Search Results (155)

Background: The link between clinical recovery and immune restoration after severe COVID-19 remains poorly defined. Although most survivors experience symptomatic improvement, persistent symptoms have been hypothesized to reflect ongoing immune dysregulation. Methods: This prospective cohort study followed 93 unvaccinated adults with RT-PCR-confirmed moderate-to-critical COVID-19 at 3, 6, and 12 months post-discharge. Clinical assessments used structured interviews to evaluate the persistent symptoms. Peripheral blood analyses were used to measure lymphocyte subsets, immunoglobulins, and complement components. Results: Clinical recovery was substantial; fatigue prevalence declined from 70.9% to 24.7% and dyspnea prevalence from 81.7% to 25.8% by 12 months (p < 0.001 for both). However, immune recovery exhibited divergent patterns. Activated T cells (CD3⁺HLA-DR⁺) decreased significantly (from 20% to 13%; p < 0.001), complement C3c levels paradoxically increased from 1.23 to 1.35 g/L (p < 0.001), and serum IgA increased by 32% (p = 0.003). NK cells remained stable overall but were persistently reduced in a subset (~25%) of patients, particularly among those with fatigue and dyspnea. Critical illness was associated with slower T-cell resolution, prolonged IgM elevation, and increased complement activity. Conclusions: One year after hospitalization, most patients achieved substantial clinical improvement, but immune reconstitution lagged behind. These findings highlight the dissociation between clinical and immunological recovery and suggest that persistent immune dysregulation may be associated with long COVID manifestations. Incorporating immune monitoring into post-COVID care may help identify patients at risk of prolonged sequelae and guide targeted therapeutic strategies. Full article

Background: Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS) is a life-threatening complication of immune recovery, often triggered by antiretroviral therapy and characterized by Th1-skewed CD4⁺ T cell hyperactivation, neuroinflammation, and pulmonary dysfunction. Methods: Using a validated murine model of unmasking C-IRIS, we assessed the therapeutic potential of star-shaped glatiramer acetate (sGA), a structurally enhanced derivative of the FDA-approved immunomodulator glatiramer acetate (GA). sGA was administered intraperitoneally on days 1 and 3 post-CD4⁺ T cell reconstitution. Results: sGA significantly ameliorated C-IRIS-associated respiratory dysfunction, including increasing breaths per minute by ~35% and improved minute volume, total respiratory cycle time, expiration time, and inspiration time. Survival rate grew to 75% on day 14 for sGA-treated C-IRIS mice. In both the lung and the brain, sGA reduced total CD4⁺ T cells and selectively diminished Th1 cells by 50–60% and Th17 cells by 40–50%. Activated microglia decreased by 45% within the brain, indicating attenuated innate immune activation. Golgi-Cox analysis revealed region-specific neuroprotection: neuronal loss in the prefrontal cortex, lateral hypothalamus, and periaqueductal gray was rescued by 25–40%, whereas hippocampal neurons were relatively preserved, and basolateral amygdala neurons showed no significant recovery. Conclusion: Collectively, our findings suggest that sGA exerts neuroprotection in C-IRIS by limiting peripheral CD4⁺ T cell effector activity and suppressing CNS-resident immune activation. This study supports the use of sGA as a promising preclinical therapeutic candidate for C-IRIS and other Th1-mediated neuroinflammatory conditions. Full article

Childhood acute lymphoblastic leukemia (ALL) is the most common pediatric cancer, and while chemotherapy has significantly improved survival rates, it can also lead to long-term side effects, including immune system dysfunction. This study aimed to investigate in detail, using flow cytometry, the T-cell subpopulations in the peripheral blood of children who have completed ALL treatment and compare them to a group of healthy children. The study group consisted of 20 patients, aged 5 to 18 years, with blood samples collected at least one year after treatment completion. Of the 52 T-cell subpopulations analyzed, 16 showed statistically significant differences. Children after ALL treatment had lower absolute values of TCRγδ+ and higher values of double-positive CD4+CD8+ and CD8+ T cells. They also had higher absolute numbers of memory T cells, including total CD45RO+ T cells, and the CD45RO+CD8+ and CD45RO+CD27+ subpopulations. Furthermore, post treatment patients showed higher absolute values of activated T cells (HLA-DR+, HLA-DR+CD8+, HLA-DR+CD57+, and CD25+CD8+), as well as CD57+ and CCR7+ T cells. The absolute leukocyte and granulocyte counts were lower in the study group, while the total lymphocyte count was significantly higher compared to the control group. The findings indicate persistent changes in T-cell subpopulations after ALL treatment, suggesting ongoing immune system rebuilding and chronic antigenic stimulation, possibly due to viral reactivation or chemotherapy-related tissue damage. The increased number of TCRγδ+ cells, which are responsible for eliminating cancer cells, may be a positive aspect of this rebuilding. Full article

