Group A Streptococcus (GAS), or Streptococcus pyogenes, causes a connected spectrum of pharyngeal, cutaneous, invasive and immune-mediated diseases. Although beta-lactams remain active, treatment alone has not controlled transmission, recurrent infection, rapid invasive progression or acute rheumatic fever and rheumatic heart disease. Control is further weakened by increased macrolide and clindamycin resistance, heterogeneous diagnostic access, asymptomatic carriage, crowded living conditions and unreliable continuity of secondary prophylaxis. These limitations have shifted the field from a predominantly treatment-centered approach toward the development of vaccines as a prevention strategy. Target selection is guided by virulence functions that are required for colonization, immune evasion and tissue injury. These include the M protein, group A carbohydrate (GAC), streptolysin O, Streptococcus pyogenes cell envelope protease (SpyCEP), Streptococcus pyogenes adhesion and division protein (SpyAD), C5a peptidase and other conserved surface or secreted antigens. Current strategies include multivalent type-specific M-protein vaccines, conserved M-protein peptide vaccines, glycoconjugates, multicomponent non-M-protein formulations and mRNA-lipid nanoparticle platforms. The clinical pipeline has recently broadened. Phase I studies have been completed for StreptAnova and MJ8VAX, whereas the J8-K4S2 and p*17-K4S2 clinical trial studies have been completed, with peer-reviewed results pending. The GSK four-component vaccine initiated phase I evaluation in 2025 and remained under clinical evaluation in 2026, whereas the VAX-A1 formulation entered a first-in-human phase I study in 2026. However, no licensed GAS vaccine is available. Progress remains constrained by uncertain correlates of protection, autoimmune safety requirements, geographical emm diversity, endpoint selection and the need for trials in high-burden populations. This narrative review therefore focuses on the disease problem, targetable virulence mechanisms, limits of antimicrobial control, current vaccine pipeline and interventions required to complement future vaccine use.

APDS is a rare inborn error of immunity characterized by clinical manifestations, including recurrent infections. This real-world, retrospective analysis evaluated patient-reported infection rates before and after leniolisib initiation. Patients (aged ≥ 12 years) newly initiating leniolisib therapy were eligible for inclusion. Data were retrieved from PANTHERx Rare Pharmacy. Patient-reported infection rates during the baseline period (one year before leniolisib initiation) were compared with infection rates after leniolisib initiation (observation period; from initiation to end of data or death) using generalized estimating equations Poisson regression models with robust standard errors. Patients who had an infection assessment collected via a standardized questionnaire during the baseline and observation periods were included in the analysis (N = 71); subgroups for baseline infection rates (lower and higher than the median) and age (12-17 and ≥ 18 years) were also evaluated. The mean (SD) rate of infections per patient-year (PPY) decreased significantly-by 68%-from 5.8 (5.1) during baseline to 1.9 (2.0) in the observation period (rate ratio [RR], 0.32; 95% CI, 0.24-0.42; P < 0.001); infections PPY decreased by 38% in patients with low baseline infection rates (RR, 0.62; 95% CI, 0.43-0.89; P = 0.010) and 76% in those with high baseline infection rates (RR, 0.24; 95% CI, 0.17-0.34; P < 0.001); infections PPY decreased by 70% in those aged 12 - 17 years (RR, 0.30; 95% CI, 0.20-0.45; P < 0.001) and by 67% in those aged ≥ 18 years (RR, 0.33; 95% CI, 0.23-0.49; P < 0.001). Real-world evidence demonstrated that leniolisib treatment provided a significant reduction in infection rates overall and among subgroups.

