Background SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteitis) syndrome is a rare autoinflammatory disease. Paradoxical reactions and immune deviation following biologic therapy are occasionally observed in clinical practice; however, to our knowledge, no previous cases of paradoxical skin rash accompanied by Hyperimmunoglobulinemia E have been reported. Case presentation A 35-year-old male with SAPHO syndrome experienced significant exacerbation of palmoplantar pustulosis and a sharp increase in immunoglobulin E(IgE) levels following treatment with secukinumab and infliximab. After one month of upadacitinib therapy, the patient showed marked improvement in cutaneous lesions and bone pain, along with significant normalization of inflammatory markers and a pronounced reduction in IgE levels. Conclusion This case suggests that upadacitinib may be a valuable therapeutic option for patients with refractory SAPHO syndrome, particularly those presenting with paradoxical reactions or hypersensitivity. The unique mechanism of action of Janus kinase (JAK) inhibitors may offer superior efficacy in such cases, though further clinical validation and mechanistic studies are warranted.

Efficacy of Chinese herbal medicine in allergic rhinitis: a meta-analysis.

Objective To analyze the effect of plasma exchange on immune function in patients with hyperbilirubinemia of different severity after liver cancer surgery. Methods A total of 100 patients diagnosed with hyperbilirubinemia following liver cancer resection at Ganzhou People's Hospital from January 1, 2021 to December 31, 2024 were enrolled as the study participants. Using a random number table, they were assigned to either a control group (conventional drug therapy, n=50) or an observation group (conventional drug therapy+plasma exchange therapy, n=50). All patients were further categorized by hyperbilirubinemia severity as mild, moderate, or severe. The distribution within the control group was 12 (mild), 25 (moderate), and 13 (severe); the distribution within the observation group was 14 (mild), 24 (moderate), and 12 (severe). Fasting venous blood samples were collected from all participants to assess immune function and other indicators. Generalized estimating equation (GEE) models were used to analyze the differences in immune function indicators across different severity levels and between the two groups before and after treatment, as well as the interactive effects of time point, group, and disease severity on the relevant scores. Results Compared with the pre-treatment levles, the immune, liver, and coagulation function indicators in both groups were significantly improved after treatment. Before treatment, as hyperbilirubinemia severity increased from mild to severe, levels of immunoglobulin A (IgA), immunoglobulin G (IgG), immunoglobulin M (IgM), the Child-Pugh score for liver function, and the albumin-bilirubin (ALBI) score showed an upward trend, while the CD4+/CD8+ ratio showed a downward trend in both groups. After treatment, this trend persisted in both the control group and the observation group. Post-treatment comparisons between patients of the same severity level in the two groups showed that the observation group had significantly lower IgA, IgG, IgM, Child-Pugh, and ALBI score, and a significantly higher CD4+/CD8+ ratio than the control group. Furthermore, the magnitude of improvement in coagulation, liver, and immune function indicators was significantly greater in the observation group across all severity levels. The total clinical effectiveness rate was significantly higher in the observation group. GEE analysis showed that the levels of IgA, IgG, and IgM were significantly increased, while the CD4+/CD8+ ratio was significantly decreased with the increase in the severity of hyperbilirubinemia. The levels of IgA, IgG, and IgM were significantly decreased and the CD4+/CD8+ ratio was significantly increased after treatment. The decline in IgA, IgG, and IgM levels in the observation group was greater than that in the control group, and the increase in the CD4+/CD8+ ratio was also greater. The observation group demonstrated superior improvement in Child-Pugh and ALBI scores for patients with mild, moderate, and severe disease after treatment compared to the control group. Conclusion Plasma exchange therapy can effectively improve the immune, liver, and coagulation functions of patients with hyperbilirubinemia of different severity levels following liver cancer surgery, thereby offering significant clinical benefits.

Effects of dietary selenium nanoparticles and pennyroyal essential oil on growth performance, immune-biochemical and antioxidant parameters and disease resistance in Nile tilapia, Oreochromis niloticus.

