Search Results (1,008)

Autoimmune flares are often accompanied by abrupt surges of circulating plasmablasts—short-lived, high-output antibody-secreting cells generated through extrafollicular B-cell activation in response to microbial cues. Three categories of microbial input appear to repeatedly trigger these “plasmablast storms”: latent herpesvirus reactivations (Epstein–Barr virus, cytomegalovirus, human herpesvirus-6, varicella–zoster virus), acute respiratory or gastrointestinal infections including SARS-CoV-2, and chronic oral or gut dysbiosis. Although biologically distinct, these stimuli converge on innate sensing pathways driven by pathogen-associated molecular patterns such as unmethylated CpG DNA, single-stranded RNA, lipopolysaccharide, and bacterial lipoglycans. Through Toll-like receptors and type I interferon signalling, microbial signatures accelerate class switching, amplify inflammatory cytokine milieus, and lower B-cell activation thresholds, enabling rapid plasmablast mobilisation. Dysbiosis further maintains B cells in a hyper-responsive state by disrupting mucosal homeostasis and altering microbial metabolite profiles, thereby reducing the stimulus required to trigger plasmablast bursts. Once generated, these waves of oligoclonal plasmablasts home to inflamed tissues, where chemokine and adhesion landscapes shape their retention during flares. Emerging evidence suggests that such episodic plasmablast expansions promote autoantibody diversification, somatic hypermutation, and epitope spreading, progressively eroding tolerance. This review synthesizes these insights into a unified model in which infections and dysbiosis promote microbe-licensed plasmablast storms that influence the tempo and severity of autoimmune disease. Full article

Background/Objectives: Polymerase chain reaction (PCR) testing of ocular fluids is an essential diagnostic method for identifying infectious causes of uveitis. However, multiplex PCR kits specifically developed for ophthalmic use are not commercially available in many regions, including Korea. Given the biochemical similarity between cerebrospinal fluid (CSF) and aqueous humor, this study evaluated the diagnostic utility of a commercially available CSF multiplex PCR panel for detecting herpesviruses in patients with suspected viral uveitis. Methods: We retrospectively reviewed the medical records of patients whose aqueous humor samples were analyzed using a multiplex PCR assay originally designed for CSF testing (Seeplex Meningitis-V1 ACE Detection kit, Seegene, Seoul, Republic of Korea). The samples were obtained between May 2019 and June 2023 at two tertiary referral hospitals. The assay targeted herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human herpesvirus 6 (HHV-6). Patients were classified into three groups: (I) anterior uveitis with suspected herpesviral infection, (II) acute retinal necrosis (ARN), and (III) CMV retinitis. Baseline characteristics, PCR positivity rates, and virus prevalence were compared among the groups. Results: Among 149 eyes tested, 86 were included in the final analysis. The overall positivity rate was 38.4%. PCR positivity was 19.7% (12/61) in Group I, 93.8% (15/16) in Group II, and 66.7% (6/9) in Group III. CMV was the most common pathogen in Groups I (66.7%) and III (100%), while VZV was predominant in Group II (80%). No HHV-6 infection was detected. Conclusions: The positivity rate in anterior uveitis (Group I) was lower than previously reported, likely due to the limited sample volume relative to the assay’s requirement. Nevertheless, the assay demonstrated diagnostic reliability comparable to previous reports for ARN and CMV retinitis. Therefore, the CSF-based multiplex PCR panel serves as a feasible and cost-effective diagnostic option for sight-threatening posterior segment infections, facilitating prompt diagnosis and treatment, although further optimization is warranted for anterior uveitis. Full article

