Search Results (430)

Non-coeliac wheat sensitivity (NCWS) is characterised by gastrointestinal and extra-intestinal symptoms following gluten/wheat ingestion in individuals without coeliac disease or wheat allergy but remains controversial due to symptom overlap with irritable bowel syndrome (IBS). This narrative review aims to provide a comprehensive, critical analysis of NCWS as a clinical and biological entity, examining the evidence for its distinction from related disorders. While self-reported rates are high (often >10%) in the general population, rigorous double-blind, placebo-controlled challenge (DBPCC) studies confirm the diagnosis in only a minority of cases (typically <30%). The clinical presentation is heterogeneous, combining IBS-like symptoms with systemic complaints such as “brain fog,” headaches, and fatigue. The pathophysiology is distinct from coeliac disease, involving innate immune activation, altered intestinal barrier function, and gut dysbiosis. Non-gluten wheat components, particularly fructans and amylase-trypsin inhibitors, are implicated as potential triggers. Diagnosis is challenging, requiring the exclusion of other disorders and adherence to complex dietary challenge protocols such as the Salerno Experts’ Criteria, which are impractical for routine clinical use. The search for validated biomarkers is a key research area and investigated candidates include serological markers such as IgG anti-gliadin antibodies, inflammatory markers such as faecal calprotectin, and proteins related to intestinal permeability such as zonulin, but results have been conflicting and require further validation. Management primarily involves elimination of wheat and gluten from the diet, although a low-FODMAP diet has also proven effective as an adjunctive treatment. In conclusion, NCWS is a clinical entity whose study and management are critically hampered by the absence of validated diagnostic criteria and biomarkers. Progress requires methodologically rigorous DBPCC trials to elucidate its mechanisms and develop reliable diagnostic tools. Full article

Background and Objectives: The Hepatitis E Virus (HEV) is increasingly recognized as a cause of chronic infection in immunocompromised patients, but its precise role in cryptogenic cirrhosis (CC) is unclear. CC is defined as liver cirrhosis in which all known causes, including viral, autoimmune, metabolic, and alcohol-related etiologies, have been meticulously excluded. We aimed to address this gap by definitively assessing HEV’s etiological contribution in CC through seroprevalence comparison and evaluating its long-term prognostic impact on disease progression and adverse clinical outcomes. Materials and Methods: This is a retrospective, single-center, observational, and longitudinal cohort study, conducted between July 2017 and June 2025. The study included 52 CC patients, whose diagnosis was strictly confirmed by excluding all known etiologies, and 900 healthy blood donors from the same region. CC patients were retrospectively followed for five years to assess long-term clinical outcomes. We compared HEV seropositive and seronegative patients for accelerated disease progression (assessed by follow-up MELD-Na scores) and cirrhosis-related death. We employed multivariable logistic regression to adjust for demographic confounders in the prevalence comparison and multivariable COX regression for survival analysis to determine the independent prognostic role of HEV seropositivity. Results: The anti-HEV IgG seroprevalence in CC patients (42.3%) was significantly higher than in healthy donors (12.8%) (p < 0.001). Multivariable logistic regression confirmed CC status as an independent predictor of HEV seropositivity (Adjusted OR = 6.142, p < 0.001). During the five-year follow-up, the cirrhosis-related death rate was significantly higher in the anti-HEV IgG positive group (36.4% vs. 13.4%; p = 0.047), and their follow-up MELD-Na score was significantly higher (p = 0.029). However, multivariable COX analysis did not sustain anti-HEV IgG positivity as an independent risk factor for death (p = 0.294). Conclusions: HEV exposure is independently and significantly higher in CC patients. While anti-HEV IgG positivity correlates with higher mortality and accelerated disease progression in univariable analysis, its lack of independent prognostic significance suggests it may primarily function as a marker for a more advanced stage of CC or underlying immune dysfunction. Further rigorous prospective studies are necessary to precisely define HEV’s long-term prognostic role and evaluate its impact on disease progression. Full article