This study investigates the effect of alpha-lipoic acid-loaded chitosan nanoparticles (ALA-CHNPs) on growth performance, feed utilization, and health in heat-stressed growing rabbits. A total of 125 healthy, 5-week-old rabbits were randomly assigned to five groups of 25. One group served as a thermoneutral control, while the other four groups were subjected to heat stress and received diets supplemented with 0, 100, 200, or 400 mg of ALACHNPs per kilogram, respectively. Dietary supplementation resulted in significant improvements in growth performance, feed conversion ratio, physiological responses, liver weight, and dressing percentage. Supplementation with ALA-CHNPs resulted in a linear reduction in liver enzymes activities, as well as in the levels of total bilirubin, hydrogen peroxide, glutathione, catalase, superoxide dismutase, immunoglobulin G, lysozyme activity, interleukin (IL)-6 and IL-10. No significant differences were observed between the ALA-CHNPs200 and ALACHNPs400 groups (p>0.05). The levels of blood serum total protein, albumin, globulin, total antioxidant capacity, glutathione peroxidase activity, immunoglobulin A and M, and nitric oxide showed a quadratic increase, reaching a peak at ALA-CHNPs doses ranging from 250-300 mg/kg diet. Conversely, the concentrations of triglycerides, cholesterol, glucose, malondialdehyde, interferon-gamma, tumor necrosis factor-alpha, and nuclear factor kappa B exhibited a quadratic decrease, with optimal reductions observed at doses between 250-300 mg/kg diet. Supplementation with ALA-CHNPs reduced liver damage caused by heat stress, restoring normal hepatic morphology. The hydrophobic interactions of ALA with antioxidant enzymes and cytokines contributed to the reduction of heat stress-induced oxidative stress. The inclusion of 250-300 mg ALA-CHNPs/kg diet enhanced growth performance, redox balance, immune function, and inflammatory response in fattened rabbits raised during the summer season.

Chronically elevated cortisol levels increase cognate pathogen load but reduce red mark syndrome pathology in rainbow trout (Oncorhynchus mykiss).

Longitudinal MuSK antibody levels may correlate with disease severity in MuSK myasthenia gravis.

Primary immunodeficiencies (PIDs) are rare disorders caused by immune system defects that are commonly screened using multi-parameter flow cytometry (FCM). To counter the subjective and time-consuming manual data analysis of FCM data, we present PIDgeon, a fully automated computational pipeline based on artificial intelligence (AI) techniques. PIDgeon is designed to characterize PID immune profiles, suggest PID subtypes based on altered immune profiles, age, and immunoglobulin levels, and generate interpretable reports. The PIDgeon pipeline, including FlowSOM and extreme gradient boosting models, was trained and tested on standardized FCM data generated according to EuroFlow procedures on 74 healthy controls and 399 patients (281 lymphoid-PID patients and 118 non-PID diseased controls) collected by the Ghent University Hospital. Subsequently, multi-centric validation was performed on internal (n = 211) and external (n = 338) independent data sets collected across 4 EuroFlow centers. Validation demonstrated high accuracy in cell count enumeration, achieving correlation scores above 0.90 for the major lymphocyte subsets. Interestingly, PIDgeon showed high sensitivity (93% to 100%) in predicting PID with severe T-cell defects, such as severe combined immunodeficiency and late-onset combined immunodeficiency, and low false-negative rates (1.5% to 5.4%) for distinguishing other lymphoid-PID vs non-PID diseased controls across data sets. Additionally, PIDgeon gives a first hint toward prediction of subtypes of primary antibody deficiencies, such as common variable immunodeficiency. In summary, PIDgeon is an accessible and explainable AI-pipeline aligned with current clinical needs, aiding laboratory immunologists in early PID diagnostics and increasing data analysis efficiency.

