bims-conane 2025-12-14 papers

Cureus. 2025 Nov;17(11): e96168

Confounding Factors in the Diagnosis of Hereditary Spherocytosis and Gallstone Formation in Related Hemolytic Disorders From a Tertiary Care Center in North India.

Rizwan Athar, Rajesh Kashyap, Jalaj Gupta.

INTRODUCTION: Gallstones are a significant complication in individuals with hereditary spherocytosis (HS) and related hemolytic disorders. Chronic hemolysis leads to elevated bilirubin levels, a precursor for pigment gallstone formation. Despite advancements in understanding HS, the mechanisms driving gallstone pathogenesis remain incompletely understood, particularly in the presence of genetic factors such as Gilbert syndrome, beta-thalassemia trait, and G6PD deficiency.
OBJECTIVE: This study aims to investigate gallstone patterns in individuals with HS and related hemolytic conditions, focusing on the role of genetic, metabolic, and clinical factors in gallstone development.
MATERIALS AND METHODS: A five-year prospective observational study was conducted on 100 patients with HS and related conditions. Clinical, hematological, biochemical, and genetic data were analyzed. Gallstone presence was confirmed via ultrasonography. Correlations between gallstone incidence and various parameters, including bilirubin levels, hemoglobin (Hb) levels, spleen size, and genetic predisposition, were assessed. Statistical significance was determined using chi-square correlation and regression analyses.
RESULTS: Gallstones were present in 42% of the cohort, with increased incidence in participants with homozygous Gilbert syndrome (28%) compared to heterozygous individuals (20%; p = 0.04). Hb levels <12.5 g/dL were significantly associated with gallstone presence (71%; p < 0.05). Elevated total bilirubin correlated positively with gallstones (r = +0.63; p < 0.001), while increased spleen size showed a strong negative correlation (ρ = -0.744; p < 0.001).
CONCLUSIONS: The development of gallstones in hemolytic disorders involves a multifactorial interplay of hemolysis, bilirubin metabolism, and genetic factors. Homozygous Gilbert syndrome significantly increases the susceptibility to gallstones, highlighting the importance of genetic screening in at-risk patients.

Keywords: beta-thalassemia; bilirubin; g6pd deficiency; hemolysis; ultrasonography

DOI: https://doi.org/10.7759/cureus.96168

Eur J Haematol. 2025 Dec 07.

Pubertal Assessment and Growth in Patients With Hemoglobinopathies: A Longitudinal Multicenter Study on the Association With Ferritin Levels.

OBJECTIVES: Although Advancements in the Treatment of Hemoglobinopathies have Considerably Increased Life Expectancy, Hormonal and Pubertal Development Have Been Continuously Affected by Complications From Transfusion-Related Iron Overload and Cytotoxic Therapies. This Study Investigated the Association Between Serum Ferritin Levels and Pubertal Progression in Patients With Thalassemia and Sickle Cell Disease (SCD).
METHODS: Data Collected From 10 Hospitals in Austria, Germany, and Switzerland From 2012 to 2020 Were Retrospectively Analyzed. We Enrolled 140 Individuals (Median Age: 16.5 Years) With Thalassemia or SCD.
RESULTS: Overall, Delayed Puberty Was Observed in 14.7% (6.7% Females; 21.1% Males) and 13.2% of Patients With Thalassemia and SCD (6.9% Females; 20.8% Males), respectively. Gonadal Insufficiency Was Found in 13.3% and 8.6% of Females With Thalassemia and SCD, Respectively. Abnormal Growth Trajectories Were Observed in 32.5% (28.5% Females; 36.8% Males) and 18.7% of Patients With Thalassemia and SCD (13.3% Females; 23.5% Males), respectively. A Statistically Significant Association Was Found Between Elevated Ferritin Levels and Growth Delays in Patients With Thalassemia. Notably, Tanner Staging Data Were Missing in 80.7% of the Medical Records.
CONCLUSIONS: Our Results Indicated the Need for Comprehensive Pubertal Screening and Underscored the Importance of Robust Endocrine Follow-Up Care in Individuals With Hemoglobinopathies.

Keywords: chronic transfusion; hemoglobinopathies; iron overload; puberty

DOI: https://doi.org/10.1111/ejh.70075

PLoS Biol. 2025 Dec;23(12): e3003512

When two signals are better than one: Synergistic control of erythropoiesis.

Nicola K Wilson.

Red blood cell production is one of the most dynamic processes, yet the underlying mechanisms responsible are only partially understood. A new study in PLOS Biology suggests a broadly applicable mechanism able to balance the maintenance of the steady-state and effective stress response.

DOI: https://doi.org/10.1371/journal.pbio.3003512

PLoS Biol. 2025 Dec;23(12): e3003462

IL-17 stimulates erythropoiesis in vivo by amplifying the response of erythroid progenitors to erythropoietin.

Qiu C Wu, Aishwarya Swaminathan, Ashley Winward, Logan Lalonde, Yung Hwang, Noah Littman, Merav Socolovsky, Allon M Klein.