In haploidentical hematopoietic stem cell transplantation (HSCT), the addition of post-transplantation cyclophosphamide (Cy) can help to induce immunotolerance between the donor and haploidentical immune system, preventing graft-versus-host disease between the haploidentical immune system and organs/ tissues of the recipient. We hypothesized that the situation could be reversed and replicated during the transplantation of allogenic tissue and syngeneic (autologous model) HSCT with post-HSCT Cy. We hypothesized that conditioning (pre-HSCT Cy) causes immunoablation of the recipient, and post-HSCT Cy deletes allo-reactive clones from transplanted HSC thus enabling immunotolerance to simultaneously transplanted tissue (organ). To test this hypothesis, we developed a model of autologous HSCT (syngeneic HSCT) with simultaneous transplantation of allogenic tissue in rat. The study rats received: first immunoablation, then allogenic skin graft and syngeneic HSCT, and later post-transplantation Cy. The administration of Cy before and after syngeneic HSCT with simultaneous transplantation of skin graft prolonged skin graft survival from 3 to 12 days and changed the pattern of rejection. The addition of Cy post-HSCT resulted in a statistically significant increase in TNFα secretion before rejection compared to acute rejection without Cy post-HSCT. The sole administration of Cy before and after syngeneic HSCT with simultaneous organ transplantation is not sufficient to achieve full tolerance to allogenic tissue. However, with changes to conditioning or additional immunosuppression, this goal could be achieved.

In many autoimmune and autoinflammatory diseases, the head and neck are the first sites of symptom manifestation. Recognizing these early signs is crucial to prevent diagnostic delays and fatal consequences. This review addresses: (1) specific otorhinolaryngological (ENT) manifestations indicating systemic diseases (2), evidence for differentiating these from isolated ENT disorders, and (3) the multidisciplinary role in patient management. A comprehensive narrative literature review was conducted utilizing established scientific databases, including PubMed/Medline, Scopus, Web of Science, and Embase, covering articles published from 1983 up to 2026. A structured search strategy applied keywords like "systemic disorders," "ENT symptoms," "granulomatosis with polyangiitis," and "Sjögren syndrome." Peer-reviewed clinical trials, mechanistic studies, and authoritative guidelines were included to synthesize current evidence regarding the clinical detection and management of systemic diseases through ENT manifestations. ENT symptoms typically manifest locally before systemic organ involvement. Sensorineural hearing loss (SNHL) frequently accompanies autoinflammatory diseases. Auricular chondritis strongly indicates relapsing polychondritis (RP). Granulomatosis with Polyangiitis (GPA) and RP classically present with refractory rhinosinusitis, nasal crusting, and saddle-nose deformities. Orally, Sjögren syndrome causes severe sicca syndrome, while Behçet's disease leads to mucosal ulcerations. Furthermore, GPA (developing in 2-20% of cases) and RP are common causes of potentially fatal laryngeal involvement, including progressive subglottic stenosis. ENT manifestations frequently herald severe systemic diseases. Early detection by otolaryngologists is vital. Implementing a multidisciplinary strategy that integrates rheumatology and internal medicine ensures timely diagnosis, facilitates appropriate systemic immunosuppression, and significantly improves patient survival and overall quality of life.

This meta-analysis explored the association of immune checkpoint-related single-nucleotide polymorphisms (SNPs) in programmed death-1 (PD-1), programmed death ligand-1 (PD-L1), and cytotoxic T-lymphocyte antigen-4 (CTLA-4) genes with susceptibility to various genitourinary (GU) cancers, including urothelial carcinoma (UC), renal cell carcinoma (RCC), and prostate cancer (PCa). PubMed, Embase, Cochrane Library, and Web of Science were searched for case-control studies from inception to April 2026. Six SNPs, including PD-1 (rs2227981), PD-L1 (rs4143815), and CTLA-4 (rs3087243, rs231775, rs5742909, and rs11571302), were examined. The relationships between the SNPs and cancer susceptibility were evaluated using pooled odds ratios (ORs) and 95% confidence intervals (CIs) for dominant, recessive, and allele models. This study considered 16 case-control studies. PD-L1 rs4143815 was associated with a significantly decreased risk of UC in Asian populations under the dominant model (CC + CG vs. GG: OR = 0.34, 95% CI = 0.14-0.87). CTLA-4 rs5742909 polymorphism was associated with an increased risk of GU cancer in dominant model (TT + TC vs. CC: OR = 1.41, 95% CI = 1.11-1.80) and allele model (T vs. C: OR = 1.34, 95% CI = 1.05-1.72). A significantly increased risk of UC was further identified among Asian population in the dominant model (OR = 1.56, 95% CI = 1.04-2.34). No significant associations were observed for the other SNPs. In conclusion, specific polymorphisms in immune checkpoint-related genes, particularly PD-L1 rs4143815 and CTLA-4 rs5742909, are associated with susceptibility to GU cancer in Asian populations.

