Search Results (290)

Cutaneous lupus erythematosus is an autoimmune skin disorder with a known association with cigarette smoking. Smokers with cutaneous lupus have a worse disease course and may be refractory to treatments. Despite many studies documenting this association, minimal work exists examining the molecular drivers of these clinical differences. This review delves into how cigarette smoke may influence key immunopathogenic pathways in cutaneous lupus, including oxidative stress, interferon signaling, inflammatory cell recruitment, extracellular vesicles, and immune regulation. Additionally, factors such as epigenetics and heat injury are considered as well. Here, we integrate the existing and emerging literature on the pathophysiology of cutaneous lupus with known effects of cigarette smoke on the skin and immune system and propose hypotheses that may explain clinical differences in smokers. Understanding the molecular underpinnings of these differences may yield a clearer picture of the disease and more effective treatment strategies. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most prevalent chronic hepatopathy and a leading precursor of hepatocellular carcinoma (HCC) worldwide. Initially attributed to insulin resistance (IR)-driven metabolic imbalance, recent insights highlight a multifactorial pathogenesis involving oxidative stress (OS), chronic inflammation, and immune dysregulation. The hepatic accumulation of free fatty acids (FFAs) initiates mitochondrial dysfunction and excessive reactive oxygen species (ROS) production, culminating in lipotoxic intermediates and mitochondrial DNA damage. These damage-associated molecular patterns (DAMPs), together with gut-derived pathogen-associated molecular patterns (PAMPs), activate innate immune cells and amplify cytokine-mediated inflammation. Kupffer cell activation further exacerbates OS, while ROS-induced transcriptional pathways perpetuate inflammatory gene expression. Traditional immunity refers to the well-established dichotomy of innate and adaptive immune responses, where innate immunity provides immediate but non-specific defense, and adaptive immunity offers long-lasting, antigen-specific protection. However, a paradigm shift has occurred with the recognition of trained immunity (TI)—an adaptive-like memory response within innate immune cells that enables enhanced responses upon re-exposure to stimuli. Following non-specific antigenic stimulation, TI induces durable epigenetic and metabolic reprogramming, leading to heightened inflammatory responses and altered functional phenotypes. These rewired cells acquire the capacity to produce lipid mediators, cytokines, and matrix-modifying enzymes, reinforcing hepatic inflammation and fibrogenesis. In this context, the concept of immunometabolism has gained prominence, linking metabolic rewiring with immune dysfunction. This literature review provides an up-to-date synthesis of emerging evidence on immunometabolism and trained immunity as pathogenic drivers in MASLD. We discuss their roles in the transition from hepatic steatosis to steatohepatitis, fibrosis, and cirrhosis, and explore their contribution to the initiation and progression of MASLD-related HCC. Understanding these processes may reveal novel immunometabolic targets for therapeutic intervention. Full article

Introduction: Endometriosis is a chronic inflammatory disease affecting women of reproductive age, often accompanied by chronic pelvic pain and infertility. Despite numerous studies, its pathogenesis remains incompletely understood. Increasing evidence indicates the important role of immunological disorders, especially in the mechanisms of innate immunity and Toll-like receptors (TLRs). Study objective: This study aimed to assess the expression of selected TLRs (TLR2, TLR3, TLR4, TLR7, TLR8, and TLR9) on peripheral blood lymphocyte subpopulations (CD4+, CD8+, and CD19+ cells) in patients diagnosed with endometriosis and to quantify the levels of their soluble forms in serum and urine. This study was conducted on patients who were not undergoing hormonal bridging therapy and were not using any form of hormonal contraception to eliminate potential confounding effects on immune parameters. Methods: Flow cytometric analysis of TLR expression on peripheral blood lymphocytes was performed, and the levels of their soluble forms in serum and urine samples were determined. Additionally, ROC curve analysis was used to evaluate the diagnostic potential of the studied parameters. Results: We found increased expression of TLRs in lymphocyte populations in patients with endometriosis compared to the control group, suggesting their involvement in both local and systemic immune responses. In addition, ROC analysis showed the diagnostic potential of TLR expression in differentiating patients with endometriosis from healthy women, and it may also identify disease subtypes. Conclusions: The findings support the role of TLRs in the immunopathogenesis of endometriosis and highlight their promise as diagnostic biomarkers and therapeutic targets. Further studies on larger patient cohorts and functional signaling analyses are warranted. Full article