The periparturient period in mares is metabolically demanding and requires optimal nutrition to support maternal health and fetal development. Vitamin D 3 , particularly its metabolite 25(OH)D 3 , plays crucial roles beyond bone health, including immune and antioxidant functions. This study investigated the effects of supplementing pregnant and lactating mares with 25-hydroxyvitamin D 3 (25(OH)D 3 ) at a dose of 120,000 IU/day during late gestation and early lactation. Twelve Yili horses were randomly divided into two groups of six, matched by gestation and foaling date. One group received a standard diet, while the other was supplemented with 120,000 IU/day of 25(OH)D 3 for 60 days (30 days before and 30 days after birth). Serum and milk samples were collected at the start and midpoint (days 0 and 30) for analysis of 25(OH)D 3 , mineral concentrations (calcium and phosphorus), proteins, lipids, antioxidants, immunoglobulins, and cytokine levels. The supplementation significantly elevated serum and milk concentrations of 25(OH)D 3 , calcium, phosphorus, glucose, total protein, and globulin, whereas bilirubin levels diminished in both mares and foals ( P < 0.05). In supplemented mares, milk fat percentage, protein content, and immunoglobulin levels (IgA, IgG, and IgM) were elevated ( P < 0.05). Improvements were observed in immunoglobulin levels, inflammatory markers, and antioxidant capacity in the supplemented group ( P < 0.05). In conclusion, 25(OH)D 3 supplementation in pregnant and lactating mares enhanced serum and milk nutrient levels, decreased bilirubin levels, and increased immunoglobulin levels. It also boosted antioxidant capacity and immunoglobulin levels and reduced cytokine levels in both mares and foals.

Hyper-IgE syndromes (HIES) are rare primary immunodeficiency disorders characterised by markedly elevated serum immunoglobulin E (IgE) levels, recurrent cutaneous and respiratory infections, and variable multisystem involvement. They arise from mutations in genes central to immune signalling pathways, most notably STAT3 in autosomal dominant HIES (AD-HIES) and DOCK8 in autosomal recessive HIES (AR-HIES). The first case, an 11-month-old boy with recurrent staphylococcal skin infections, sepsis, eosinophilia and an IgE level of 9,867 IU/ml, was found on whole-exome sequencing to have a heterozygous STAT3 mutation, confirming AD-HIES. The second case, a 2-year-old boy with severe atopic dermatitis, recurrent wheezing, repeated pneumonias and an IgE level exceeding 100,000 IU/ml, was diagnosed with AR-HIES due to a homozygous DOCK8 mutation. These cases highlight the distinct clinical patterns of the two forms: AD-HIES commonly presents with non-immunologic features such as skeletal and dental anomalies, whereas AR-HIES is associated with severe viral infections, profound IgE elevation and higher mortality. Early recognition through clinical suspicion and genetic confirmation is essential, as management requires multidisciplinary care, prophylactic antimicrobial strategies and, in severe DOCK8 deficiency, consideration of haematopoietic stem-cell transplantation.

Sarcoidosis is a systemic disease of unknown etiology, characterized by granulomatous inflammation in various organs. Elevated serum Immunoglobulin G4 (IgG4) levels are typically associated with IgG4-related disease (IgG4-RD), characterized by plasma cell infiltration and fibrosis, but their role in sarcoidosis remains unclear. Given the fibro-inflammatory nature of both conditions, this study aimed to describe a cohort of sarcoidosis patients with elevated IgG4 levels and explore the potential clinical relevance of this finding. We retrospectively analyzed biopsy-confirmed sarcoidosis cases with measured serum IgG4 levels. Clinical data were gathered, including demographics, organ involvement, pulmonary function tests (PFTs), sarcoidosis-associated pulmonary hypertension (SAPH), and markers of autoimmunity. The study cohort included ten patients with a mean age of 50 ± 15 years, comprising six males and seven Black individuals. Two patients reported a family history of sarcoidosis; the mean body mass index (BMI) was 28.5 ± 5.7. Five patients were never smokers, and four were former smokers. Eight patients had lung involvement, two with advanced Scadding stage 4, four with airflow obstruction, and two with restriction physiology on PFT. Out of seven patients with echocardiography, five had SAPH. Other organ manifestation included ocular disease in three patients, joint involvement in two, liver disease in two, and heart disease in one. Autoimmune markers were present in five patients. These findings suggest a potential overlap between IgG4-RD and sarcoidosis. Further research is needed to clarify IgG4's role in sarcoidosis and whether elevated serum IgG4 identifies a subset of patients who may benefit from B-cell depletion therapies.

