Search Results (755)

Polycystic ovary syndrome (PCOS) is a prevalent endocrinological condition among women of reproductive age, characterized by several well-known symptoms, including hyperandrogenism, anovulation, irregular menstrual cycles, and insulin resistance. In addition, women suffering from PCOS are also at an increased risk of developing several autoimmune diseases, including thyroid disorders, type 1 diabetes, and rheumatoid arthritis. Furthermore, an elevated prevalence of diverse autoantibodies is observed in women diagnosed with PCOS. These include antibodies specific to autoimmune diseases, e.g., anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG), and antinuclear antibodies (ANAs), as well as those that are non-specific, such as anti-malondialdehyde-modified human serum albumin (anti-HSA-MDA) or anti-α-crystallin. It appears that several mechanisms may be responsible for this phenomenon. PCOS has been observed to co-occur with autoimmune diseases, potentially attributable to shared genetic susceptibility or the presence of hormonal disorders resulting from autoimmune diseases. Moreover, PCOS is a chronic low-grade inflammatory disease that may contribute to immune dysfunction and subsequent overproduction of autoantibodies. A further intriguing aspect may be the yet-unknown role of autoantibodies in the pathogenesis of PCOS, considering PCOS as a disease with an autoimmune etiology. Full article

Background: This study aimed to investigate the impact of the diabetic environment on the development of experimental autoimmune uveoretinitis (EAU) and the activation status of microglia in the eye. Methods: EAU was induced in wild-type (WT) and streptozotocin (STZ)-induced diabetic mice (STZ-EAU mice). Disease severity was assessed using funduscopy, optical coherence tomography (OCT), and histopathological analysis. The proportions of Th1, Th17, and regulatory T cells in the spleen were analyzed by flow cytometry. Retinal microglia were quantified using immunohistochemistry. To further characterize retinal cell populations and gene expression profiles, single-cell RNA sequencing (scRNA-seq) was performed. Results: STZ-EAU mice exhibited significant reductions in both the incidence and severity of EAU compared with WT-EAU mice. These were accompanied by a decreased proportion of Th1 cells, which are crucial for EAU pathogenesis, in the spleens of STZ-EAU mice. Retinal microglial accumulation was markedly reduced in STZ-EAU mice compared with WT-EAU mice. scRNA-seq analysis revealed a significant change in the microglial phenotype in STZ-EAU mice, characterized by decreased expression of MHC class I/II and the suppression of antigen presentation signaling pathways. Activated microglia in STZ-EAU mice showed reduced gene expression of M1 markers (CD68, CD74, and IL1B) and increased gene expression of M2 markers (MSR1, CD163, and MRC1), suggesting a shift toward an anti-inflammatory M2 phenotype. Conclusions: EAU is suppressed in STZ-induced diabetic mice, likely due to alterations in microglial polarization toward an M2 phenotype. These results suggest a decrease in T cell responses to pathogens in a diabetic environment, which could be one of the underlying factors for the increased susceptibility to infection in diabetic patients. Inhibiting the M2 polarization of microglia may reduce the susceptibility to infection in patients with diabetes. Full article

Regulatory T (Treg) cells were first identified through the observation that Foxp3 gene mutations in mice and humans can result in their dysfunction, leading to a catastrophic multi-organ autoimmune syndrome. Since then, it has become increasingly evident that Foxp3⁺ Treg cells serve functions extending well beyond dominant tolerance and the mere prevention of autoimmune pathology. Highlighting their pivotal role in metabolic regulation, dysfunction of Treg cells has been implicated in the pathogenesis of both type 1 and type 2 diabetes. Emerging evidence further suggests that Treg cells contribute to tissue homeostasis and regeneration by facilitating repair processes, modulating immune responses to curb excessive inflammation, and supporting stem cell function in key metabolic organs such as muscle, adipose tissue, and the liver. This review aims to highlight recent progress in elucidating the functional specialization of Treg cells in the regulation of metabolic homeostasis. It explores the distinct roles of thymic and peripheral Treg cells in constraining pancreatic β-cell autoimmunity and the inflammation of metabolic organs, while also underscoring the pathogenic potential of Treg cell instability and their dedifferentiation into pathogenic effector cells. Investigating the roles of thymic and peripheral Treg cells in both forms of diabetes is a valuable endeavor, offering insight into their distinct and shared contributions to disease progression, while shedding light on immune dysregulation, metabolic inflammation, and immune–metabolic crosstalk. These insights may provide a foundation for the development of targeted therapeutic approaches directed at specific Treg cell subsets, offering the potential to attenuate disease progression or even entirely prevent its onset. Full article