Primary biliary cholangitis (PBC) is a chronic, immune-mediated liver disease characterized by progressive destruction of the small intrahepatic bile ducts, leading to cholestasis, inflammation, and ultimately fibrosis and cirrhosis. This review emphasizes the central role of bile acids in PBC pathogenesis, exploring how disruptions in their synthesis, transport, and detoxification contribute to cholangiocyte damage and disease progression. In addition to discussing the autoimmune features of PBC, including the presence of specific autoantibodies and cellular immune responses, we examine how bile acid dysregulation exacerbates cholestasis and promotes lipid metabolic disturbances. Particular attention is given to the “bicarbonate umbrella” hypothesis, which describes a protective mechanism by which cholangiocytes resist bile acid–induced injury—an essential factor disrupted in PBC. The aim of this review is to summarize current knowledge gaps in the pathophysiology of PBC, with a focus on the role of bile acids not only as key drivers of disease mechanisms, but also as potential biomarkers of disease progression and treatment response. Full article

Although Torque Teno Viruses (TTVs) were initially considered to be ubiquitous members of the mammalian virome, the finding that swine TTVs (TTSuV) can act as primary pathogens elevates the possible status of swine TTVs (TTSuVs) to an emerging swine pathogen. Since their discovery, the molecular mechanisms of TTV–host interactions remain largely unknown as robust in vitro culture systems and in vivo animal models have not been available. This study was undertaken to address some of these long-standing gaps. Recombinant TTSuV1 rescued from an infectious clone was used to infect C57BL/J6 mice. Infected mice seroconverted within 15 days post-infection and mounted virus neutralizing antibody responses. Viral DNA was detected in blood and lung tissue for the duration of the study. TTSuV1 isolated from the lung tissue of infected mice productively and serially infected PK-15 cells in vitro, indicating that the treatment produced viable, replicative viral particles in the host. TTSuV1 antigen was also detected by flow cytometry in lymphocytes, including the T and B lymphocyte subsets. Infected mice exhibited mild splenic hyperplasia and lymphopenia. The ability to respond to mitogenic stimuli was highly diminished in infected mice and a striking lack of virus-specific recall responses was observed for the 30-day duration of the study. Therefore, this study is the first to provide experimental evidence that recombinant TTSuV1 rescued from an infectious clone is infective and induces immune responses in laboratory mice. This model provides a critical tool for advancing research on TTV immunopathogenesis. Full article

Respiratory syncytial virus (RSV) remains a leading cause of acute lower respiratory tract infections globally, particularly affecting infants, older adults, and immunocompromised individuals. While recent advances in prophylaxis, such as long-acting monoclonal antibodies and maternal immunization, offer promise for prevention, therapeutic options for active infection remain limited. Severe RSV disease is often driven not solely by viral replication but by dysregulated host immune responses, including excessive cytokine production, T helper type 2 (Th2) and T helper type 17 (Th17) cell polarization, and impaired interferon signaling. RSV has evolved sophisticated immune evasion strategies, such as inhibition of dendritic cell maturation, degradation of signal transducer and activator of transcription 2 (STAT2) via nonstructural proteins 1 and 2 (NS1/NS2), and interference with pattern recognition receptor signaling, particularly Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors. These mechanisms result in attenuated innate immune responses and defective adaptive immunity, contributing to viral persistence, immunopathology, and recurrent infections. Moreover, age-dependent vulnerabilities, such as immune immaturity in infants and immunosenescence in older adults, exacerbate disease severity. Excessive immune activation leads to bronchiolitis, airway remodeling, and long-term sequelae including wheezing and asthma. Emerging immunomodulatory therapies aim to restore immune balance, targeting cytokines (e.g., interleukin-6 [IL-6], interleukin-1 beta [IL-1β]), the Janus kinase–signal transducer and activator of the transcription (JAK-STAT) pathway, or inflammasome activity. Host-directed therapies and direct-acting antivirals are also under investigation. A better understanding of RSV–host immune interactions is critical for optimizing therapeutic strategies and designing effective vaccines. This review synthesizes current knowledge on RSV immunopathogenesis and highlights immunomodulation as a promising frontier for therapeutic intervention. Full article

