Immunological Disorders Research Articles

Microbiome of pregnancy (literature review)

Background. Pregnancy represents a unique immunological and physiological period during which microbial communities can have a significant impact on both maternal health and birth outcomes. Hormonal, immunological, and metabolic changes during pregnancy influence the microbiome and clinical outcomes, potentially impacting the well-being of both mother and child.Objective: generalization of modern scientific concepts about the relationship between the composition of the mother’s microbiota during pregnancy and its complications, discussion of the possibility of predicting pregnancy complications using the microbiome.Materials and methods. An extensive literature review was conducted using the MEDLINE (PubMed) database as of December 2024 with the following keywords and filter: randomized controlled trial, meta-analysis, systematic review.Research results: Extensive research links the dominance of certain Lactobacillus strains to different pregnancy outcomes, with L. cripatus being the most favorable strain. Only by existing in a normal symbiotic relationship between the organism and the microbiome is it possible to maintain homeostasis. Any shift in the balance in this system leads to the growth of opportunistic flora, which in turn triggers a cascade of immunological and physiological disorders. GDM, PCOS, premature birth — these conditions have features of the vaginal microbiocenosis.Conclusion. The microbiome composition of the female reproductive tract and intestine is dynamic during pregnancy and is influenced by a number of factors. More evidence suggests that dysbiosis is associated with various adverse pregnancy outcomes. Knowledge of the microbiome composition has the potential to improve the accuracy of diagnosis, develop targeted interventions, and reduce the risk of perinatal complications.

Characterization of a chitinase from Trichinella spiralis and its immunomodulatory effects on allergic airway inflammation in mice.

A fundamental tenet of the hygiene theory is the inverse association between helminth infections and the emergence of immune-mediated diseases. Research has been done to clarify the processes by which helminth-derived molecules can inhibit immunological disorders. This study aimed to evaluate the ability of Trichinella spiralis chitinase (Ts-chit) to ameliorate the symptoms of allergic airway inflammation. Recombinant Trichinella spiralis chitinase (rTs-chit) was expressed in Escherichia coli BL21, and its structural homology to murine acidic mammalian chitinase (AMCase) was comprehensively analyzed. The expression of Ts-chit was examined across all T. spiralis life stages. To explore its immunomodulatory potential, a murine model of allergen-induced airway inflammation was established. The effects of rTs-chit were evaluated by assessing airway hyperresponsiveness and cytokine profiles in bronchoalveolar lavage fluid and performing detailed histopathological and immunohistochemical analyses. Recombinant Ts-chit (rTs-chit) was successfully expressed in E. coli BL21, showing strong structural similarity to murine acidic mammalian chitinase (AMCase). Expression profiling revealed that Ts-chit is present throughout all stages of the T. spiralis life cycle. In an allergic airway inflammation model, rTs-chit reduced weight loss and lung inflammation, lowering inflammatory cell infiltration and Th2 cytokines (IL-4, IL-5, IL-13) while increasing the immunosuppressive cytokine IL-10. Additionally, rTs-chit treatment decreased the expression of GATA3, arginase-1, MCP-1, CCL-11, and AMCase, along with reducing OVA-specific IgE, IgG, and IgG1 levels, suggesting its potential as an immunomodulatory agent. This study highlights rTs-chit's potential as a therapeutic agent for allergic airway diseases, leveraging its structural similarity to host chitinases to regulate Th2 responses and inflammatory pathways. The findings provide new insights into helminth-derived proteins as promising candidates for immune-based therapies.

Beyond Dermatological Findings: Multisystem Involvement in Prolidase Deficiency.