Emerging evidence suggests that vitamin D and dipeptidyl peptidase-4 (DPP-4) inhibitors exert synergistic immunomodulatory, anti-inflammatory and antioxidant actions. Moreover, intervention studies showed that combination therapy based on the concomitant use of vitamin D and DPP-4 inhibitors (VIDPP-4i) may preserve beta-cell function in patients with type 1 diabetes mellitus (T1D) and latent autoimmune diabetes in adults (LADA). These effects are particularly relevant in the context of beta-cell replacement strategies, whose long-term efficacy can be hampered by various factors, such as immune-mediated graft rejection, inadequate vascularization, hypoxia, trauma-induced cell apoptosis, fibrosis, host immune response, and recurrence of autoimmunity. Based on preclinical and clinical studies conducted in the fields of autoimmune diabetes and solid organ/cell transplantation, the present narrative review aims to describe the rationale behind the investigation of VIDPP-4i combination therapy as an adjuvant treatment strategy to enhance the efficacy of novel beta-cell replacement therapies for T1D. In this regard, we discuss the potential immune and metabolic mechanisms through which vitamin D and DPP-4 inhibitors can promote the long-term function and survival of transplanted islets in patients with T1D receiving various types of beta-cell replacement therapies, including therapeutic approaches using encapsulated stem cell-derived beta cells. Full article

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have evolved from glucose-lowering agents to transformative therapies across multiple organ systems. This comprehensive review synthesizes current evidence on the mechanisms, established applications, and emerging therapeutic frontiers of GLP-1 RAs. Methods: We conducted a systematic literature search of PubMed, Embase, Cochrane Library, and ClinicalTrials.gov from inception through May 2025, using controlled vocabulary and free-text terms related to GLP-1 RAs, their mechanisms, and clinical applications. Results: GLP-1 RAs demonstrate pleiotropic effects through fundamental cellular mechanisms, including enhanced mitochondrial function, anti-inflammatory actions, improved cellular quality control, and comprehensive metabolic regulation. Established applications demonstrate robust efficacy in diabetes management (HbA1c reductions of 1.5–2.0%), obesity treatment (weight loss of 7–24%), and cardiovascular protection (14–20% reduction in major adverse cardiovascular events, or MACE). Emerging applications span neurological disorders, dermatological conditions, respiratory diseases, and novel applications in addiction medicine and autoimmune disorders. Conclusions: GLP-1 RAs represent a paradigmatic shift toward multi-system therapeutic intervention, with expanding evidence supporting their role as comprehensive metabolic modulators. Full article

Systematic Background/Objectives: Type 1 diabetes mellitus (T1DM) is an autoimmune condition in which pancreatic β-cells are selectively destroyed, predominantly by autoreactive T lymphocytes. Despite decades of research, the achievement of durable immune tolerance remains elusive. This review presents a historically grounded and forward-looking perspective on the evolution of immunotherapy in T1DM, from early immunosuppressive interventions to advanced precision-based cellular approaches. Specifically, we focus on systemic immunosuppressants (e.g., corticosteroids, cyclosporine), monoclonal antibodies (e.g., anti-CD3, anti-IL-1, anti-TNF), regulatory cell-based approaches (e.g., Tregs, CAR-Tregs, MDSCs), and β-cell replacement strategies using stem cell-derived islets. Methods: We analyzed major clinical and translational milestones in immunotherapy for T1DM, with particular attention to the transition from broad immunosuppression to targeted modulation of immune pathways. Emerging data on cell-based therapies, artificial intelligence (AI)-driven stratification, and personalized intervention timing have been incorporated to provide a comprehensive overview of current and future directions. Results: Initial therapies such as corticosteroids and cyclosporine offered proof-of-concept for immune modulation, yet suffered from relapse and toxicity. The introduction of monoclonal antibodies (e.g., teplizumab) marked a shift toward immune-specific intervention, particularly in stage 2 preclinical T1DM. More recent approaches include low-dose IL-2, checkpoint modulation, and antigen-specific tolerance strategies. Cellular therapies such as Treg adoptive transfer, chimeric antigen receptor Tregs (CAR-Tregs), and stem cell-derived islet replacements (e.g., VX-880) have shown promise in preserving β-cell function and modulating autoimmunity. Myeloid-derived suppressor cells (MDSCs), although still preclinical, represent a complementary avenue for immune tolerance induction. Concurrently, AI-based models are emerging as tools to stratify risk and personalize immunotherapeutic timing, enhancing trial design and outcome prediction. Conclusions: In conclusion, the historical progression from broad immunosuppression to precision-driven strategies underscores the importance of stage-specific, mechanism-based interventions in T1DM. The convergence of targeted biologics, regenerative cell therapies, and β-cell replacement approaches, supported by AI-enabled patient stratification, offers a realistic path toward durable immune tolerance and functional β-cell preservation. Continued integration of these modalities, coupled with rigorous long-term evaluation, will be essential to transform these scientific advances into sustained clinical benefit. Full article