Human T-lymphotropic virus type 1 (HTLV-1) infection is associated with a spectrum of clinical outcomes, ranging from lifelong asymptomatic carriage to severe conditions such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although antibody responses are known to shape immune regulation, the functional relevance of IgG idiotype repertoires in HTLV-1 pathogenesis remains poorly understood. This study investigated the immunomodulatory effects of IgG from individuals with distinct HTLV-1 clinical outcomes. IgG was purified from pooled serum samples of asymptomatic carriers (ACs), HAM/TSP, and ATLL patients and used to stimulate peripheral blood mononuclear cells (PBMCs) from healthy donors. Cytokine production in CD4⁺, CD8⁺, and γδ T cells was assessed by flow cytometry. Additionally, proteome-wide IgG reactivity was evaluated using a human protein microarray encompassing over 21,000 proteins, and bioinformatic analyses were conducted to identify protein–protein interaction networks and tissue-specific autoreactivity. HAM/TSP-derived IgG selectively enhanced IFN-γ production in all T-cell subsets and suppressed IL-4 in CD4⁺ T cells. ATLL-derived IgG induced IL-9 and IL-13 production in CD4⁺ T cells, and both HAM/TSP and ATLL IgG elevated IL-13 levels in CD8⁺ T cells. Microarray data revealed distinct autoreactive IgG profiles across clinical groups, targeting immune-related proteins, apoptotic regulators, and proteins expressed in T cells, monocytes, and non-immune tissues such as brain and testis. Notably, no functional or structural clustering was observed in protein–protein interaction networks, suggesting these reactivities reflect complex, idiotype-specific immune alterations rather than compensatory responses. The present findings suggest that HTLV-1 infection may be associated with the development of distinct IgG repertoires that potentially modulate cytokine responses and exhibit broad reactivity toward human proteins. Such patterns could contribute to immune dysregulation and may partially explain the divergent clinical trajectories observed in HAM/TSP and ATLL. Further investigations are warranted to validate these observations at the individual level and to clarify their mechanistic relevance in disease progression. Full article

Studies examining IgG subclasses within circulating immune complexes (CICs) in patients with IgG4-related disease remain scarce. A Japanese man in his 50s with a history of diabetes mellitus and chronic pancreatitis was referred to our department because of an increase in serum creatinine levels. Serum IgG and IgG4 levels were markedly high, accompanied by eosinophilia and elevated serum IgE levels. C3 hypocomplementemia and an increase in CICs were also noted, and imaging revealed swollen mediastinal lymph nodes. Renal biopsy revealed extensive tubulointerstitial nephritis with numerous IgG4-positive plasma cells and dense interstitial fibrosis. The patient was diagnosed with IgG4-related disease, and glucocorticoid therapy was initiated; renal function, serological abnormalities, and swelling of the mediastinal lymph nodes improved. Subsequent analyses revealed that the patient’s CICs mainly comprised IgG4 and that there was tubular deposition of complement components C1q, C4d, C3, and C5b-9 in the renal biopsy tissue, suggesting that immune complexes containing IgG4 activated the complement pathway in circulation and locally in the kidneys. Hypocomplementemia and CICs are observed in a subset of patients with IgG4-related diseases; however, the underlying mechanisms remain unclear. Further accumulation of IgG4-related disease cases is required to evaluate the possibility of IgG4-mediated complement activation. Full article

To describe unusual findings and management of neuroretinitis in patients with cat scratch disease (CSD), their functional outcome after a case-oriented treatment was anaylsed, and the current literature was reviewed. A retrospective monocentric case series and a literature review. Review of medical records, multimodal imaging, and literature review. Five patients (four females and one male) with a mean age of 29.75 years (range: 11–71 years) had unusual findings of ocular bartonellosis, including inner retinitis, focal choroiditis, retinal microaneurysms, and bilateral sectorial optic nerve swelling. Bartonella-related ocular infections were not limited to the posterior segment of the eye. Molecular tests, such as polymerase chain reaction (PCR), showed that elevated markers of IgG titers were used and were positive in the aqueous humour of one patient. Reference to the use of intravitreal treatment in one of the cases was useful. Case-oriented management is associated with improvement in visual acuity, retinal, and choroidal lesions. The range of ocular signs of Bartonella infection could be extended. Molecular tests, such as PCR, are useful diagnostic approaches in the diagnosis of posterior uveitis. Treatment could require intravitreal antibiotic injections in unusual ocular bartonellosis. Full article