Epstein-Barr virus (EBV) infection shows the strongest causative association with multiple sclerosis (MS), but its contribution to disease progression and the mechanisms allowing for viral persistence in the MS brain are still elusive. Studies in post-mortem MS brain tissue indicate an ongoing yet ineffective antiviral immune reaction in advanced stages of the disease. EBV has evolved strategies to evade immune recognition and clearance by the host immune system during both the latency and lytic phase of its life cycle. Recent evidence demonstrates that cells expressing EBV latent membrane protein (LMP) 2A exploit the PD-1/PDL1 inhibitory immune checkpoint to escape immune surveillance and maintain a persistent latent infection in the MS brain. This study investigated whether the virus also utilizes this inhibitory mechanism during other phases of the viral life cycle. By using multiple immunostainings on highly inflamed MS brain tissues containing meningeal tertiary lymphoid structures (TLSs), we analyzed PD-L1 expression on EBV-infected cells expressing EBNA2, five EBV lytic gene products, BZLF1, BHRF1, BMRF1, BALF2, and gp350/220, as well as on follicular dendritic cells within the TLSs. This is the first study describing in secondary progressive MS brain tissue the expression and the cellular and tissue distribution of PD-L1 on EBV-infected cells being in different stages of the viral life cycle, and confirms the meningeal TLSs as immune-permissive habitats favoring the maintenance of an intracerebral EBV reservoir. Full article

Background and clinical significance: Primary cardiac diffuse large B-cell lymphoma (DLBCL) arising in bioprosthetic valves is exceedingly rare. Most patients present with localized disease often masquerading as suspected thrombi or vegetations. Imaging studies are inconclusive and due to the rarity of the disease, treatment and follow-up data are very limited. Case presentation: We present one such case developing 9 years after aortic valve replacement in an otherwise immunocompetent patient, who presented with minor symptoms despite significant disease burden. This tumor contained Epstein–Barr virus (EBV), was confined to the site of origin, and has behaved non-aggressively after excision with a follow-up of 59 months. Conclusions: This unique disease is classified as Fibrin-associated large B-cell lymphoma (FA-LBCL) in view of its distinct clinical-pathological features. This report also addresses the unique features of this type of lymphoma. Full article

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17–24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent. This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases. Full article

Background and Objectives: Nasopharyngeal carcinoma (NPC) displays marked geographic and histopathological heterogeneity, and prognostic determinants in non-endemic regions remain incompletely defined. This study aimed to evaluate the impact of clinicopathological characteristics and treatment modalities on survival outcomes among patients with stage II–IVA NPC treated with curative intent at a single tertiary cancer center. Materials and Methods: A retrospective analysis was conducted on 81 consecutive patients with histologically confirmed NPC treated between 2000 and 2022. Demographic, clinical, and treatment parameters were extracted from institutional records. Survival outcomes—including disease-free survival (DFS), locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), cancer-specific survival (CSS), and overall survival (OS)—were estimated using the Kaplan–Meier method and compared using the log-rank test. Prognostic variables identified in univariate analysis were further assessed by multivariable Cox proportional hazards regression (Cox’s model). Results: The cohort included 59 men (72.8%) and 22 women (27.2%), with a median age of 50.8 years (range, 19–78). Most patients presented with locally advanced disease (T3–T4, 53.1%; N2, 60.5%; stage III–IVA, 87.7%). Non-keratinizing undifferentiated carcinoma (World Health Organization [WHO] type III) was the predominant histology (71.6%), followed by the non-keratinizing differentiated subtype (17.3%). Median DFS and OS were 94.6 and 139.4 months, respectively. According to the univariate analysis, histological subtypes and a family history of cancer were significantly associated with DFS, whereas comorbid systemic disease showed an unexpected association with longer DMFS. The multivariable Cox model identified the histological subtype as an independent predictor of disease recurrence (HR = 2.23, 95% CI: 1.00–4.94; p = 0.049). For OS, both histological subtype (HR = 2.40, 95% CI: 1.10–5.25; p = 0.029) and age at diagnosis (HR = 1.05, 95% CI: 1.02–1.09; p = 0.005) were independent adverse prognostic factors. Conclusions: In this long-term, single-center study from a non-endemic region, histological subtype emerged as the most powerful determinant of prognosis, significantly influencing both DFS and OS. Patients with non-keratinizing undifferentiated (WHO type III) carcinoma demonstrated superior outcomes compared with those with differentiated histology. Additionally, increasing age at diagnosis was independently associated with poorer OS. In contrast, inflammatory and nutritional biomarkers, the Pan-Immune–Inflammation Value (PIV) and the Prognostic Nutritional Index (PNI), showed no prognostic significance. These findings underscore the continued prognostic relevance of histopathologic classification and age and highlight the need for large-scale, standardized studies integrating Epstein–Barr virus (EBV) status and host-related factors in non-endemic NPC populations. Full article