Patients with 22q11.2 deletion are known to have immune abnormalities. Data on the immune profile of non-syndromic patients with conotruncal heart defects are limited. A prospective study evaluated the genetic and immunological profiles and early to mid-term postoperative outcomes of patients with conotruncal heart defects. Infants with 22q11.2 deletion had low leukocyte counts, while low total lymphocyte counts were observed in all patients except infants without a genetic syndrome. Reduced CD3+, CD4+, and CD8+ cells were found in 22q11.2 deletion neonates and infants, as well as in infants without a genetic syndrome. Immunoglobulin G, M, and A abnormalities occurred across all groups. T cell receptor excision circle levels were lowest in patients with complex heart defects. Kappa-deleting recombination excision circle levels were increased in patients without a genetic syndrome. Early postoperative infections were frequent in all groups. Neonates with 22q11.2 deletion had longer ICU stay and higher need for antibiotics and hospital readmission at 3 and 6 months of follow-up. Neonates and infants with conotruncal heart defects have low preoperative T lymphocyte counts, reduced T cell receptor excision circle and immunoglobulin levels, and high incidence of postoperative infections. Higher kappa-deleting recombination excision circle levels compensated the T cell disbalances in patients without a genetic syndrome. The presence of a 22q11.2 deletion with conotruncal heart defects was associated with prolonged mechanical ventilation, longer ICU length of stay, higher need for antibiotic treatment after discharge from the hospital, and readmission risk in neonates after cardiac surgery.

The sole approved treatment for egg allergy is abstaining from consuming eggs. We assessed the effectiveness of oral immunotherapy (OIT) utilizing egg-white powder to treat egg allergy in children. This is a randomized clinical trial on patients with egg white allergy. A desensitization protocol for egg allergies involves a modify rush desensitization method with a build-up and maintenance phase. During the build-up phase, patients consume increasing doses of egg white powder mixed with mashed potatoes for 5-7 days until they can tolerate a whole egg white. During the maintenance phase, patients consume a daily intake of whole cooked egg whites for six months. After two weeks of abstinence, a food challenge test is administered to determine if the patient has developed tolerance. Thirty-two patients aged 4-7 years with egg white hypersensitivity were recruited. Sixteen participants were in the intervention group, and 16 were in the control group. The intervention group had the highest number of anaphylaxis reactions on day one. During the build-up phase, all patients in the intervention group experienced 60 responses, with skin reactions being the most common. In the maintenance phase, patients were prescribed medications to ensure the success of desensitization. After six months, the intervention group demonstrated a higher tolerance rate for egg whites compared to the control group. Before OIT, the levels of total immunoglobulin E (IgE), serum immunoglobulin G4 (IgG4), and Radioallergosorbent Test (ImmunoCAP RAST) were similar between the intervention and control groups. After OIT, the level of IgG4 increased in the intervention group and decreased in the control group. ImmunoCap RAST increased in both groups, but significantly more in the intervention group. Skin Prick Test (SPT) wheal decreased significantly in the intervention group but not in the control group. The size of the SPT flare significantly decreased in the intervention group but remained the same in the control group. OIT is adequate for most children with egg allergies. It is a promising intervention for food allergies, but the mechanism underlying its efficacy remains unclear. A better understanding of risks and effective dosing schedules is needed for it to become a recommended standard of care. Long-term immune tolerance strategies are also critical. (No. IRCT20190116038387N1).