NOD-like cytosolic receptors (NLRs) are crucial in both nonspecific and specific immunity. Among them, the NLRP3 (NOD-like receptor family pyrin domain-containing 3) gains clinical attention, where its hyperactivation causes inflammatory, autoimmune, and metabolic illnesses. We investigated the effects of the flavone eupatorin (3', 5-Dihydroxy 4', 6, 7-trimethoxy flavone) on the NLRP3 inflammasome and associated proteins utilizing in vitro and in silico approaches. Eupatorin modulates the NLRP3 and associated molecules' expression in lipopolysaccharide (LPS)-primed, adenosine 5'-triphosphate (ATP)-stimulated THP-1 cells through downregulation of NF-ĸB phosphorylation, with promising effects as observed with standard tranilast. Additionally, the suppression of zymosan-induced intracellular oxidative stress and LPS-induced nitric oxide (NO) revealed anti-inflammatory effects. The strong binding affinity of -8.276 kcal/mol of the compound with NLRP3 was observed at the ATP binding pocket as shown by the standard tranilast, -7.834 kcal/mol, where interaction with NF-kB also provides comparable results with binding affinities of -3.93 and - 3.17 kcal/mol, respectively. The in silico results support the in vitro findings. Eupatorin appears to be a potential medication option for NLRP3-driven inflammatory and metabolic diseases and deserves further development as an inflammasome inhibitor.

Antiretroviral therapy suppresses HIV replication, but 10-40% of people living with HIV do not reconstitute CD4 + T cell counts despite viral suppression. Cellular exhaustion and alteration in the frequency of CD4 + T cell subsets are mechanisms involved in immunological nonresponse. This study investigated cellular exhaustion through gene expression and frequencies of CD4 + T cell subpopulations through flow cytometry in 36 male individuals living with HIV (28 immunological responders and 8 immunological non-responders) after 18 months of treatment. Gene expression analysis revealed significantly upregulation of PDCD1 (fold change = 1.81; p = 0.0003) and TIGIT (fold change = 1.80; p = 0.0055) in immunological non-responders compared to immunological responders, with ROC curve analysis confirming discriminatory ability. Flow cytometry demonstrated lower frequencies of recent thymic emigrant (19.42 ± 7.76 vs. 32.29 ± 10.68; p = 0.0285) and naive CD4 + T cells (26.10 ± 9.41 vs. 47.65 ± 13.45; p = 0.0194) in immunological non-responders compared to immunological responders. Moreover, we observed higher frequency of central memory CD4 + T cells (47.94 ± 13.42 vs. 32.58 ± 9.89; p = 0.0184), with excellent discriminatory capacity. TIGIT expression inversely correlated with recent thymic emigrant (r = -0.7284; p = 0.0013) and naive CD4 + T cells (r = -0.7394; p = 0.0010), and directly with central memory CD4 + T cells (r = 0.7264; p = 0.0014). These findings emphasize cellular exhaustion and dysregulated CD4 + T cell subsets as critical factors of immunological nonresponse.

Human endogenous retroviruses (HERVs) represent approximately 8% of the human genome and have been increasingly implicated in the pathophysiology of immune-related disorders. In this study, we investigated the humoral response against specific antigenic peptides derived from HERV-H, HERV-K, and HERV-W in the plasma of patients across different asthma phenotypes, including non-severe and severe cases, compared to healthy controls (HCs). Our results show that antibody levels against HERV-W were significantly low in the asthmatic population, showing a progressive downregulation that was more pronounced in severe cases. Conversely, a distinct and robust upregulation was uniquely observed for HERV-H in severe asthma cases, reaching a 100% positivity rate. Furthermore, HERV-K antibody levels were significantly lower in the non-severe asthmatic subtype compared to HCs. Interestingly, Spearman analysis revealed significant positive correlations among all tested HERV peptides within the Asthmatic cohort, a co-regulatory trend that became substantially reinforced within the Severe Asthma subgroup. These findings highlight a specific immune dysregulation pattern where a synchronized HERV expression tightly correlates with disease severity and phenotypical classification. The HERV epitopes identified in this exploratory study appear to be key targets of the humoral response in asthmatic patients, suggesting that circulating antibody levels against these retroviral elements could serve as potential tools for exploratory disease stratification and refractory phenotype characterization.