The use of highly active combined antiretroviral therapy (cART) has increased life expectancy in people living with HIV (PLWH). As a result of ongoing monitoring and surveillance in established HIV out-patient clinics, thyroid dysfunction amongst this population has become increasingly reported. In this narrative review, primary studies, case reports, and meta-analyses published on PubMed, Embase, and Cochrane were analysed. The most reported thyroid dysfunction is subclinical hypothyroidism (SCH). The prevalence of subclinical hypothyroidism was as high as 40% in PLWH with CD4 T-cell count < 350 cells/mm³, which is a level indicating a state of immunosuppression. Some less commonly reported thyroid dysfunctional conditions include overt hyperthyroidism and thyroid malignancy. Reports have linked the development of thyroid dysfunction to the use of cART, leading to immune reconstitution inflammatory syndrome (IRIS), which has also been linked to the development of Grave’s disease (GD). It is also important to check for thyroid malignancy, as PLWH are prone to having a high risk of developing non-AIDS-related or -defining cancer (NADC). Most research suggests symptom-driven monitoring. However, evidence also suggests that monitoring with cART status change, monitoring for patients with significant comorbidities, or with immune reconstitution may be useful. The screening should include Free Thyroxine (FT4), triiodothyronine (FT3), and thyroid-stimulating hormone (TSH) testing. Furthermore, vigilance for Grave’s disease and performing thyroid antibody checks are advised, especially once the reconstitution of T-cells is achieved. Full article

A reassessment of the risk-benefit balance of the two lipid nanoparticle (LNP)-based vaccines, Pfizer’s Comirnaty and Moderna’s Spikevax, is currently underway. While the FDA has approved updated products, their administration is recommended only for individuals aged 65 years or older and for those aged 6 months or older who have at least one underlying medical condition associated with an increased risk of severe COVID-19. Among other factors, this change in guidelines reflect an expanded spectrum and increased incidence of adverse events (AEs) and complications relative to other vaccines. Although severe AEs are relatively rare (occurring in <0.5%) in vaccinated individuals, the sheer scale of global vaccination has resulted in millions of vaccine injuries, rendering post-vaccination syndrome (PVS) both clinically significant and scientifically intriguing. Nevertheless, the cellular and molecular mechanisms of these AEs are poorly understood. To better understand the phenomenon and to identify research needs, this review aims to highlight some theoretically plausible connections between the manifestations of PVS and some unique structural properties of mRNA-LNPs. The latter include (i) ribosomal synthesis of the antigenic spike protein (SP) without natural control over mRNA translation, diversifying antigen processing and presentation; (ii) stabilization of the mRNA by multiple chemical modification, abnormally increasing translation efficiency and frameshift mutation risk; (iii) encoding for SP, a protein with multiple toxic effects; (iv) promotion of innate immune activation and mRNA transfection in off-target tissues by the LNP, leading to systemic inflammation with autoimmune phenomena; (v) short post-reconstitution stability of vaccine nanoparticles contributing to whole-body distribution and mRNA transfection; (vi) immune reactivity and immunogenicity of PEG on the LNP surface increasing the risk of complement activation with LNP disintegration and anaphylaxis; (vii) GC enrichment and double proline modifications stabilize SP mRNA and prefusion SP, respectively; and (viii) contaminations with plasmid DNA and other organic and inorganic elements entailing toxicity with cancer risk. The collateral immune anomalies considered are innate immune activation, T-cell- and antibody-mediated cytotoxicities, dissemination of pseudo virus-like hybrid exosomes, somatic hypermutation, insertion mutagenesis, frameshift mutation, and reverse transcription. Lessons from mRNA-LNP vaccine-associated AEs may guide strategies for the prediction, prevention, and treatment of AEs, while informing the design of safer next-generation mRNA vaccines and therapeutics. Full article