Background: Cytokines participate in regulating the immune response of lymphocytes. Interleukin 2 (IL-2) is the main modulator of T lymphocyte development, homeostasis, and function, whereas interleukin 7 (IL-7) regulates the development and homeostasis of immune cells and plays a crucial role in the maintenance of memory cells. The study aims to assess the blood IL-2 and IL-7 concentration in relation to the obtained cellular and humoral response in adults, six months after vaccination against COVID-19. Methods: We measured the concentration of IL-2 and IL-7 with ELISA, CoV2-IgG with an indirect chemiluminescence test, and the levels of IFN-γ with interferon gamma release assay (IGRA) post SARS-CoV-2 antigen stimulation. The study group (n = 76; F = 66, M = 10) was divided into 41 individuals, who did not report any chronic disorder (ChrD-Neg), and 35, who did (ChrD-Pos). Results: ChrD-Pos group presented higher IL-7 compared to ChrD-Neg (p = 0.023). Negative correlations were observed in the entire study population between IL-2 and age (R = −0.252, p = 0.028), as well as between IL-7 and IFN-γ (R = −0.295, p = 0.010). We found a positive correlation between IL-2 and IL-7 concentrations in the entire study population (R = 0.305, p = 0.007) and the ChrD-Pos group (R = 0.358, p = 0.035), and people with a positive IGRA result (R = 0.359, p = 0.005). Conclusions: The interaction of IL-2 and IL-7 may be important for achieving post-vaccination immunity, especially in adults with chronic diseases. Age is a factor modifying the post-vaccination response (decreased IL-2), whereas IL-7 may be an important factor in achieving a satisfactory post-vaccine response in people with chronic diseases. Full article

Background/Objectives: Infections of the urogenital tract have experienced renewed interest in recent years, due to their frequency and also their impact on sperm parameters and the fertilizing quality of spermatozoa. Chlamydia trachomatis (CT) represents an intracellular microorganism responsible for sexually transmitted infections (STIs) in men and women. A reliable method of diagnosing this infection is therefore necessary because of the rapid onset of infection and the increase in STI-related diseases and their treatment costs. Methods: We analyzed 2371 semen samples from infertile men and detected the presence anti-CT IgG antibodies by Enzyme-Linked Immunosorbent Assay (ELISA), followed by real-time PCR confirmation of CT DNA whose target is the lipopolysaccharide (LPS). We assessed the effect of CT infections on characteristic parameters of sperm quality, including concentration, motility, viability, and morphology. The impact on sperm DNA quality was assessed by DNA fragmentation index (S) and decondensation of chromatin index (SDI) by the TUNEL technique. Results: Analysis of the results showed significant differences in mobility, concentration, and morphology (p < 0.05) between the control group, positive CT infection with normal spermiogram status (CT+/Normal SG) group, and positive CT infection with abnormal spermiogram status (CT+/Abnormal SG) group. A significant increase in the DFI and the SDI was found between the control group and the case groups, respectively (p < 0.01). Conclusions: Our results confirm that CT infection is associated with significant alterations in sperm parameters and sperm DNA quality. Regular CT screening by qPCR should be encouraged in couples suffering from unexplained infertility. Full article

Background/Objectives: Pemphigus vulgaris (PV) and foliaceus (PF) are autoimmune blistering diseases mediated by IgG antibodies directed against desmogleins 1 and 3 and are still considered life-threatening disorders. In recent years, rituximab has been shown to be very effective, especially in PV and mainly in short follow-ups. The role of rituximab in achieving long-lasting complete clinical remission (cCR) in pemphigus still needs to be determined. Therefore, the aim of our study was to assess the efficacy, measured by achieving long-lasting cCR, and safety of rituximab in both PV and PF over an 8-year follow-up in light of several factors (body mass index—BMI, severity of disease—PDAI, age, gender, disease duration, COVID-19 period). Methods: In total, 28 patients with pemphigus were treated with rituximab and followed-up at one center. The entire analysis was performed using statistical methods. Results: Long-lasting cCR was achieved in 5 out of 6 patients (83%) with PF and 10 of 22 (45.5%) patients with PV. Univariate and multivariate analysis disclosed that studied factors did not statistically correlated with achieving long-lasting cCR. Among studied patients, few developed side effects, mainly urinary tract infection; one patient had sepsis, and one patient died. Conclusions: This study has demonstrated that rituximab is highly effective in PF and quite effective in PV over an 8-year follow-up in relation to independently studied factors. Moreover, the COVID-19 pandemic was not a negative factor influencing cCR achievement since 82% of patients treated with rituximab during that time still achieved cCR. Full article