Epstein–Barr virus (EBV) infection is closely associated with gastric cancer, yet its role in m6A-dependent gene regulation remains poorly understood. In this study, we investigated how EBV infection alters the m6A methylation pattern in gastric cancer cells and examined its impact on TSC22D1 mRNA stability through interaction with the m6A reader protein YTHDF1. m6A RNA immunoprecipitation sequencing (MeRIP-seq) revealed a significant reduction in m6A methylation of TSC22D1 in EBV-infected gastric cancer cells (AGS-EBV) compared with EBV-negative cells (AGS). Moreover, YTHDF1 knockdown increased both the stability and expression of TSC22D1. These findings demonstrate that YTHDF1 binds to TSC22D1 mRNA and promotes its m6A-dependent degradation. Collectively, our results suggest that EBV infection modulates m6A modification to regulate gene stability and identify the YTHDF1–TSC22D1 axis as a potential therapeutic target in EBV-associated gastric cancer. Full article

Epstein–Barr virus (EBV) is distributed worldwide and shows a seroprevalence of over 90% in adults, while seroprevalence in children varies depending on geographic and socioeconomic factors. Although primary EBV infection (pEBV) is often asymptomatic in early childhood, infection later in life may present with a variety of symptoms, most commonly as infectious mononucleosis, though many other clinical manifestations may occur. We present four clinical cases to illustrate the diverse and uncommon manifestations of pEBV and to support diagnostic reasoning. The first case demonstrates a diagnostic challenge of pEBV in a patient with severe cholestatic hepatitis in the setting of a recent travel. The second case highlights bilateral eyelid swelling (Hoagland sign) as a potentially isolated early symptom of pEBV, which clinicians should consider within its broad differential diagnosis. In the third case, we emphasize the importance of clinical judgment in contrast to premature closure in the face of repeatedly negative EBV serologies and advocate for further diagnostic evaluation, such as PCR testing, when pEBV is strongly suspected. The fourth case describes a fatal outcome of pEBV late in life, complicated by hemophagocytic lymphohistiocytosis. Unusual presentations of pEBV may complicate the diagnostic process and may lead to unnecessary testing. Our case series underscores the broad clinical spectrum of pEBV and highlights key features that aid in distinguishing it from important differential diagnoses. Awareness of characteristic laboratory findings, including reactive lymphocytosis, elevated large unstained cells, persistent fever, and lymphadenopathy, splenomegaly, as well as mild-to-moderate hepatitis is essential for guiding a targeted diagnostic approach for pEBV. Full article

Background: Long COVID (LC) is a multi-system disorder with persistent symptoms following SARS-CoV-2 infection. The presence of SARS-CoV-2 in the oral cavity and periodontium raises questions about its potential impact on periodontal health. Methods: A comprehensive literature search was conducted in PubMed using terms related to LC (e.g., “long-COVID,” “post-acute sequelae of SARS-CoV-2 infection,” “PASC,” “post-COVID-19,” “long-haul COVID”) and oral/periodontal diseases (e.g., “periodontal disease,” “periodontitis,” “gingiva,” “oral disease,” “dental”), filtered for English-language full-text articles published from 2019 to 2024. The search yielded 260 articles, which were supplemented with targeted searches on pathogenesis, immune mechanisms, microbiome alterations, and clinical outcomes, resulting in approximately 248 studies included in this review. Results: LC exhibits systemic immunoinflammatory dysregulation, including neutrophil activation, elevated pro-inflammatory cytokines, and complement activation, overlapping with mechanisms implicated in periodontitis. LC also leads to gastrointestinal and pulmonary dysbiosis, with potential effects on oral microbial communities. Gingival epithelium and periodontal ligament cells express ACE2, which is increased in periodontitis, facilitating viral entry. LC has been associated with reactivation of herpesviruses, such as Epstein–Barr virus, which are linked to autoimmune disorders and periodontitis. Conclusions: LC may act as a systemic risk factor for periodontitis. This review provides the theoretical foundation for the interactions between LC and oral health and highlights priorities for future epidemiologic and mechanistic research to better understand these relationships. Full article