Objective: Prolidase deficiency is a metabolic and immunological disorder that is inherited in an autosomal recessive manner. In prolidase deficiency, a broad spectrum of differences is observed in patients, ranging from asymptomatic to multisystem involvement. There is scarce information in the literature on the atypical features and immunophenotypes of this disease. Aim of this study is to present 4 new cases to provide information on the rare features of the disease and to raise awareness. Materials and Methods: This study included 4 female patients with prolidase deficiency. Their demographic, clinical, and immunologic characteristics were obtained from their medical records. Results: There were 4 female patients (P1-P4), with a mean age of 18.5 years (min-max: 10-29) and a mean age of symptom onset of 6.9 years (min-max: 0.04-27). The main presenting complaints of the patients were skin lesions (100%), dysmorphic features (100%), neurodevelopmental delay (100%), frequent infections (100%), and prolonged diarrhea (50%). P2 had diffuse large B-cell lymphoma, resulting in early death. Interestingly, P1 and P2 experienced opportunistic infections such as cytomegalovirus, Epstein-Barr virus, and Pneumocystis jirovecii. Three patients (75%) had lymphopenia. Two patients had elevated IgE levels. Lymphocyte subgroup analysis showed an inverted CD4/CD8 ratio in all patients. In patients P1 and P2, the percentages of naive T cells and recent thymic emigrants were reduced, suggesting combined immune deficiency at the time of diagnosis. CD19+ B cells were also low in P1 and P2. Metabolic evaluations revealed low prolidase enzyme activity in P1 and P2. Conclusion: Beyond the well-known classical dermatological findings, the presence of recurrent opportunistic infections, gastrointestinal involvement, malignancy, and flow cytometry findings suggestive of combined immunodeficiency indicate that the diagnosis of prolidase deficiency may be underestimated. Knowing the atypical and rare presentations will facilitate diagnosis and treatment of affected patients.

Subclinical myocardial dysfunction of the left ventricular in patients with systemic lupus erythematosus

The aim – to study the frequency of left ventricular (LV) myocardial dysfunction and its relationship with disease activity in patients with systemic lupus erythematosus (SLE).Materials and methods. The study included 100 patients with SLE who met the criteria of SLICC/ACR 2012, 87% were women, the average age was 33 [25; 40] years, the average duration of the disease was 1 [1; 9] year, patients with varying degrees of activity according to SLEDAI-2K (low/moderate/high) – 30/45/25 (30%/45%/25%). All the subjects had not previously received biological therapy and had no previously diagnosed cardiovascular diseases and other rheumatic diseases. All patients received glucocorticoids (GCs) and hydroxychloroquine therapy in different dosages depending on the severity of the disease, according to the standards recommended by the Association of Rheumatologists of Russia from 2021. Methotrexate was received by 6% of patients, azathioprine – 14%, cyclophosphamide – 3%, nonsteroidal anti-inflammatory drugs – 81.2%. The control group consisted of 20 healthy individuals, having no signs of rheumatic diseases and CVD comparable in age and gender. All the subjects underwent echocardiography (ECHO) with tissue dopplerography and left ventricle global longitudinal strain (LV GLS) assessment by speckle tracking.Results. Violation of LV GLS was observed in 65 (65%) patients with SLE. In the SLE group, compared with the control group, a significantly more damaged LV GLS was revealed. In all patients with impaired diastolic function of the left ventricular myocardium, deterioration of LV GLS parameters is observed. Impairment of LV GLS correlated with clinical and immunological parameters in patients with SLE: the degree of SLE activity according to SLEDAI-2K (r=0.219), the level of antibodies to double-stranded DNA (a/b to ds-DNA) (r=0.316), the C3 level of the complement component (r=–0.389), the C4 level of the complement component (r=–0.238), the hemoglobin level (r=–0.255), the number of red blood cells (r=–0.286), the level of C-reactive protein (r=–0.284) and CRP (r=–0.927). Also, patients with SLE with diagnosed nephritis (n=26) had a significant violation of LV GLS parameters.Conclusions. In patients with SLE, according to ECHO using the Speckle tracking technique, violation of LV GLS occurs with a high frequency (65%). Violation of LV GLS parameters is associated with SLE activity, immunological and hematological disorders. In all patients with impaired diastolic function of the left ventricular myocardium, LV GLS was obviously decreased. The presence of lupus nephritis is associated with a significant violation of the GLS parameters.