Early thymectomy during congenital heart disease repair may impair thymic output, but long-term effects across age groups remain incompletely defined. We evaluated T-cell receptor excision circles (TRECs) and a comprehensive panel of lymphocyte subsets in 20 adults (mean age, 29.6 years) and 16 children (mean age, 10.7 years) who underwent thymectomy within the first year of life, and in age- and sex-matched controls. TRECs were lower in patients than controls in adults (34 ± 25 vs. 79 ± 45 copies/μL; FDR-adjusted p = 0.001) and children (9 [7-15] vs. 95 [65-160] copies/μL; FDR-adjusted p < 0.0001). Total lymphocyte and T-cell counts were reduced in both age groups, mainly due to lower naïve CD4[+] and CD8[+] T cells, including recent thymic emigrants. Most non-naïve subsets did not differ significantly from controls. Regulatory T-cell (Treg) alterations differed by age: children showed broad reductions, whereas adults showed selective naïve Treg reduction. Early thymectomy is associated with persistent thymic output impairment, including in adults approximately three decades after surgery, and with age-specific Treg alterations.

As a major gastrointestinal malignancy, colon cancer (CC) demands more effective therapies. Gene therapy is an emerging promising strategy, and pyroptosis, a novel lytic cell death form, serves as a vital antitumor target, with Gasdermin D (GSDMD)-a key pore-forming protein in pyroptosis-showing anti-CC potential. We constructed an engineered attenuated Salmonella strain to deliver a GSDMD-expressing plasmid, and verified its therapeutic efficacy via in vitro and in vivo studies. In CC cell lines, the Salmonella vector upregulated GSDMD and cleaved caspase-1 (its upstream activator), inhibiting cell proliferation and inducing pyroptosis. In CC-bearing mice, the strain significantly suppressed tumor progression, reduced Ki67 expression, elevated intratumoral GSDMD and cleaved caspase-1 levels, and enhanced CD4[+] and CD8[+] T cell infiltration to boost antitumor immunity. This study suggests that attenuated Salmonella-mediated GSDMD delivery combats CC by triggering pyroptosis and stimulating antitumor immunity, laying a foundation for GSDMD-targeted gene therapeutics.

Allergen immunotherapy (AIT) represents a cornerstone in managing IgE-mediated allergic diseases, such as allergic rhinitis and asthma. By administering controlled doses of allergens over time, AIT aims to readjust immune tolerance, thereby modifying allergic responses. However, clinical responses to AIT remain heterogeneous, with a subset of patients achieving only partial benefit. This heterogeneity underlines the need for novel adjunctive approaches to potentiate the immunomodulatory effects of AIT. In this context, vitamin D has gained considerable interest, given its well-established role in immune homeostasis and regulation, as well as its emerging relevance in modulating allergic disease. This structured narrative review aims to assess the potential role of vitamin D supplementation during AIT on clinical outcomes as well as the significance of endogenous vitamin D levels on AIT clinical efficacy. A total of 18 studies were reviewed, 13 evaluating the impact of vitamin D supplementation during AIT and 5 assessing the influence of endogenous vitamin D levels on AIT outcomes. Most supplementation studies reported clinical outcomes favoring the addition of vitamin D to AIT, but three found no additional benefit, and two reported a benefit only at an earlier time point, respectively in vitamin D-deficient patients. Of the five studies examining endogenous status, three reported that higher 25-hydroxyvitamin D (25(OH)D) levels were associated with better AIT outcomes. Other findings that were reported as secondary outcomes included favorable immunologic changes, such as IL-10 production, decreased allergen-specific IgE levels, and enhanced regulatory Treg-cell activity, without formal assessment of their contribution to clinical benefit. Nevertheless, findings remain inconsistent across studies due to heterogeneity in study design, supplementation regimens, and outcome measures. While the available evidence suggests that adequate vitamin D status or supplementation may be associated with better clinical responses to AIT, the current findings remain limited by heterogeneity in study design, supplementation regimens, outcome measures, and generally small sample sizes. Therefore, the evidence should be considered suggestive rather than conclusive. Although correction of vitamin D deficiency is appropriate on general clinical grounds, its specific use as an adjunct to improve AIT outcomes cannot yet be routinely recommended. Further adequately powered, standardized, placebo-controlled studies are needed to clarify its role and inform clinical recommendations.