IgA nephropathy (IgAN) is the most prevalent type of primary glomerulonephritis, with heterogeneous clinical outcomes. Conventional prognostic factors, such as proteinuria, eGFR, and Oxford histologic classification, have poor sensitivity and specificity. Recently, transcriptomic profiling has been employed to provide insights into the molecular definition of IgAN and facilitate patient stratification in those at risk of disease progression. In this review, we summarize our current understanding of IgAN derived from bulk RNA sequencing, single-cell transcriptomics, spatial transcriptomics, and gene expression profiling to elucidate the molecular characteristics of IgAN. Bulk transcriptomics of glomerular and tubulointerstitial compartments highlighted consistently upregulated genes (e.g., CCL2, CXCL10, LCN2, HAVCR1, COL1A1) and altered pathways (e.g., NF-κB, TGF-β, JAK/STAT, and complement) that are associated with clinical decline. Single-cell and single-nucleus RNA-sequencing has also identified the value of pathogenic cell types and regulatory networks in mesangial cells, tubular epithelium, and immune infiltrates. Furthermore, noninvasive transcriptomic signatures developed from urine and blood may represent useful real-time surrogates of tissue activity. With the advent of integrated analyses and machine learning approaches, personalized risk models that outperform traditional metrics are now available. While challenges remain, particularly related to standardization, cohort size, and clinical deployment, transcriptomics is likely to revolutionize IgAN by providing early risk predictions and precision therapeutics. Unlike prior reviews, our work provides an integrative synthesis across bulk, single-cell, spatial, and noninvasive transcriptomics, linking molecular signatures directly to clinical translation in risk stratification and precision therapeutics. Full article

Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract, characterized by dysregulated inflammatory responses throughout the gastrointestinal tract. It includes two major phenotypes, Crohn’s disease (CD) and ulcerative colitis (UC), which present with varying gastrointestinal and systemic symptoms. The pathophysiology of IBD is multifactorial including genetic predisposition, mucosal and epithelial dysfunction, environmental injury, and both innate and adaptive immune response abnormalities. Several predisposing genetic factors have been associated with IBD explaining the strong hereditary risk for both CD and UC. For example, Caspase Recruitment Domain 9 (CARD9) variant rs10781499 increases risk for IBD, while other variants are specific to either CD or UC. CD is related to loss-of-function mutations in the nucleotide oligomerization domain containing the protein 2 (NOD2) gene and Autophagy-Related 16-like 1 (ATG16L1) gene. UC risk is increased particularly in Chinese populations by the A-1661G polymorphism of the Cytotoxic T-lymphocyte antigen 4 (CTLA-4) gene. This abnormal CTLA-4 interferes with B- and T-cell responses causing predisposition to autoimmune conditions. Previous studies suggested that IBD results from breakdown of the adaptive immune system, primarily of T-cells. However, new evidence suggests that a primary breakdown of the innate immune system in both CD and UC increases susceptibility to invasion by viruses and bacteria, with a compensatory overactivation of the adaptive immune system as a result. When this viral and microbial invasion continues, further damage is incurred, resulting in a downward cycle of further cytokine activation and epithelial damage. Released biomarkers also affect the permeability of the epithelial membrane, including lactoferrin, nitric oxide (NO), myeloperoxidase (MPO) and its activation of hypochlorous acid, matrix metalloproteinases (MMPs), especially MMP-9, omentin-1, and others. Increased macrophage and dendritic cell dysfunction, increased neutrophil activity, increased numbers of innate lymphoid cells, increased T-cells with decreased regulatory T-cells (Tregs), and changes in B-cell populations and immunoglobulin (Ig) functions are all associated with IBD. Finally, treatment of IBD has typically consisted of medical management (e.g., aminosalicylates and corticosteroids) and lifestyle modification, and surgical intervention in extreme cases. New classes of medications with more favorable side effect profiles include anti-integrin antibodies, vedolizumab, etrolizumab, and carotegrast methyl. Additionally, fecal microbiota transplant (FMT) is a newer area of research for treatment of IBD along with TNF-blockers, JAK inhibitors, and S1PR modulators. However, expense and long preparation time have limited the usefulness of FMT. Full article

Rabies, a zoonotic infectious disease causing central nervous system inflammation, remains a threat to public health in regions with limited medical resources. Vaccination effectively reduces rabies incidence and mortality, underscoring the need for vaccines that are cost-effective, immunogenic, protective, and safe. This study constructed a recombinant rabies virus (rRABV)-overexpressing glucocorticoid-induced tumor necrosis factor receptor ligand (GitrL), named rLBNSE-GitrL, using a reverse genetic operating system. rLBNSE-GitrL exhibited similar in vitro phenotypic characteristics and immune safety as the parent RABV (rLBNSE). This recombinant virus stimulated the production of a greater number of activated dendritic cells (DCs) compared to rLBNSE. The enhanced innate immune response induced by rLBNSE-GitrL may be mediated through the activation of innate immune-related signaling pathways, such as the tumor necrosis factor (TNF), and chemokine signaling pathways, and the upregulation of a series of innate immune-related genes, including MMP2, IL-6, CXCL9, TIMP1, IL-17d, and TNF-α. Consequently, rLBNSE-GitrL elicited significantly higher levels of RABV vaccine-induced virus-neutralizing antibodies (VNA), IgG, and IgM compared to rLBNSE as early as 3 days post-immunization (dpi), thereby improving the protective effect in mice. Collectively, the overexpression of GitrL facilitated the induction of early and potent antibody responses following RABV immunization. Full article