Vitamin D has emerged as a modulatory factor in the pathogenesis and management of diabetes mellitus due to its influence on pancreatic β-cell function, immune regulation, and inflammatory pathways. This narrative review critically examines mechanistic and clinical evidence linking vitamin D status with type 1 diabetes (T1DM), type 2 diabetes (T2DM), and gestational diabetes (GDM). In T1DM, vitamin D’s immunomodulatory effects are thought to protect β-cells from autoimmune destruction; epidemiological studies associate vitamin D sufficiency with lower T1DM incidence and improved glycemic control, although causality remains under investigation. In T2DM, vitamin D deficiency is associated with worsened metabolic control and may contribute to disease development in at-risk individuals; however, it does not influence the initial onset of T2DM in patients who are already diagnosed. Intervention trials indicate that correcting the deficiency can modestly improve insulin sensitivity, β-cell function, and metabolic parameters. GDM has similarly been linked to hypovitaminosis D, with low maternal vitamin D levels associated with higher GDM risk and adverse perinatal outcomes; mechanistic insights suggest that adequate vitamin D supports glucose homeostasis in pregnancy, and emerging trials demonstrate improved insulin resistance with maternal vitamin D supplementation. Across these diabetes subtypes, maintaining sufficient vitamin D levels appears to confer metabolic benefits and may serve as an adjunct to current preventive and therapeutic strategies. However, definitive evidence from large-scale trials is required to establish optimal vitamin D supplementation protocols and confirm its efficacy in diabetes care. Full article

Nephrotic syndrome (NS) is characterized by proteinuria, hypoalbuminemia, edema, and hyperlipidemia. Apart from the traditional causes of NS, such as minimal change disease, focal segmental glomerulosclerosis, diabetes, infections, malignancies, autoimmune conditions, and nephrotoxic agents, there are also rare causes of NS, whose knowledge is of the utmost importance. The aim of this article was to highlight the less well-known causes that have a significant impact on diagnosis and treatment. Genetic syndromes such as Schimke immuno-osseous dysplasia, familial lecithin-cholesterol acyltransferase deficiency with two clinical variants (fish-eye Disease and the p.Leu364Pro mutation), lead to NS through mechanisms involving podocyte and lipid metabolism dysfunction. Congenital disorders of glycosylation and Nail–Patella Syndrome emphasize the role of deranged protein processing and transcriptional regulation in glomerular injury. The link of NS with type 1 diabetes, though rare, suggests an etiology on the basis of common HLA loci and immune dysregulation. Histopathological analysis, particularly electron microscopy, shows mainly podocyte damage, mesangial sclerosis, and alteration of the basement membrane, which aids in differentiating rare forms. Prompt recognition of these novel etiologies by genetic analysis, renal biopsy, and an interdisciplinary panel is essential to avoid delays in diagnosis and tailored treatment. Full article

Type 1 diabetes mellitus (T1DM) is a chronic autoimmune disorder characterized by the destruction of insulin-producing pancreatic beta cells, resulting in lifelong insulin dependence. While genetic susceptibility—particularly human leukocyte antigen (HLA) class II alleles—is a major risk factor, accumulating evidence implicates viral infections as potential environmental triggers in disease onset and progression. This narrative review synthesizes current findings on the role of viral pathogens in T1DM pathogenesis. Enteroviruses, especially Coxsackie B strains, are the most extensively studied and show strong epidemiological and mechanistic associations with beta-cell autoimmunity. Large prospective studies—including Diabetes Virus Detection (DiViD), The environmental determinans of diabetes in the young (TEDDY), Miljøfaktorer i utvikling av type 1 diabetes (MIDIA), and Diabetes Autoimmunity Study in the Young (DAISY)—consistently demonstrate correlations between enteroviral presence and the initiation or acceleration of islet autoimmunity. Other viruses—such as mumps, rubella, rotavirus, influenza A (H1N1), and SARS-CoV-2—have been investigated for their potential involvement through direct cytotoxic effects, immune activation, or molecular mimicry. Interestingly, certain viruses like varicella-zoster virus (VZV) and cytomegalovirus (CMV) may exert modulatory or even protective influences on disease progression. Proposed mechanisms include direct beta-cell infection, molecular mimicry, bystander immune activation, and dysregulation of innate and adaptive immunity. Although definitive causality remains unconfirmed, the complex interplay between genetic predisposition, immune responses, and viral exposure underscores the need for further mechanistic research. Elucidating these pathways may inform future strategies for targeted prevention, early detection, and vaccine or antiviral development in at-risk populations. Full article