Management of Acute Liver Failure in Children

Introduction: Pediatric Acute Liver Failure (PALF) incidence has been increasing in recent times. It is an emergency and needs appropriate management in a specialized center with availability for liver transplant. Methods: In this article, we shall provide an overview of etiologies and approach to the management of PALF. Conclusions: Various known etiologies for pediatric acute liver failure involve infections, immunologic disorders, and metabolic and drug/toxin-mediated illnesses. However, a known etiology for liver failure may be lacking in approximately 30–50% of cases. In developing countries like India, infections still dominate as the leading cause of pediatric ALF, with the hepatitis A virus (HAV) being the most identified etiology. Metabolic disorders account for approximately 23–30 percent of the PALF in infancy or early childhood (less than 5 years). Around 9–52% of children with PALF have indeterminate etiology. Management requires a multidisciplinary approach involving hepatologists, pediatric intensive care specialists, nephrologists, and a liver transplant surgery team. Cerebral edema is the most frightful complication of acute liver failure, which may progress rapidly, leading to irreversible brain damage, so every possible measure should be taken to identify as well as prevent the progression of cerebral edema and raised intracranial pressure. Elective intubation and mechanical ventilation should be started in patients with significant encephalopathy (Grade II). Identification of the need for liver transplantation and early referral for the same before irreversible brain damage sets in. Extracorporeal liver assist devices have shown promising results in bridging these children to native liver survival or liver transplantation, but continuous careful monitoring should be done to assess for treatment failure and the need for liver transplantation. Liver transplantation is the only definite treatment that improves survival in PALF, and with several advances in surgical techniques and good intensive care, the overall survival after LT for ALF has improved significantly.

Training undergraduate biomedical science majors in peer review and constructive criticism through a senior capstone course.

Effective scientific communication is crucial for undergraduate students to succeed in future graduate or professional careers in the biomedical sciences. Peer review and constructive criticism are essential to producing written science communications. Unfortunately, training in how to perform peer review and incorporate constructive criticism is minimal in undergraduate science courses. Here, I describe a senior thesis course for immunology and microbiology majors that encourages students to integrate iterative peer review to improve their writing skills and their ability to incorporate feedback. In this course, students are expected to complete one of the following written projects that focuses on an immunological disorder or infectious disease: a research proposal, a case study, or a meta-analysis/systematic review. Each project is separated into six assignments, and each assignment is assessed through specifications (SPECS)-based grading and peer review where students have multiple attempts to improve their scores on each assignment. Approximately 40% of each student's grade is based on their ability to incorporate feedback from peers and instructors. Preliminary survey results suggest that students are eager to learn how to effectively incorporate peer and instructor feedback. Enhancing training in peer review will encourage students to embrace constructive criticism, which will be essential for their future careers. Initial findings indicate that students are positively engaging with the peer-review process, and the use of SPECS grading fosters a growth mindset. Continued research will further explore how this method can enhance students' confidence and skill in integrating feedback into professional scientific communication.

Engineered Mesenchymal Stem Cell-Derived Extracellular Vesicles Scavenge Self-Antigens for Psoriasis Therapy via Modulating Metabolic and Immunological Disorders.

Psoriasis is a chronic inflammatory dermatosis driven by excessive activation of the immune system. Recent studies have demonstrated the therapeutic potential of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) to psoriasis because of their immunomodulation functions. Yet, the outcome of MSC-EVs alone is still unsatisfactory and the underlying mechanisms are also unclear. Here, it is uncovered that arginase1 (Arg1)/polyamine is overexpressed in psoriasis patients and murine, inducing the in-situ accumulation of self-antigens. Engineered nor@MSC-EVs are fabricated by loading Arg1 inhibitor nor-NOHA into MSC-EVs for studying the therapeutic effect and mechanism of psoriasis. The nor@MSC-EVs exhibited profound suppression of the NF-κB signaling pathway by targeting Arg1/polyamine-mediated DCs/Th17 axis through scavenging self-antigens, resulting in superior mitigation of skin lesions and modulation of local and systemic metabolic and immunological disorders compared to the MSC-EVs and clinically used anti-IL17A both in vitro and in vivo. Together, the results highlight a novel perspective for psoriasis therapy by nor@MSC-EVs with broad clinical translational potential.

The Role of Immune Semaphorins in Sepsis-A Prospective Cohort Study.