Background/Objectives: Branched-chain fatty acids (BCFAs) exhibit a range of biological activities; however, their limited natural abundance and high cost have constrained in vivo research. Lanolin represents a promising source for enriching BCFAs. Nevertheless, the in vivo application, safety, and dose-effect relationship of BCFAs derived from lanolin (BCFAs-DFL) remain unassessed. Methods: In this study, the acute toxicity in C57BL/6J mice was first evaluated for 7 days by a single oral administration of 5000 mg/kg BW of BCFAs-DFL. Subsequently, 40 mice were divided into four groups (control group, low dose of 100 mg/kg BW, medium dose of 300 mg/kg BW, and high dose of 600 mg/kg BW) and were continuously administered by gavage for 28 days to study the effects of BCFAs-DFL on the growth, blood biochemistry, intestinal morphology, and intestinal flora of the mice. Results: In the acute toxicity test, BCFAs-DFL exhibited no lethality or abnormalities in mice, indicating its non-toxic nature. Throughout the 28-day trial, mice in the medium- and high-dose groups experienced a notable decrease in average daily feed intake (p < 0.05), yet their weight gain remained unaffected (p > 0.05). Hemoglobin and hematocrit levels declined in the high-dose group (p < 0.05). Conversely, serum aspartate aminotransferase and total bilirubin levels escalated in the medium- and high-dose groups, while triglycerides and urea nitrogen levels decreased (p < 0.05). The serum’s total antioxidant capacity and immunoglobulin levels (IgA, IgG) rose in proportion to the dosage (p < 0.05). BCFAs-DFL notably enhanced the villus height of the jejunum and ileum in mice (p < 0.05). Gut microbiota analysis indicated no significant impact on overall α and β diversity. Conclusions: The 28-day intervention revealed that BCFAs-DFL can modulate feeding behavior, TG, T-AOC, and immunoglobulin levels in mice. Additionally, it promotes the development of intestinal villi. Based on various indicators, a dosage of 100 mg/kg BW effectively induces beneficial metabolic regulation, such as the reduction of triglycerides, without causing a burden on liver metabolism. This dosage may represent a more suitable application for potential use.

Apple pomace, a major by-product of juice production, represents both an environmental burden and an underutilized resource. This study aimed to enhance the nutritional value of apple pomace via solid-state fermentation (SSF) to develop a functional feed ingredient and systematically evaluate its effects on growth, metabolism, and intestinal health in weaned piglets. Apple pomace was fermented using a multi-species consortium (Geotrichum candidum, Saccharomyces cerevisiae, Rhizopus oryzae, Bacillus subtilis, and Trichoderma viride). A total of 180 weaned piglets were fed iso-nitrogenous diets containing 0, 2, 4, 6, 8, or 10% fermented apple pomace for 35 days. Growth performance, serum biochemical and immuno-antioxidant indices, diarrhea incidence, jejunal morphology, and fecal microbiota were analyzed. Dietary fermented apple pomace supplementation showed dose-dependent effects. The 8% fermented apple pomace group exhibited optimal growth performance, with increased average daily gain and feed intake and reduced feed-to-gain ratio (p < 0.05). Serum analysis indicated enhanced protein synthesis, antioxidant capacity (T-AOC, SOD, GSH-Px), and immunoglobulin levels (IgA, IgG, IgM), along with reduced urea nitrogen and oxidative stress marker MDA. This group also had the lowest diarrhea rate, associated with improved jejunal villus morphology. Microbiota analysis revealed that 8% fermented apple pomace effectively increased α-diversity, promoted beneficial bacteria (e.g., lactic acid bacteria and butyrate-producing Clostridium sensu stricto_1), and suppressed pathogens (Escherichia coli, Salmonella, Streptococcus). Multi-species SSF successively enhanced the nutritional profile of apple pomace. Inclusion at 8% showed the most favorable response in terms of growth performance, metabolic profile, and immune-antioxidant status in weaned piglets, mediated through improved intestinal morphology and targeted modulation of the gut microbiota toward a more diverse and beneficial ecosystem. These findings support the high-value, functional utilization of apple pomace as a feed additive in swine nutrition.