Chronic kidney disease (CKD) is a heterogeneous condition with various etiologies, including type 2 diabetes mellitus (T2D), hypertension, and autoimmune disorders. Both diabetic CKD (CKD_T2D) and non-diabetic CKD (CKD_nonT2D) share overlapping clinical features, but understanding the molecular mechanisms underlying each subtype and distinguishing diabetic from non-diabetic forms remain poorly defined. To identify differentially expressed genes (DEGs) and enriched biological pathways between CKD_T2D and CKD_nonT2D cohorts, including autoimmune (CKD_nonT2D_AI) and hypertensive (CKD_nonT2D_HT) subtypes, through integrative transcriptomic analysis. Publicly available gene expression datasets from human glomerular and tubulointerstitial kidney tissues were curated and analyzed from GEO and ArrayExpress. Differential expression analysis and Gene Set Enrichment Analysis (GSEA) were conducted to assess cohort-specific molecular signatures. A considerable overlap in DEGs was observed between CKD_T2D and CKD_nonT2D, with CKD_T2D exhibiting more extensive gene expression changes. Hypertensive-CKD shared greater transcriptomic similarity with CKD_T2D than autoimmune-CKD. Key DEGs involved in fibrosis, inflammation, and complement activation—including Tgfb1, Timp1, Cxcl6, and C1qa/B—were differentially regulated in diabetic samples, where GSEA revealed immune pathway enrichment in glomeruli and metabolic pathway enrichment in tubulointerstitium. The transcriptomic landscape of CKD_T2D reveals stronger immune and metabolic dysregulation compared to non-diabetic CKD. These findings suggest divergent pathological mechanisms and support the need for tailored therapeutic approaches. Full article

Crohn’s disease is a chronic inflammation affecting the gastrointestinal tract. To date, patients are commonly treated with corticosteroids or more aggressive biologics for high-risk subjects. Stem Cell Educator therapy has been successfully utilized to treat patients with type 1 diabetes and other autoimmune conditions. A 78-year-old patient with long-standing Crohn’s disease received one treatment with the Stem Cell Educator therapy, followed by clinical, radiographic, pathological examinations and immune marker testing by flow cytometry. After the treatment with Stem Cell Educator therapy, the patient’s clinical symptoms were quickly improved with normal bowel movements, without abdominal pain or rectal bleeding. Flow cytometry analysis revealed a marked decline in inflammatory markers, such as the percentage of monocyte/macrophage-associated cytokine interleukin-1 beta (IL-1β)⁺ cells, which reduced from 94.98% at the baseline to 18.21%, and down-regulation of the percentage of chemokine CXCL16⁺ cells from 91.92% at baseline to 42.58% at 2-month follow-up. Pathologic examination of the biopsy specimens from colonoscopy five weeks and six months post-treatment showed ileal mucosa with no specific abnormality and no significant inflammation or villous atrophy; no granulomas were identified. A follow-up CT scan four and one-half months post-treatment showed no evidence of the previously seen stenosis of the ilio-colonic anastomosis with proximal dilatation. Stem Cell Educator therapy markedly reduced inflammation in the subject with Crohn’s disease, leading to durable clinical, immunological, radiographic, and pathological improvements. Full article

Xerostomia, the subjective complaint of a dry mouth, is frequently associated with salivary flow reduction and/or salivary gland hypofunction. This condition significantly impacts an individual’s quality of life and oral health, including difficulties in speaking, chewing, and swallowing. Xerostomia may be caused by autoimmune diseases, xerogenic medications, and radiation therapy. Our objective was to identify differentially expressed proteins in the saliva of patients with medication and autoimmune disease-associated xerostomia compared to non-xerostomic control subjects. Two groups of individuals (N = 45 total) were recruited: non-xerostomic subjects (NX-group; n = 18) and xerostomic patients (XP-group; n = 27). Dried saliva spot samples were collected from major salivary glands, i.e., parotid (left and right) and submandibular glands. Proteomic analysis was performed by deep nanoLC-MS/MS. Differential protein expression in the XP-group relative to the NX-group was determined by the Mann–Whitney U-test with FDR Benjamini–Hochberg correction (p_adj < 0.05). The Search Tool for Recurring Instances of Neighboring Genes (STRING_v12.0) was used to generate interaction networks and perform pathway analysis. A total of 1407 proteins were detected. Of these, 86 from the left parotid gland, 112 from the right parotid gland, and 73 from the submandibular gland were differentially expressed proteins (DEPs). Using STRING analysis, we identified, for the first time, several neurodegenerative disease-associated networks, primarily involving the downregulation of the 20S proteasome core complex and glyoxalase proteins across salivary glands. In this study, we determined neuronal dysregulation and impaired methylglyoxal (MGO) detoxification, possibly through reduced protein expression of glyoxalase Parkinson’s Disease (PD) Protein 7 (encoded by the PARK7 gene) in major salivary glands of xerostomic patients. Indeed, impaired MGO detoxification has been previously shown to cause salivary gland dysfunction in a mouse model of type 2 diabetes. Based on other DEPs associated with neurodegenerative disorders, our results also suggest a possible deficiency in the parasympathetic nervous system innervation of salivary glands, warranting further investigation. Full article