Human cytomegalovirus (HCMV) establishes lifelong latency following primary infection, residing within myeloid progenitor cells and monocytes. To achieve this, the virus employs multiple immune evasion strategies. It suppresses innate immune signaling by inhibiting Toll-like receptor and cGAS-STING pathways. In addition, the virus suppresses major histocompatibility complex (MHC)-dependent antigen presentation to evade T cell recognition. As the downregulation of MHC molecules may trigger NK cell activation, the virus compensates for this by expressing proteins such as UL40 and IL-10, which engage inhibitory NK cell receptors and block activating signals, thereby suppressing NK cell immune surveillance. Viral proteins like UL36 and UL37 block host cell apoptosis and necroptosis, allowing HCMV to persist undetected and avoid clearance. In settings of profound immunosuppression, such as after allogeneic hematopoietic stem cell transplantation (allo-HSCT) or solid organ transplantation, slow immune reconstitution creates a window for viral reactivation. Likewise, immunosenescence and chronic low-grade inflammation during aging increases the risk of reactivation. Once reactivated, HCMV triggers programmed cell death, releasing viral PAMPs (pathogen-associated molecular patterns) and host-derived DAMPs (damage-associated molecular patterns). This release fuels a potent inflammatory response, promoting further viral reactivation and exacerbating tissue damage, creating a vicious cycle. This cycle of inflammation and reactivation contributes to both transplant-related complications and the decline of antiviral immunity in the elderly. Therefore, understanding the immune regulatory mechanisms that govern the switch from latency to reactivation is critical, especially within the unique immune landscapes of transplantation and aging. Elucidating these pathways is essential for developing strategies to prevent and treat HCMV-related disease in these high-risk populations. Full article

Human T-cell leukemia virus type 1 (HTLV-1) establishes lifelong infection and is associated with severe diseases such as adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Cytotoxic T lymphocytes (CTLs), especially those specific for the viral protein Tax, play a pivotal role in controlling HTLV-1 infection. However, conventional humanized mouse models fail to fully reconstitute human immune responses, limiting their utility for evaluating CTL-mediated immunity. This study aimed to establish a physiologically relevant in vivo model to investigate human CTL responses against HTLV-1. To achieve this, we utilized NOG-HLA-A02 transgenic (Tg) mice expressing human HLA-A02:01 on thymic epithelial cells, enabling proper development of HLA-restricted human T cells. Compared to conventional humanized NOG mice, HTLV-1-infected humanized NOG-HLA-A02 Tg mice exhibited significantly reduced HTLV-1 proviral load (PVL), decreased expansion of infected CD4⁺ T cells, a trend toward increased frequencies of Tax-specific CD8⁺ T cells, and prolonged survival. These results demonstrate that the expression of HLA-A02:01 facilitates robust CTL-mediated immune control of HTLV-1. This model provides a powerful platform for dissecting HTLV-1 immunopathogenesis and evaluating CTL-targeted therapeutic strategies, including vaccines and immune checkpoint inhibitors. Full article

Celiac disease (CD) is a chronic autoimmune disorder triggered by gluten in genetically susceptible individuals. While gluten-free diet (GFD) remains the primary treatment, the molecular mechanisms underlying immune reconstitution remain poorly understood in pediatric populations. This study aimed to characterize T cell receptor (TCR) repertoire remodeling in pediatric CD patients following short-term GFD. We conducted a longitudinal observational study analyzing peripheral blood circulating T cells from five pediatric CD patients at two time points: pre-GFD (at diagnosis) and post-GFD (after 9–10 months of strict dietary adherence). Single-cell TCR sequencing was performed to analyze clonotype diversity, gene usage patterns and TRAV-TRBV pairing combinations. Analysis of 9661 T cells revealed significant TCR repertoire remodeling post-GFD. Expanded clones, predominantly cytotoxic CD8+ T cells, contracted post-GFD (p = 0.02), while increasing clonotype diversity. Notably, specific αβ chain pairings underwent clear reorganization in the complete T cell compartment. Pathogenic combinations were depleted post-GFD, especially in CD4+ T cells, while beneficial pairings became enriched. GFD induced comprehensive TCR repertoire remodeling, revealing that changes occur at the level of specific TCR pairings rather than individual gene usage. Our findings highlight the precision of single-cell approaches in capturing functionally relevant immune changes for monitoring treatment response in pediatric CD. Full article