The gut microbiota plays an essential role in mucosal immunity, with secretory immunoglobulin A (IgA) acting as a key effector in neutralizing pathogens and maintaining host-microbiota homeostasis. IgA production occurs via T cell-dependent (TD) and -independent pathways, with T follicular helper (Tfh) cells driving high-affinity, antigen-specific IgA responses. However, the specific microbial taxa and metabolites that regulate Tfh-mediated IgA responses under steady-state conditions remain poorly understood. This study investigated how gut microbiota-derived signals shape Tfh responses and IgA production, with implications for enhancing mucosal vaccine efficacy. We demonstrate that Peyer's patches (PP)-derived Tfh cells exhibit superior IgA-inducing capacity compared to splenic Tfh cells. RNA sequencing revealed distinct transcriptional profiles in PP-Tfh cells, including upregulation of the genes associated with Tfh differentiation and activation (Bcl6, Cd40lg, Maf), T-B cell interactions (Il21, Sh2d1a, Fyn), and migration (Ccr6, Cxcr5). Functionally, PP-Tfh cells formed larger T-B cell contact areas and induced significantly higher IgA secretion in co-culture than their splenic counterparts. Microbiota depletion experiments revealed that eliminating neomycin-depleted bacteria reduced fecal IgA levels and diminished PP-Tfh cell frequencies. Fecal microbiota transplantation from neomycin-treated mice restored both IgA production and Tfh responses in germ-free (GF) mice. Bioinformatic analysis (PICRUSt2 and LEfSe) identified butyrate-producing Lachnospiraceae and Ruminococcaceae as key drivers of the Tfh-IgA axis. Butyrate supplementation enhanced Tfh differentiation and IgA⁺ germinal center B cell development in vitro and increased fecal IgA levels in vivo. Mechanistically, butyrate promoted IgA production via GPR43 signaling, as its effect was lost in co-cultures with Gpr43⁻/⁻ Tfh cells. Moreover, treatment with tributyrin, a butyrate prodrug, enhanced vaccine-induced IgA and protected mice against Salmonella Typhimurium infection, reducing bacterial burden and tissue damage. These findings define a functional microbiota-Tfh-IgA axis sustained by neomycin-depleted, butyrate-producing bacteria. Our study underscores the crucial role of the gut microbiota, particularly neomycin-depleted butyrate producing taxa, in regulating PP-Tfh cell function and IgA production. Butyrate emerges as a metabolite linking microbial metabolism to Tfh differentiation and IgA class switching. Together, these findings establish a microbiota-metabolite-Tfh cell axis essential for mucosal immune homeostasis and suggest novel strategies for enhancing vaccine efficacy and protection against enteric infections. Video Abstract.

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare, autosomal recessive primary immunodeficiency, with fewer than 120 cases reported worldwide. ICF type 1 (ICF1) is the most prevalent subtype. Despite its rarity, ICF1 presents a distinct set of clinical features that necessitate increased awareness, particularly in populations with high rates of consanguinity. This case presents a two-year-old Palestinian boy born to consanguineous parents who presented with recurrent respiratory tract infections, facial dysmorphisms, and hypogammaglobulinemia. A comprehensive immunologic evaluation confirmed markedly reduced immunoglobulin levels consistent with an antibody deficiency. Genetic testing identified a homozygous missense mutation in DNMT3B (Arg826Cys), establishing the diagnosis. The patient was started on intravenous immunoglobulin (IVIG) replacement therapy, which was well tolerated and led to a noticeable reduction in infection frequency and an overall clinical well-being improvement. While treatment remains supportive, early recognition and immunologic management can significantly reduce morbidity. This case highlights the importance of early diagnosis and immunologic support in ICF1 syndrome, reinforces genotype–phenotype correlations, and provides valuable insights from an underrepresented region to improve global awareness, diagnosis, and care, being only the second genetically confirmed case from Palestine.

