or immunological factors underlying PCOS. In recent years, new reports have emerged on the possible involvement of antibodies directed against HPO axis components in the development of PCOS. Some of these have been shown to be able to interfere with hormone receptors or receptor binding by targeting the key domains for their function. However, the evidence is heterogeneous and challenging to interpret, given the overall predisposition to high levels of various autoantibodies found in women with PCOS. This review focuses on autoantibodies affecting the HPO axis in PCOS and their potential role in the pathogenesis of PCOS. The authors discuss PCOS as a potential antibody-mediated autoimmune disease in light of recent reports on its possible pathogenesis. Full article