The renin–angiotensin–aldosterone system (RAAS) plays a central role in cardiovascular and renal homeostasis and is increasingly recognized for its broad immunomodulatory effects. Pharmacological RAAS inhibition, primarily via angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), has demonstrated therapeutic value beyond its use in hypertension and heart failure, extending to autoimmune, infectious, oncologic, and neurodegenerative conditions. ACEIs and ARBs modulate both innate and adaptive immune responses through Ang II-dependent and -independent mechanisms, influencing macrophage polarization, T-cell differentiation, cytokine expression, and antigen presentation. Notably, ACEIs exhibit Ang II-independent effects by enhancing antigen processing and regulating amyloid-β metabolism, offering potential neuroprotective benefits in Alzheimer’s disease. ARBs, particularly telmisartan and candesartan, provide additional anti-inflammatory effects via PPARγ activation. In cancer, RAAS inhibition affects tumor growth, angiogenesis, and immune surveillance, with ACEIs and ARBs showing distinct yet complementary impacts on tumor microenvironment modulation and chemotherapy cardioprotection. Moreover, ACEIs have shown promise in autoimmune myocarditis, colitis, and diabetic nephropathy by attenuating inflammatory cytokines. While clinical evidence supports the use of centrally acting ACEIs to treat early cognitive decline, further investigation is warranted to determine the long-term outcomes across disease contexts. These findings highlight the evolving role of RAAS inhibitors as immunomodulatory agents with promising implications across multiple systemic pathologies. Full article

Over the past century, the understanding of type 1 diabetes mellitus (T1DM) has evolved significantly, transitioning from a fatal metabolic disorder to a well-characterized autoimmune disease. This review explores the historical developments and scientific milestones that have reshaped the perception of T1DM, highlighting key discoveries and shifts in medical paradigms. Methods: A comprehensive narrative review was conducted, examining literature spanning from ancient medical texts to contemporary research up to 2024. Emphasis was placed on pivotal moments such as the discovery of insulin in 1921, the recognition of autoimmune mechanisms in the 1970s, and recent advancements in immunotherapy. Results: The reclassification of T1DM as an autoimmune disease was supported from multiple lines of evidences including the presence of islet cell autoantibodies, the identification of lymphocytic infiltration in pancreatic islets, and the associations of the disease with certain HLA class II alleles. The development of animal models and large-scale cohort studies facilitated the establishment of disease staging and risk prediction models. Notably, the approval of immunotherapies like teplizumab underscores the translational impact of these scientific insights. Conclusions: The historical trajectory of T1DM exemplifies the dynamic nature of medical knowledge and the interplay between clinical observations and scientific research. Recognizing these developments enhances our comprehension of disease mechanisms and informs current approaches to diagnosis and treatment. Full article

Type 1 diabetes is classified into three clinical subtypes: fulminant type 1 diabetes, acute-onset type 1 diabetes, and slowly progressive type 1 diabetes, also known as latent autoimmune diabetes in adults. Among these, the fulminant and slowly progressive forms may develop in association with pregnancy and are herein collectively referred to as “pregnancy-associated type 1 diabetes”. Fulminant type 1 diabetes can manifest suddenly during pregnancy, often accompanied by ketoacidosis, posing a significant risk to both the mother and the fetus. Early diagnosis and treatment are, therefore, critical. In pregnant women with no prior history of diabetes who present with marked hyperglycemia (≥288 mg/dL) but relatively low HbA1c levels (<8.7%), fulminant type 1 diabetes should be suspected, and insulin therapy should be initiated immediately. Conversely, women diagnosed with gestational diabetes who test positive for anti-islet autoantibodies are at high risk of developing slowly progressive type 1 diabetes postpartum. For these patients, regular monitoring of blood glucose levels, HbA1c, and endogenous insulin secretion is essential for early detection and management. Full article