In sepsis, a balanced pro-inflammatory and anti-inflammatory response results in the bacterial clearance and resolution of inflammation, promoting clinical recovery and survival. Semaphorins, a large family of secreted and membrane-bound glycoproteins, are newly recognized biomarkers and therapeutic targets in immunological and neoplastic disorders. Although semaphorins might also be a crucial part of host defense responses to infection, their role in sepsis is yet to be determined. This study aimed to analyze the association of serum semaphorin concentrations with sepsis severity and outcomes. Serum semaphorin concentrations (SEMA3A, SEMA3C, SEMA3F, SEMA4D, and SEMA7A) were measured in 115 adult patients with community-acquired sepsis and 50 healthy controls. While SEMA3A was decreased, SEMA3C, SEMA3F, SEMA4D, and SEMA7A were increased in sepsis patients. All analyzed SEMA showed good accuracy in identifying patients with sepsis. SEMA kinetics were related to sepsis complications; SEMA3A, SEMA3C, SEMA3F, and SEMA4D with respiratory failure; SEMA3C and SEMA7A with acute kidney injury; and SEMA3C and SEMA3F were related to septic shock. Importantly, SEMA3A, SEMA3C, SEMA4D, and SEMA7A were associated with 28-day mortality. In conclusion, we provide evidence that semaphorins are associated with sepsis course and outcomes.

The role of placenta Hofbauer cells during pregnancy and pregnancy complications.

Placental Hofbauer cells (HBCs) are specialized macrophages present in the human placenta that play a crucial role in maintaining a healthy pregnancy. These cells are derived from the fetal mesoderm and are responsible for various functions, including immune regulation, angiogenesis, and nutrient transport. In normal pregnancies, HBCs primarily exhibit an M2 or immunomodulatory phenotype, which helps maintain a tolerant and anti-inflammatory environment at the maternal-fetal interface. However, in pregnancies complicated by conditions such as immunological disorders, inflammation, or infection, the phenotype and function of HBCs may be altered. Although emerging evidence has highlighted the vital role of HBCs in both normal pregnancies and those with complications, such as chorioamnionitis, gestational diabetes, preeclampsia, and viral infections, their role remains unclear. Recent research also suggests a relationship between HBCs and the development of diseases in offspring. Understanding the role of HBCs in pregnancy could provide insights into the pathophysiology of various pregnancy-related disorders and offer potential therapeutic targets for improving maternal and fetal outcomes. This review explores the functions of HBCs in normal pregnancy and their involvement in complications, emphasizing their potential as biomarkers or targets for interventions aimed at reducing the incidence of adverse pregnancy outcomes. Additionally, we reviewed their potential for perinatal research in recent studies.

Advancements in Pediatric Allergology and Immunology

Pediatric allergology and immunology have emerged as a distinct subspecialty and addressed the necessity of studying allergic and immunologic disorders in the pediatric population, further progressing therapeutic regimens and treatment approaches, especially for children. The main objective of this study was to review the updates of the literature regarding the advancements of pediatric allergology and immunology. Main research engines were employed to extract the appropriate data. Literature showed the importance of this topic and its diagnosis and therapeutic approached.

A literature review of the use of daratumumab in non-neoplastic immunologic disorders

A literature review of the use of daratumumab in non-neoplastic immunologic disorders

Cesarean delivery and blood DNA methylation at birth and childhood: Meta-analysis in the Pregnancy and Childhood Epigenetics Consortium.

Children born via cesarean delivery have a higher risk of metabolic, immunological, and neurodevelopmental disorders compared to those born via vaginal delivery, although mechanisms remain unclear. We conducted a meta-analysis of epigenome-wide association studies to examine the associations between delivery mode and blood DNA methylation at birth and its persistence in early childhood. Participants were from 19 pregnancy cohorts (9833 term newborns) and 6 pediatric cohorts (2429 children aged 6 to 10 years). We identified six CpGs in cord blood associated with cesarean delivery (effect size range: 0.4 to 0.7%, P < 1.0 × 10-7): MAP2K2 (cg19423175), LIM2 (cg01500140), CNP (cg13917614), BLM (cg18247172), RASA3 (cg22348356), and RUNX3 (cg20674490), independent of cell proportions and other confounders. In childhood, none of these CpGs were associated with cesarean delivery, and no additional CpGs were identified. Delivery mode was associated with cell proportions at birth but not in childhood. Further research is needed to elucidate cesarean delivery's molecular influence on offspring health.

What Is New in Morphea-Narrative Review on Molecular Aspects and New Targeted Therapies.