Hepatocellular carcinoma (HCC) remains a major global health problem for which there are few effective treatments. Phytochemicals from natural sources, such as those found in cacti, exhibit chemoprotective and hepatoprotective properties. In this study, the effect of the polar fraction of Lophocereus schottii (LsPF) was investigated in a Wistar rat model of HCC induced by weekly administration of diethylnitrosamine (DEN, 50 mg/kg, i.p.) and 2-acetylaminofluorene (2-AAF, 25 mg/kg, i.g.) for 13 weeks. LsPF (50 mg/kg, i.g., three times per week) was administered either concurrently with HCC induction beginning in the first week or after seven weeks of HCC induction. LsPF did not lead to a significant improvement in macroscopic, biochemical or histologic results. However, when LsPF was administered after 7 weeks of HCC induction, it modulated the expression of genes related to liver carcinogenesis, including SOD, CAT, CYP2E1, TGFB1, AFP, and COL1A. In addition, co-administration of LsPF along with the damage treatment decreased the number of mitotic hepatocytes. These results suggest that LsPF can modulate gene expression and hepatocyte proliferation in HCC, with efficacy depending on the timing of administration, disease stage, and administration method. Further studies are needed to optimize its therapeutic potential. Full article

Hepatic actinomycosis (HA) and IgG4-related inflammatory pseudotumors are rare and often overlooked causes of liver mass, which can easily be misdiagnosed as primary liver cancer or metastasis. Diagnosis is arduous due to unspecified clinical and radiological features and the fact that histology is not always conclusive. In cases of actinomycosis, the use of molecular diagnostic techniques—such as polymerase chain reaction (PCR) for bacterial DNA—can aid in establishing a definitive diagnosis, especially when conventional cultures are non-diagnostic. We present a case report of one of our patients who was incidentally diagnosed with a hepatic lesion presenting aspecific radiological features. Since radiological imaging was inconclusive, a biopsy was performed, and a diagnosis of IgG4 related hepatic inflammatory pseudotumor was then made. Because of the disease progression, during immunosuppressive therapy, our diagnosis was questioned and a new liver biopsy was carried out. At the end, it took three consequent biopsies to finally find out the presence of an actinomyces infection. Full article

Background: To reduce work-related illnesses among teachers, various types of programs were implemented. Objectives: The aim of this study was to evaluate the effects of a 12-week multicomponent program on mental disorders, biochemical parameters, and immunological markers in female teachers with overweight. Methods: A total of 33 women who were basic education teachers with a body mass index (BMI) ≥ 25 kg/m² participated in this study. Participants were randomly assigned to either a control group (n = 16), which did not participate in the program, or an intervention group (n = 17), which underwent the multicomponent intervention. The program included physical exercise (three sessions per week), cognitive–behavioral therapy delivered monthly across three modules, and nutritional education consisting of both general and specific guidance. Assessments were conducted at baseline and after 12 weeks and included measurements of symptoms of depression, anxiety, and stress; fasting glucose; total cholesterol; LDL cholesterol; HDL cholesterol; VLDL cholesterol; triglycerides; and concentrations of immunoglobulins IgA, IgG, and IgM. Results: After 12 weeks, the intervention group showed a significant reduction in symptoms of depression, anxiety, and stress (p < 0.05), as well as in fasting glucose, triglycerides, and VLDL cholesterol levels compared to the control group (p < 0.05). No significant changes were observed in the levels of immunoglobulins IgA, IgG, or IgM (p > 0.05). Conclusions: The multicomponent program improved mental health and reduced the risk of developing metabolic and cardiovascular diseases in female teachers with overweight. Full article

Immunoglobulin G4–related disease (IgG4-RD) is an uncommon fibro-inflammatory process characterized by the infiltration of tissues and organs and a typically dramatic response to glucocorticoids. Its relapsing–remitting course, multisystemic involvement, and variability in epidemiological and prognostic features pose a significant diagnostic challenge for clinicians. Despite their effectiveness in symptom relief, prolonged glucocorticoid use remains a challenge in IgG4-RD management, prompting the search for steroid-sparing alternatives. Although rituximab has recently demonstrated efficacy in the treatment of IgG4-RD, no consensus exists regarding the optimal maintenance regimen. The emergence of new B-cell–targeted therapies and other immunomodulators represents a promising step toward more personalized treatment approaches. In this review, we provide an updated and integrative overview of the emerging treatment strategies for IgG4-RD, highlighting future directions towards individualized management. Full article