Hepatic viruses, such as hepatitis B and C (HBV and HCV), evade immune defenses and drive liver cirrhosis and cancer. They remain a major global health burden, requiring deeper research into immune responses; specifically, adaptive immunity. This study aims to analyze T cellular subsets in chronic HBV and HCV infection and investigate their potential role in the immunopathogenesis of these conditions. Methods: For our study, we collected 123 blood samples taken from patients infected with HCV (n = 36) and HBV (n = 34) and healthy volunteers (n = 53). With the use of flow cytometry, we assessed levels of CD4+ and CD8+ minor T cell subpopulations (naïve, central, and effector memory cells (CM and EM), terminally differentiated EM (TEMRA), Th1, Th2, Th17, Tfh, Tc1, Tc2, Tc17, Tc17.1). Results: Despite similar total CD4+ T cell frequencies across chronic HCV, HBV, and healthy groups, patients with hepatitis showed elevated TEMRA, EM, and CM subsets alongside depleted naïve Th cells and specific CM subpopulations compared to controls. Patients with chronic HCV and HBV showed elevated CD8+ T cell frequencies versus controls, with disease-specific shifts: reduced EM CTLs but increased TEMRA CTLs, Tc1/Tc17.1 depletion (notably Tc17.1 in HCV), and higher Tc2 levels. Conclusions: Viral clearance in HBV and HCV requires a delicate balance between immunity and viral activity. Despite similar T cell frequencies (CD3+/CD4+/CD8+), minor subsets revealed distinct patterns differentiating HCV, HBV, and healthy controls. Full article

Persistent type I interferon (IFN-I) signaling compromises adaptive anti-HIV-1 T cell immunity and promotes viral reservoir persistence, yet its effects on innate lymphoid cells during chronic infection remain unclear. Through integrated single-cell RNA sequencing and functional validation in HIV-1-infected humanized mice with combination antiretroviral therapy (cART) and IFN-I signaling blockade, we reveal IFN-I-induced dysfunction of natural killer (NK) cells and group 3 innate lymphoid cells (ILC3s). Mechanistically, the IFN-I-CD9 axis drives NK cells toward a decidual NK cell-like phenotype, impairing their cytotoxic activity. Furthermore, IFNAR blockade rescues ILC3 functionality, which is critical for IL-17/IL-22-mediated antimicrobial defense and mucosal barrier maintenance. Our study delineates IFN-I-driven immunosuppression across innate lymphocyte compartments and proposes the targeted modulation of this pathway to enhance antiviral and mucosal immunity in HIV-1 management. 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

Background: Despite distinct etiologies, type 1 diabetes (T1D) and type 2 diabetes (T2D) share chronic inflammation as a core feature. Interleukins, key immune mediators, play important yet still not fully understood roles in the development and complications of both conditions. Objective: This narrative review aims to provide a comprehensive and critical synthesis of current evidence on the role of key interleukins in T1D and T2D, highlighting their immunological functions, genetic associations, clinical correlations, and translational potential. Methods: A targeted literature search was conducted in PubMed, Google Scholar, and ScienceDirect up to January 2025, focusing on English-language clinical and experimental studies involving interleukins and their relevance to T1D and T2D. Reference lists were manually screened for additional sources. Interleukins (ILs) were reviewed individually to assess their immunobiology, disease specificity, and biomarker or therapeutic value. Findings: Pro-inflammatory cytokines such as IL-1β, IL-6, and IL-17 contribute to islet inflammation, insulin resistance, and microvascular damage in both T1D and T2D. Anti-inflammatory mediators including IL-4, IL-10, and IL-13 exhibit protective effects but vary in expression across disease stages. Less-characterized interleukins such as IL-3, IL-5, IL-9, and IL-27 demonstrate dual or context-dependent roles, particularly in shaping immune tolerance and tissue-specific complications such as nephropathy and neuropathy. Polymorphisms in IL-10 and IL-6 genes further suggest genetic contributions to interleukin dysregulation and metabolic dysfunction. Despite promising insights, translational gaps persist due to overreliance on preclinical models and limited longitudinal clinical data. Conclusions: Interleukins represent a mechanistic bridge linking immune dysregulation to metabolic derangements in both T1D and T2D. While their diagnostic and therapeutic potential is increasingly recognized, future research must address current limitations through isoform-specific targeting, context-aware interventions, and validation in large-scale, human cohorts. A unified interleukin-based framework may ultimately advance personalized strategies for diabetes prevention and treatment. Full article