Morphea, also known as localized scleroderma, is an autoimmune chronic connective tissue disease. It is characterized by excessive collagen deposition in the dermis and/or subcutaneous tissue. The etiopathogenesis of this disease is not fully understood, with endothelial cell damage, immunological disorders, extracellular matrix disorders and factors such as infection, trauma and other autoimmune diseases being considered. As medicine advances, there is increasing evidence that genetic factors play a significant role in disease risk and progression. In addition to environmental factors and genetic predisposition, epigenetic factors may be potential triggers for morphea. Epigenetics studies changes that affect gene expression without altering the DNA sequence, such as microRNAs, long non-coding RNAs or DNA methylation. Understanding the pathogenesis of this disease is key to identifying potential new treatments. There are anecdotal reports of good therapeutic effects following the use of biological drugs such as tocilizumab, a humanized IgG monoclonal antibody; abatacept, a recombinant soluble fusion protein; JAK inhibitors, such as tofacitinib and baricitinib; and a drug used successfully in cancer treatment, imatinib, a tyrosine kinase receptor inhibitor. In this article, we aim to review up-to-date knowledge on the pathogenesis of morphea, with particular emphasis on genetic and epigenetic factors. In addition, we present the new options of morphea treatment based on several case series treated with new drugs that are potential targets for the development of therapies for this disease.

Respiratory Syncytial Virus: A WAidid Consensus Document on New Preventive Options.

Background/Objectives: Respiratory syncytial virus (RSV) is a leading cause of respiratory infections, particularly affecting young infants, older adults, and individuals with comorbidities. Methods: This document, developed as a consensus by an international group of experts affiliated with the World Association of Infectious Diseases and Immunological Disorders (WAidid), focuses on recent advancements in RSV prevention, highlighting the introduction of monoclonal antibodies (mAbs) and vaccines. Results: Historically, RSV treatment options were limited to supportive care and the monoclonal antibody palivizumab, which required multiple doses. Recent innovations have led to the development of long-acting mAbs, such as nirsevimab, which provide season-long protection with a single dose. Nirsevimab has shown high efficacy in preventing severe RSV-related lower respiratory tract infections (LRTIs) in infants, reducing hospitalizations and ICU admissions. Additionally, new vaccines, such as RSVpreF and RSVpreF3, target older adults and have demonstrated significant efficacy in preventing LRTIs in clinical trials. Maternal vaccination strategies also show promise in providing passive immunity to newborns, protecting them during the most vulnerable early months of life. This document further discusses the global burden of RSV, its economic impact, and the challenges of implementing these preventative strategies in different healthcare settings. Conclusions: The evidence supports the integration of both passive (mAbs) and active (vaccines) immunization approaches as effective tools to mitigate the public health impact of RSV. The combined use of these interventions could substantially reduce RSV-related morbidity and mortality across various age groups and populations, emphasizing the importance of widespread immunization efforts.

Porto-sinusoidal vascular disorder with known etiologies had more severe portal hypertension and poorer outcomes

BackgroundPorto-sinusoidal vascular disorder (PSVD) is a clinicopathological entity and often associated with various etiologies. We aimed to compare the clinical and pathological features and outcomes of PSVD in patients with and without known etiologies in a Chinese cohort. MethodsThis retrospective study enrolled liver-biopsy confirmed patients with PSVD. Patients’ demographics, comorbidities, laboratory and imaging information were collected and the outcomes were followed up. ResultsTotally 128 patients with PSVD were included, with 75 (58.6 %) having known etiologies including prothrombotic conditions, immunological disorders, hematological disorders, drug exposure. PSVD patients with known etiologies exhibited significantly higher rates of gastroesophageal varices (87.0 % vs 54.0 %, p < 0.001), portosystemic collaterals (94.0 % vs. 58.0 %, p < 0.001), lower level of serum albumin (36.5 vs 40.0, p < 0.001), and a higher prevalence of portal vein thrombosis (PVT, 34.0 % vs 13.0 %, p = 0.010). During follow-up, PSVD patients with known etiologies had a significantly higher incidence of liver-related events (ascites, variceal hemorrhage or HE) (p = 0.027). ConclusionsPSVD with known etiologies had more severe portal hypertension, poorer liver function reserve, higher PVT prevalence, and worse clinical outcomes.

Regulatory T-cells: The Face-off of the Immune Balance.