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT. Full article

Background: Hematopoietic cell transplantation (HCT) and chimeric antigen receptor T-cell (CAR-T) therapy have markedly improved survival in pediatric patients with hematological malignancies. However, these treatments cause profound immunosuppression, leading to significant susceptibility to vaccine-preventable diseases (VPDs), including invasive pneumococcal disease and measles. Timely and tailored immunization strategies are crucial to mitigate infectious risks in this vulnerable population. Methods: We conducted a narrative review of the English-language literature from 2000 to 2024, including clinical guidelines, surveys, and original studies, to evaluate immune reconstitution and vaccination practices in pediatric patients undergoing HCT and CAR-T therapy. Literature searches in PubMed, Scopus, and Web of Science used disease-specific, therapy-specific, and pathogen-specific terms. Data synthesis focused on vaccine schedules, immune recovery markers, and adherence challenges. Results: Profound immune deficits post-HCT and CAR-T therapy compromise both innate and adaptive immunity, often necessitating revaccination. Key factors influencing vaccine responses include time since therapy, graft source, immunosuppressive treatments, and chronic graft-versus-host disease. Although inactivated vaccines are generally safe from three to six months post-HCT, live vaccines remain contraindicated until documented immune recovery. CAR-T therapy introduces unique challenges due to prolonged B-cell aplasia and hypogammaglobulinemia, leading to delayed or reduced vaccine responses. Despite established guidelines, real-world adherence to vaccination schedules remains suboptimal, driven by institutional, logistic, and patient-related barriers. Conclusions: Effective vaccination strategies are essential for reducing infectious morbidity in pediatric HCT and CAR-T recipients. Personalized vaccine schedules, immune monitoring, and multidisciplinary coordination are critical to bridging gaps between guidelines and practice, ultimately improving long-term outcomes for immunocompromised children. Full article

Cannabinoid receptor 1 (CB1) has been implicated in multiple inflammatory diseases by regulating pro-inflammatory mediators or altering immune cell polarization. However, the expression and direct functional role of CB1 in T cells remain largely unexplored. Here, we demonstrate that primary murine T cells express CB1 and that its novel agonist, BI-5756, directly increases the frequencies of regulatory T cells (Tregs) in primary murine pan T cells after activation. In addition, BI-5756 exhibits an in vivo protective effect against graft-versus-host disease (GvHD), an allogeneic T cell-mediated inflammatory complication after allogeneic hematopoietic cell transplantation (allo-HCT), resulting in an improved overall survival with enhanced platelet recovery and reconstitution of bone marrow-derived B and T cells. BI-5756 also directly suppresses tumor cell growth and upregulates MHC I, MHC II, and CD80 on tumor cells, which may subsequently enhance T cell-mediated anti-tumor responses in mixed lymphocyte reaction with A20 cells. The ability of BI-5756 to increase Tregs was significantly abrogated by rimonabant, a potent and selective CB1 antagonist, suggesting that the immunomodulatory effect of BI-5756 is mediated via CB1. In summary, BI-5756, a potent CB1 agonist, increases Tregs while preserving anti-tumor responses in vitro and effectively reduces GvHD in vivo. Full article

Chimeric antigen receptor (CAR) T cell immunotherapy has changed the landscape of B cell hematological malignancies’ management, while it has recently shown promising results in the treatment of refractory autoimmune rheumatic disorders (ARDs). Targeting B cell antigens such as CD19 and BCMA, CAR-T cell therapy can induce sustained remission by the elimination of autoreactive B cell populations resistant to the standard of care treatment options. Clinical data from case reports and small case series demonstrate profound clinical responses in ARDs, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs), rheumatoid arthritis (RA), antiphospholipid syndrome (APS), and primary Sjögren’s syndrome (pSS). Treatment outcomes include reduced disease activity, normalization of serologic markers, improved organ function, and drug-free remission, even after B cell reconstitution. Additionally, toxicities, primarily limited to mild cytokine release syndrome (CRS), were generally manageable with supportive care. Encouraging preliminary results have led to the development of several ongoing clinical trials investigating CAR-T cell therapy across multiple ARDs and patient populations, including pediatric patients. This review summarizes the current clinical experience and provides a comprehensive overview of ongoing clinical trials exploring CAR-T cell immunotherapy for ARDs. Full article