Protein–protein interactions (PPIs) are fundamental to viral replication, regulating transcription, assembly, and genome packaging. Despite their biological importance, few FDA-approved therapeutics directly target these complexes. The split luciferase complementation assay (SLCA) is a quantitative bioluminescence system to measure protein–protein interactions in vitro after the proteins in question have been fused in-frame to N and C luciferase fragments. The SLCA can be performed both in vitro using purified protein components and in live cells, as the luciferase substrate luciferin is cell-permeable, allowing detection of protein interactions in intact cells. Assay performance, however, depends on the expression level and stability of the fusion proteins used. SLCA has been successfully applied to target Rev–Rev interactions in human immunodeficiency virus type 1 (HIV-1) for high-throughput small-molecule screening, establishing a proof-of-concept to target other parts of the viral life cycle. The system can be extended to other pathogens that currently do not have specific antiviral therapies such as HIV-1 Tat–cyclin T1, Capsid dimerization in Dengue virus, capsid interactions in equine encephalitis viruses, capsid assembly in Epstein–Barr virus, and nucleoprotein oligomerization in rabies virus. These applications demonstrate how the assay’s ability to quantify multimeric structural interactions is essential to viral replication, providing an avenue to identify small-molecule inhibitors that prevent viral replication and spread. Although there are challenges to protein stability and assay optimization, the sensitivity and adaptability of the SLCA has broader implications in virology to accelerate antiviral drug development. Full article

Background: Breast cancer (BC) is the most frequently diagnosed malignancy and a dominant cause of cancer mortality among women worldwide. Alongside established risk factors, recent studies highlight oncoviruses like Epstein–Barr virus (EBV) and human papillomavirus (HPV) as potential contributors. However, their role and association with BC development is still debatable. Study design and Methods: This systematic review and meta-analysis involved two distinct approaches: one assessing the worldwide prevalence of EBV and HPV coinfection in BC patients and another investigating the association between such coinfection and BC risk. A systematic search across PubMed, Scopus, Web of Science, and Embase was conducted up to 5 May 2025. Studies using PCR to detect both viruses in breast tissue samples were included. Random-effects models were used to estimate pooled prevalence and odds ratios with 95% confidence intervals. Results: Out of 307 non-duplicate records, 16 studies were found to be eligible for quantitative analysis. The pooled prevalence of EBV/HPV coinfection among BC patients was 14% (95% CI: 12–16%; I² = 91.0%). Prevalence varied by region, ranging from 6% in South America to 22% in the Middle East. In addition, a general trend towards increasing EBV/HPV coinfection prevalence among women with BC over time was detected. Moreover, analyzing case–control studies to investigate the relationship between EBV/HPV coinfection and the risk of BC, the pooled odds ratio was 5.87 (95% CI: 2.31–14.93; I² = 0%, p = 0.91). Conclusion: Our analysis shows that EBV and HPV coinfection prevalence varies by region and appears to be rising over time among women with breast cancer. Additionally, the strong statistical association between coinfection and breast cancer risk suggests a potential role for these oncoviruses in disease development, highlighting the possible preventive value of EBV and HPV vaccination. Full article

Objectives: To investigate the profile of Th1- and Th2-type cytokines in response to Epstein–Barr virus (EBV) antigens and to correlate this immune signature with clinical relapses in Multiple Sclerosis (MS). Specifically, we aimed to evaluate the cellular and humoral immune response following stimulation with a pool of lytic and latent EBV proteins. Methods: We employed ELISpot and ELISA to quantify Interferon-gamma (IFN-γ), Interleukin-18 (IL-18), Interleukin-10 (IL-10), and the B-cell activation marker soluble CD23 (sCD23). Measurements were performed on peripheral blood mononuclear cells (PBMCs) from MS patients and controls following stimulation with EBV peptide antigens. Results: MS patients exhibited significantly higher levels of all tested cytokines compared to controls. A statistically significant positive correlation was noted between IL-10 and sCD23 levels (p < 0.03), with significant correlations also found between IL-10 and IFN-γ (r = −0.56) and between IFN-γ and IL-18 (p < 0.02), a finding that warrants cautious interpretation. Crucially, both IL-10 and sCD23 levels strongly correlated with the Expanded Disability Status Scale (EDSS) score (p = 0.0003 and p = 0.0001, respectively). Conclusions: Our findings suggest a chronic, dysregulated immune response to EBV antigens in MS patients, characterized by the co-activation of inflammatory Th1 pathways and robust B-cell activation. These results support a pathogenetic model where the EBV-specific immune response, perpetuated by infected B-cells, may directly contribute to the immunopathological processes driving central nervous system (CNS) damage and clinical relapses. Full article