Regulatory T-cells (Tregs) play a crucial role in maintaining immune homeostasis, ensuring a balanced immune response. Tregs primarily operate in an antigen-specific fashion, facilitated by their distinct distribution within discrete niches. Tregs have been studied extensively, from their point of origin in the thymus origin to their fate in the periphery or organs. Signals received from antigen-presenting cells (APCs) stimulate Tregs to dampen inflammation. Almost all tumors are characterized by a pathological abundance of immune suppression in their microenvironment. Conversely, the lack thereof proves detrimental to immunological disorders. Achieving a balanced expression of Tregs in relation to other immune compartments is important in establishing an effective and adaptable immune tolerance towards cancer cells and autoantigens. In the context of cancer, it is essential to decrease the frequency of Tregs to overcome tumor suppression. A lower survival rate is associated with the presence of excessive exhausted effector immune cells and an increased frequency of regulatory cells. However, when it comes to treating graft rejection and autoimmune diseases, the focus lies on immune tolerance and the transfer of Tregs. Here, we explore the complex mechanisms that Tregs use in human disease to balance effector immune cells.

Opportunities for Therapeutic Modulation of O-GlcNAc.

O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands of nucleocytoplasmic proteins. The installation and removal of O-GlcNAc is controlled by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, O-GlcNAc has been found on diverse classes of proteins, playing important functional roles in many cellular processes. Dysregulation of O-GlcNAc homeostasis has been implicated in the pathogenesis of disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, and immunological disorders. These foundational studies of O-GlcNAc in disease biology have motivated efforts to target O-GlcNAc therapeutically, with multiple clinical candidates under evaluation. In this review, we describe the characterization and biochemistry of OGT and OGA, cellular O-GlcNAc regulation, development of OGT and OGA inhibitors, O-GlcNAc in pathophysiology, clinical progress of O-GlcNAc modulators, and emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into O-GlcNAc function and inspire strategies for therapeutic modulation of O-GlcNAc.

Impact of bone marrow nucleated cell subfractions on transplant outcomes in patients with acute lymphoblastic leukemia

ABSTRACT Objectives Our previous study showed that a high pre-transplant nucleated cell count in the bone marrow is associated with increased non-relapse mortality (NRM) and decreased overall survival (OS) in patients with acute lymphoblastic leukemia (ALL) in remission. In this retrospective multicenter study, we aimed to examine the association between nucleated cell subfractions and transplant outcomes using the same patient cohort as our previous study. Methods This study included patients with ALL who underwent their first allogeneic hematopoietic stem cell transplantation (allo-HSCT) between 2010 and 2022. The patients were stratified into high and low cell group levels to compare transplant outcomes using cutoff values for predicting OS in each subfraction determined using receiver operating curves. Results In the cohort of 134 patients, the median values for myeloid, erythroid, monocyte, and lymphocyte series were 16,860/µL (468–229,296), 15,584/µL (34–246,992), 1,446/µL (70–25,296), and 4,215/µL (90–33,856), respectively. Discussion The univariate analysis showed that the groups with high levels of myeloid cells (≥38,000/µL, n = 48), erythroid cells (≥25,000/µL, n = 45), and monocyte cells (≥4,200/µL, n = 44) were all associated with worse 3-year OS and higher NRM than the low-level groups. These findings were confirmed by using multivariate analysis. The high cell count group showed a higher incidence of NRM associated with acute graft-versus-host disease or immunological disorders. Conclusion High myeloid, erythroid, and monocytic cell levels in the bone marrow before allo-HSCT may independently increase the risk of NRM and reduce OS.

Regulated GATA1 expression as a universal gene therapy for Diamond-Blackfan anemia.

Gene therapy using hematopoietic stem and progenitor cells is altering the therapeutic landscape for patients with hematologic, immunologic, and metabolic disorders but has not yet been successfully developed for individuals with the bone marrow failure syndrome Diamond-Blackfan anemia (DBA). More than 30 mutations cause DBA through impaired ribosome function and lead to inefficient translation of the erythroid master regulator GATA1, providing a potential avenue for therapeutic intervention applicable to all patients with DBA, irrespective of the underlying genotype. Here, we report the development of a clinical-grade lentiviral gene therapy that achieves erythroid lineage-restricted expression of GATA1. We show that this vector is capable of augmenting erythropoiesis in DBA models and diverse patient samples without impacting hematopoietic stem cell function or demonstrating any signs of premalignant clonal expansion. These preclinical safety and efficacy data provide strong support for the first-in-human universal gene therapy trial for DBA through regulated GATA1 expression.

Considerations in Paediatric and Adolescent Inflammatory Bowel Disease.

The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.