Disruption of the gut microenvironment is a hallmark of HIV infection, where regulatory T cells (Tregs) play a critical role in maintaining gut homeostasis. However, the mechanisms by which gut Tregs contribute to immune reconstitution failure in HIV-infected individuals remain poorly understood. In this study, we employed single-cell RNA sequencing (scRNA-seq) to analyze gut Treg populations across three cohorts: eight immunological responders (IRs), three immunological non-responders (INRs), and four HIV-negative controls (NCs). Our findings revealed that INRs exhibit an increased proportion of gut Tregs but with significant functional impairments, including reduced suppressive capacity and heightened apoptotic activity. Notably, these Tregs underwent metabolic reprogramming in INRs, marked by an upregulation of glycolysis-related genes and a downregulation of the oxidative phosphorylation (OXPHOS) pathway. Additionally, both the abundance of short-chain fatty acid (SCFA)-producing bacteria and SCFA concentrations were reduced in INRs. In vitro SCFA supplementation restored Treg function by enhancing suppressive capacity, reducing early apoptosis, and rebalancing cellular energy metabolism from glycolysis to OXPHOS. These findings provide a comprehensive characterization of gut Treg dysfunction in INRs and underscore the therapeutic potential of targeting gut Tregs through microbiota and metabolite supplementation to improve immune reconstitution in HIV-infected individuals. Full article

Background/Objectives: Pediatric allogeneic hematopoietic stem cell transplantation (allo-HSCT) is complicated by iron overload and hypomagnesemia, both contributing to immune dysfunction and post-transplant morbidity. The combined impact of these metabolic disturbances on pediatric allo-HSCT outcomes remains unexplored. This study aims to determine whether hypomagnesemia can serve as a prognostic biomarker for delayed immune reconstitution and explores its interplay with iron overload in predicting post-transplant complications and survival outcomes. Methods: A retrospective analysis was conducted on 163 pediatric allo-HSCT recipients. Serum magnesium levels were measured at defined intervals post-transplant, and outcomes were correlated with CD4+ T cell recovery, time to engraftment, incidence of graft-versus-host disease (GVHD), and survival within 12 months. Iron status, including siderosis severity, was evaluated using imaging and laboratory parameters obtained from clinical records. Results: Patients who died within 12 months post-transplant exhibited significantly lower magnesium levels. Hypomagnesemia was associated with delayed CD4+ T cell recovery, prolonged engraftment, and an increased risk of acute GVHD. A strong inverse correlation was observed between magnesium levels and the severity of siderosis. Iron overload appeared to exacerbate magnesium deficiency. Additionally, the coexistence of hypomagnesemia and siderosis significantly increased the risk of immune dysfunction and early mortality. No significant association was found with chronic GVHD. Conclusions: Hypomagnesemia is a significant, early predictor of poor outcomes in pediatric allo-HSCT, particularly in the context of iron overload, underscoring the need for early intervention, including iron chelation and MRI, to improve outcomes. Full article

Background: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease caused by John Cunningham virus (JCV) in immunocompromised individuals, with no effective antiviral treatment currently available. This study aimed to evaluate the feasibility of adoptive JCV-specific T lymphocyte therapy in patients with PML. Methods: Nineteen patients meeting the 2013 consensus criteria for “definite PML” were included, and JCV-specific T lymphocytes expanded from autologous or allogeneic peripheral blood mononuclear cells (PBMCs) using JCV antigen-derived peptides were administered. Clinical outcomes were monitored through neuroimaging and biological markers. Results: The mean age at diagnosis was 56.5 years, with a mean time to treatment of three months. Patients received a median of two infusions. At 12 months, six patients (31.6%) survived, while 13 (68.4%) had died, primarily due to PML progression. Survivors had a higher median baseline Karnofsky performance scale (KPS) score (50% vs. 30%, p = 0.41) and a significantly shorter diagnosis delay. MRI assessment showed a reduced disease burden in survivors, and JCV-DNA copy numbers decreased overall. One case of immune reconstitution inflammatory syndrome (IRIS) was observed. Conclusions: Adoptive JCV-specific T lymphocytes may represent a safe therapeutic option for PML patients, and the MRI burden and JCV-DNA copy may serve as biomarkers for disease monitoring. Full article