Toxoplasma gondii is the most common infectious cause of posterior uveitis in immunocompetent adults. While the parasite is typically acquired through ingestion of undercooked meat or contaminated food and water, unpasteurized goat milk has been identified as a less frequent but plausible source of infection. Coinfections in ocular toxoplasmosis are rare, and the role of Epstein–Barr virus (EBV) in these coinfections remains poorly understood. We report the case of a 70-year-old immunocompetent male presenting with severe, refractory panuveitis in the left eye. Initial serologic testing confirmed acquired Toxoplasma gondii infection, and treatment was initiated with systemic antimicrobials and corticosteroids. Intraocular inflammation persisted despite sequential therapy with trimethoprim–sulfamethoxazole, clindamycin, and azithromycin, eventually requiring pars plana vitrectomy with intravitreal clindamycin and dexamethasone due to non-clearing vitreous hemorrhage. Vitreous PCR testing revealed intraocular concurrent detection of EBV DNA, prompting combined antimicrobial and antiviral therapy. Epidemiological history revealed recent consumption of unpasteurized goat milk, suggesting a potential oral transmission route for Toxoplasma gondii. Although visual acuity improved following surgical intervention and targeted therapy, it remained markedly compromised due to the severity of the disease. This case illustrates the diagnostic value of multiplex PCR in refractory uveitis, enabling the detection of Toxoplasma gondii and the concurrent detection of EBV DNA in an immunocompetent patient. It highlights the importance of early molecular testing and detailed epidemiological assessment, including atypical transmission routes such as unpasteurized goat milk. Full article

Indolent lymphoproliferative diseases or disorders (LPDs) derived from T cells or Natural Killer (NK) cells may be neoplastic or non-neoplastic, which are often difficult to distinguish from each other and from their aggressive counterparts. The etiology and pathogenesis are mostly nebulous and may be related to infections or immune dysfunction. Indolent lymphomas differ from the high-grade aggressive counterparts by a prolonged clinical course of persistent or relapsing disease, histology, immunophenotype, and genetics. In recent decades, indolent lymphomas or LPD of T or NK cell derivation have been increasingly recognized, causing diagnostic and nosologic confusion. The issue is particularly challenging in the arena of indolent intestinal lymphomas and LPD, as evidenced by the myriad of names given to the indolent intestinal T- and NK-cell lymphomas and LPD. Confounding the picture are also reports of Epstein–Barr virus (EBV) positivity in various indolent non-intestinal LPD and, rarely, even in indolent intestinal T-cell lymphoma, which have been widely accepted to be typically EBV-negative. This review aims to curate current information and understanding of these diseases with the goal of resolving these issues. The recently described indolent T-lymphoblastic proliferation (iTLBP) and the re-classified indolent primary cutaneous CD4-positive small or medium T-cell LPDs and primary cutaneous acral CD8-positive T-cell LPDs also require greater awareness and recognition. It is important to diagnose these indolent entities in order to avoid over-treatment and unnecessary therapeutic intervention and to provide for accurate prognostic prediction and appropriate follow-up. Full article

Human cytomegalovirus and Epstein–Barr virus are widely distributed viruses that, upon primary infection, establish a lifelong latency in immunocompetent subjects, whereas, in immunocompromised patients, they may give rise to secondary infection. In the latter case, either virus may cause systemic or end-organ disease that, if localized into the intestinal tract, is almost impossible to distinguish from a flare of inflammatory bowel disease. Optimal management of this condition begins with using the right diagnostic test and definitions. Viral load quantification on biological samples (blood or tissue) by real time-polymerase chain reaction not only shows the best diagnostic accuracy but also makes it possible to distinguish between viral reactivation, infection, and disease, the clinical approach to which differs substantially. A crucial role is also played by the host virus-specific T-cell immunity, monitoring of which may improve patient management. In this regard, the advent of new therapeutic and vaccination tools, as in the transplantation field, is expected to improve patients’ outcome. Full article