In this study, we aimed to identify potential variants associated with monogenic autoinflammatory diseases (AIDs) in patients with Still's disease (SD), thereby enhancing our understanding of the complex genetic mechanisms driving SD. This study included adult patients with SD who had available genetic data. Demographic characteristics, clinical findings, and laboratory test results were recorded. Genomic variants related to AIDs were detected using next-generation sequencing with a targeted gene panel for all coding exons and exon-intron boundaries of relevant genes. Identified variants were interpreted using multiple in silico prediction models and genomic databases and classified following the 2015 ACMG/AMP recommendations. Thirty-nine patients were included, of whom 19 (49%) carried at least one genetic variant. A total of 22 distinct variants were identified across 15 genes, including NLRP1, NLRP3, NLRP12, MEFV, LPIN2, IFIH1, PSMB8, IL10RA, IL10RB, IL36RN, SLC29A3, PLCG2, NOD2, CARD14, and SH3BP2. All variants were monoallelic; most were missense, whereas two were frameshift variants in IFIH1 and NLRP1. Most variants were classified as variants of uncertain significance, while variants in MEFV and IFIH1 were classified as pathogenic and likely pathogenic, respectively. Different genetic variants can be observed in patients with SD, and these variants are possibly epiphenomena rather than being Still's disease-driven mutations. Their presence may contribute to variability in clinical findings and disease course, which requires further investigation to be fully understood.

Chimeric antigen receptor (CAR) T-cell therapy is one of the most promising types of immunotherapies for the treatment of cancer. Unlike conventional T cells, which recognize antigens only when presented by the major histocompatibility complex (MHC), CARs use an antibody-derived binding domain to recognize native tumor-associated surface antigens directly, enabling MHC-independent target recognition. The two main cytotoxic mechanisms used by CAR T cells are the quick release of lytic granules containing granzymes and perforin to cause target cell apoptosis and the activation of death-receptor pathways (FasL/Fas or TRAIL) to cause caspase-dependent cell death. Four generations of CAR designs have been created to improve therapeutic efficacy and an advanced fifth generation is under development. Although CAR-T therapies have been very successful in treating hematological malignancies, their efficacy in solid tumors is limited because of immunosuppressive tumor microenvironments, tissue architecture, and antigen expression patterns that prevent CAR-T cell infiltration, activation, and persistence. With encouraging but early results, CAR T-cell therapy is moving forward into many clinical studies aimed at different solid tumors. Antigens including epidermal growth factor receptor (EGFR), mesothelin (MSLN), Disialoganglioside 2 (GD2), and B7-H3 were the subject of important clinical research conducted between 2021 and 2025. Emerging cellular treatments such as Chimeric Antigen Receptor Natural Killer cells (CAR-NK), CAR-macrophages and T-cell receptor (TCR)-engineered T cells offer alternate options to circumvent the limitations of CAR T-cells in solid tumors. This review aims to examine the evolution of next-generation CAR-T cell therapy for solid tumors by highlighting recent innovations, key clinical advancements, and persisting therapeutic challenges. It further seeks to analyze the biological and translational barriers limiting efficacy in solid malignancies and to explore emerging strategies and future directions that may enhance clinical outcomes.