In a prospective cohort from the Tampa Bay region (2016-2020), patients with autoimmune cytopenia (AIC) were evaluated to identify cellular and serum biomarkers that distinguish those with underlying inborn errors of immunity (IEI). Clinical phenotype and genetic causes of IEI were assessed using targeted panel-based sequencing. Unique lymphocyte subsets, including activated naïve and transitional B cells, CD19hiCD21lo B cells, follicular helper T (TFH) cells, regulatory T (Treg) cells, and TCRαβ+CD4-CD8- double-negative T cells (DNTαβ), were assessed by flow cytometry. Serum levels of lipopolysaccharide (LPS), B-cell activating factor (BAFF), and soluble IL-2 receptor (sIL2R) were quantified by ELISA. Among 104 AIC patients, 53 (51%) showed evidence of IEI, including 27 (26%) with monogenic disorders-most commonly partial DiGeorge syndrome (pDGS), followed by variants in NFKB1, CTLA4, and FAS. The prevalence of IEI was highest in autoimmune hemolytic anemia (AIHA) (62.5%) and Evans syndrome (61.5%). Low levels of IgG, IgA, and IgM, as well as reduced percentages of naïve CD4+ and CD8+ T cells, were significantly associated with increased odds of IEI. In AIC-IEI patients, transitional B cells, CD19hiCD21lo B cells, and TFH cells were expanded, accompanied by elevated serum levels of BAFF and sIL2R. Quantitative immunoglobulin levels and naïve T cells remain valuable indicators of IEI in AIC. Our findings highlight the diagnostic value of emerging cellular and serum biomarkers in identifying IEI, including dysregulation of early B-cell subsets (transitional B cells and CD19hiCD21lo B cells), expansion of TFH cells, and elevated levels of BAFF and sIL2R.

Immunological responses to tetanus, diphtheria, pertussis (Tdap) vaccine in Brazilian hematopoietic stem cell transplant recipients.

The recombination activating gene 1 (RAG1) is essential for V(D)J recombination and lymphocyte development. While biallelic null RAG1 mutations cause severe combined immunodeficiency (SCID), hypomorphic variants have increasingly been associated with immune dysregulation and hematologic malignancies. This study aimed to present a pediatric case of Epstein-Barr virus (EBV)-negative Burkitt lymphoma carrying a novel homozygous RAG1 variant and to discuss its potential association with immune function and malignancy risk. A 9-year-old Turkish male from a consanguineous family was evaluated for hereditary cancer predisposition. Clinical, immunologic, and genetic assessments were performed, including whole-exome sequencing (WES), Sanger validation, and mRNA expression analysis. The patient presented with cervical lymphadenopathy and was diagnosed with EBV-negative Burkitt lymphoma; he had no recurrent infections, abnormal vaccine reactions, or SCID-related features. Immunologic testing, including lymphocyte subsets and immunoglobulin levels, was within normal limits. WES identified a homozygous RAG1 variant (NM_000448.2:c.460C>T; p.Leu154Phe), predicted to be deleterious and absent from population databases. Both the patient and his healthy dizygotic twin were homozygous, while parents were heterozygous carriers. RAG1 mRNA expression was reduced in heterozygotes but similar in homozygous and wild-type individuals; enzymatic activity was not assessed. The patient responded to chemotherapy and remains in remission under follow-up. In conclusion, this case expands the phenotypic spectrum of hypomorphic RAG1 variants to include EBV-negative Burkitt lymphoma without overt immunodeficiency, suggesting a possible link between partial RAG1 dysfunction and pediatric lymphoma susceptibility.