Red blood cell production is regulated by erythropoietin (Epo), maintaining tissue oxygen tension in the steady state and in response to stress. To date, only a handful of factors other than Epo are known to stimulate erythropoiesis, limiting therapeutic options. We recently found that IL-17, a pleiotropic pro-inflammatory cytokine, interacts synergistically with Epo to increase formation of erythroid colonies in vitro. Here, we administered IL-17 to mice to determine whether it accelerates erythropoiesis in vivo. We found that while IL-17 alone had little effect on erythroid and other hematopoietic lineages, combined treatment with both IL-17 and Epo generated a specific and strong synergistic response in erythroid progenitors that significantly increased erythropoietic rate. IL-17 administration also accelerated the erythropoietic response of mice to hypoxia. Single-cell transcriptomic analysis showed that IL-17 acts by sensitizing erythroid progenitors to Epo, rather than through a distinct transcriptional response. Using a dynamical model, we propose that this mechanism optimizes conflicting requirements in the regulation of erythropoiesis, balancing the need for low-cost maintenance of the steady state, with a sufficiently fast stress response. Further, our findings suggest a potentially broadly applicable mechanism whereby pleiotropic cytokines are able to exert lineage-specific effects when their actions are dependent on synergism with lineage-specific factors.

DOI: https://doi.org/10.1371/journal.pbio.3003462

Immunology. 2025 Dec 12.

Unravelling the Immunological Enigma of Sickle Cell Disease: Current Understanding and Future Directions.

Sumit Jamwal, Cecelia Calhoun, Subhasis Mohanty, Ruth R Montgomery, Lakshmanan Krishnamurti, Albert C Shaw, Inci Yildirim.

Sickle cell disease (SCD) is caused by a mutation in the β-globin gene, resulting in abnormal haemoglobin S (HbS). Beyond genetic mutation, dysregulation of immune-related genes such as those regulating NF-κB signalling, inflammasome activation and type I interferon responses exacerbates the inflammatory milieu and drives many of the complications observed in SCD. Chronic inflammation, linked to disease severity, highlights the crucial role of the immune system in SCD pathophysiology. Immune dysregulation in SCD leads to chronic inflammation, heightened infection risk and possible autoimmune reactions. Immune dysregulation is driven by splenic damage and pro-inflammatory cytokines from sickled red blood cells. While progress has been made studying innate immune cell roles, the adaptive immune system's contributions remain poorly understood. T-cell abnormalities in SCD highlight the complexity of adaptive immune responses. Alterations in T-cell counts, shifts in Th1/Th2 responses and changes in regulatory T-cell behaviour reflect immune dysregulation, further contributing to chronic inflammation and disease progression. While studies have focused on polyclonal T-cell phenotyping, antigen-specific T-cells, crucial for immune activation, remain underexplored. Focusing on antigen-specific T-cell responses will deepen our understanding of adaptive immune dysfunction in SCD and aid in developing targeted therapies to manage the disease. Furthermore, there is significant impairment in the B cell compartment in SCD, including reduced B cell proliferation, fewer memory B cells and abnormalities in class-switching memory B cells. These defects weaken antigen-specific immune responses, mainly by lowering IgM-secreting memory B cells, essential for early defence against infections. The loss of these cells also diminishes vaccine effectiveness, leaving patients more vulnerable to infections. Additionally, impaired memory B cell differentiation and class switching contribute to an increased risk of infections and autoimmune complications, highlighting the need for targeted immune therapies in the management of SCD. This review highlights the need to explore dysregulation in innate and adaptive immune mechanisms in SCD. Investigating T and B cell dysfunctions, especially antigen-specific immune activation, is crucial for developing immune-targeted therapies and improving vaccine responses, ultimately advancing treatments and enhancing the quality of life and survival for SCD patients.

Keywords: T‐cell and B‐cell; haemoglobin; red blood cells; sickle cell disease; vaso‐occlusive crisis

DOI: https://doi.org/10.1111/imm.70080

Ann Hematol. 2025 Dec 13.

Importance of the 3'UTR region in globin synthesis: identification of two novel HBA1 mutations causing α-Thalassemia.

Sara Ferrer Benito, Mariola Abío, Eduardo J Bardón-Cancho, Jorge M Nieto, Belén Ortega, F A González, Ana Villegas, Celina Benavente, Paloma Ropero.

Alpha-thalassemia is primarily caused by large deletions in the HBA1 and HBA2 genes, but a minority of cases result from non-deletional mutations, including variants in untranslated regions (UTRs) that affect mRNA regulation. The 3'UTR is crucial for post-transcriptional control, influencing mRNA stability, localization, and translation via binding elements for RNA-binding proteins and microRNAs. We describe two patients with persistent microcytosis and normal iron levels. Standard hematological analyses were complemented by high-performance liquid chromatography (HPLC) and capillary electrophoresis to rule out common hemoglobinopathies. Molecular analysis was performed using multiplex PCR and direct sequencing of the HBA1 3'UTR. Patient 1, a 3-year-old Nigerian boy, carried a novel insertion mutation (HBA1:c.*119_120insT) five nucleotides downstream of the transcription termination signal. Patient 2, a 31-year-old Moroccan woman, exhibited a missense variant (HBA1:c.*150C > A) located 40 nucleotides downstream of the TTS. Both variants are located within regulatory regions of the HBA1 3'UTR. In silico analyses suggest disruption of RNA secondary structure, impaired interactions with HuR and AUF1 proteins, altered microRNA binding (e.g., miR-16-5p), and potential interference with polyadenylation signals, resulting in mRNA instability and reduced alpha-globin synthesis. These two novel mutations in the 3'UTR of HBA1 expand the spectrum of non-deletional alpha-thalassemia variants and highlight the importance of regulatory regions in globin gene expression. Their inclusion in routine molecular screening may enhance diagnostic accuracy in cases of unresolved microcytic anemia.

Keywords: 3′UTR; Alpha-thalassemia; HBA1; Microcytosis; Non-coding variants; Post-transcriptional regulation; mRNA stability

DOI: https://doi.org/10.1007/s00277-025-06624-3