Hidradenitis suppurativa (HS) and inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated conditions with significant impact on quality of life. Emerging evidence reveals a notable epidemiological and pathogenic overlap between HS and IBD, particularly CD. Although a bidirectional association between HS and IBD has been well documented, current evidence supports a causal effect of IBD on the development of HS, while a causal relationship in the opposite direction has yet to be established. The present review explores the important association between these immune-mediated conditions and further highlights shared risk factors, genetic predispositions and immunopathogenic mechanisms, such as dysbiosis and cytokine dysregulation, involved in both HS and IBD. Diagnostic challenges, especially in differentiating perianal HS from perianal CD, are also discussed. The coexistence of HS and IBD impacts disease severity, treatment response, and overall management strategies. Shared therapeutic approaches, such as TNF-α inhibitors and JAK inhibitors, are considered promising options for effectively managing patients affected by both conditions. Nevertheless, deeper understanding of the gut–skin axis that will offer potential for more precise interventions in patients with simultaneous HS and IBD is considered imperative. Full article

The identification of a type I interferon-induced transcriptomic signature in active tuberculosis suggests a potential role for these interferons in the pathogenesis of tuberculosis. Comorbidities such as human immunodeficiency virus, diabetes, systemic lupus erythematosus, end-stage renal disease, and coronavirus disease are epidemiologically linked to an increased risk for reactivation of latent tuberculosis infection. Notably, type I interferons are also implicated in the pathogenesis of these conditions, with a recognizable type I interferon transcriptomic signature. The mechanisms by which type I interferons in tuberculosis-risk-associated comorbidities may drive the progression of tuberculosis or maintenance of latent infection however remain largely unknown. This review summarizes the existing literature on the increased association between type I interferons, focusing on interferon-α and -β, and the heightened risk of tuberculosis reactivation. It also underscores the similarities in the immunopathogenesis of these comorbidities. A better understanding of these mechanisms is essential to guide the development of host-directed interferon therapies and improving diagnostic biomarkers in M. tuberculosis infection. Full article

Lyme disease has many different manifestations, including arthritis. There is no evidence that the pathogen Borrelia burgdorferi expresses toxins, so the presence of the organism is insufficient to cause inflammation and disease. Thus, the interaction between the causative pathogen and the many human immune system mechanisms responding to the organism is the apparent cause of inflammation and tissue damage/dysfunction. This review discusses many of the aspects of the relationship between organisms and host responses to summarize the many means by which the immune response can cause the synovitis of Lyme arthritis. Full article

Identifying immunologic predictors of clinical responses remains an unmet need in the era of biologic therapy for psoriasis. Super responders (SRs), defined as patients achieving complete skin clearance within weeks of treatment initiation, represent an emerging clinical endotype; however, their immunological profiles remain insufficiently characterized. We conducted a prospective observational study to characterize serum cytokine profiles associated with SR status in biologic-naïve patients with moderate-to-severe plaque psoriasis treated with secukinumab, an IL-17A inhibitor. Twenty-eight patients were enrolled and stratified at week 12 into SR (PASI = 0; n = 9) and non-super responder (NSR; PASI > 0; n = 19) groups. Serum concentrations of 19 cytokines were analyzed at baseline and after 12 weeks of treatment. SRs displayed a distinct immunological signature characterized by significantly higher IL-13 and lower IL-18 baseline levels compared to NSRs (p = 0.002 and p = 0.007, respectively), alongside reduced baseline monocyte counts. L1-regularized logistic regression confirmed IL-13 and IL-18 as strong independent predictors of SR status (AUC = 0.91). Moreover, the IL-18/IL-13 ratio emerged as a highly discriminative biomarker (p = 0.00001, AUC = 0.86). Notably, SRs exhibited a more pronounced decline in IL-18 and IL-23 during treatment. Our findings provide novel insights into the immunopathogenesis of super response and suggest that an immunological milieu favoring Th2 polarization may promote superior outcomes with IL-17A blockade. Incorporating IL-13, IL-18, and their ratio into clinical algorithms may facilitate precision-guided biologic therapy in psoriasis. Full article