Blog

Mol Ther. 2025 Mar 28:S1525-0016(25)00220-5. doi: 10.1016/j.ymthe.2025.03.045. Online ahead of print.

ABSTRACT

Primary Immunodeficiency Diseases (PIDs) are associated with multiple genetic alterations including mutations of the LPS responsive Beige anchor (LRBA) gene. Nonsense mutations in the LRBA gene resulting in premature termination codons cause the loss of LRBA protein expression in PID. We evaluated the impact of a translational readthrough-inducing drug (TRID) ataluren as a nonsense suppression therapy in a PID patient with a homozygous stop codon mutation in exon 30 of LRBA. A precision medicine approach allowed us to pass from “in silico” to “in vitro” to the “bedside”: following the in vitro treatment of patient-derived primary fibroblasts with ataluren, we observed a restoration of the LRBA protein expression and localization. In silico predictions suggested LRBA retained function after readthrough. Based on the successful experimental and computational results we treated the patient with ataluren resulting in an improvement of his clinical symptoms and quality of life. Importantly, the clinical symptoms were associated with a recovery of LRBA expression in liver biopsies post-treatment compared to pre-treatment. Our results provide a proof-of-concept demonstrating that ataluren, can rescue LRBA expression in PID. This work highlights the potential for personalized precision medicine approaches to be exploited for different genetic diseases due to premature termination codons.

PMID:40158206 | DOI:10.1016/j.ymthe.2025.03.045

Immunol Lett. 2025 Mar 27:107005. doi: 10.1016/j.imlet.2025.107005. Online ahead of print.

ABSTRACT

INTRODUCTION: The CARD11 (Caspase Recruitment Domain Family Member 11) gene encodes a scaffold protein critical for NF-κB signaling, regulating B-cell differentiation and T-cell effector functions. Gain-of-function (GOF) mutations in CARD11 cause BENTA disease (B cell Expansion with NF-κB and T cell Anergy), an autosomal dominant disorder typically presenting with early-onset polyclonal B-cell lymphocytosis, splenomegaly, lymphadenopathy, and recurrent infections.

METHODS: We describe three related patients harboring a novel CARD11-GOF mutation (D357E), presenting with a BENTA phenotype with atypical features, including high IgM levels and a normal B-cell count, with life-threatening HLH in one case. Additionally, we conducted a systematic literature review using PubMed and EMBASE to identify previously reported cases of CARD11 GOF mutations.

RESULTS: In vitro functional analysis demonstrated that the D357E variant activates the NF-κB signaling pathway in primary lymphocytes and in HEK293T cells transfected with mutant CARD11. Our literature review identified 13 studies describing 29 patients. Notably, HLH emerged as a common complication of CARD11 GOF mutations (18.8%), while B-lymphocytosis -though frequent- was not universally present.

CONCLUSION: We identified a novel pathogenic CARD11 variant and described its atypical phenotype, further expanding the clinical spectrum of CARD11 GOF disorders. These findings underscore the need for increased awareness of HLH risk in patients with CARD11 GOF mutations.

PMID:40157432 | DOI:10.1016/j.imlet.2025.107005

J Allergy Clin Immunol Pract. 2025 Mar 26:S2213-2198(25)00277-6. doi: 10.1016/j.jaip.2025.03.026. Online ahead of print.

ABSTRACT

BACKGROUND: Biallelic variants in DGAT1 have been implicated in causing congenital diarrhea and protein-losing enteropathy (PLE). Insights into the immunopathological features of this ultra-rare disorder remain scarce, with only one cohort published to date.

OBJECTIVE: To delineate the clinical presentations, laboratory and immunological profiles, and therapeutic responses associated with DGAT1-deficiency and identify prognostic indicators that affect survival rates.

METHODS: In this multicenter retrospective analysis of a comprehensive cohort of nine patients carrying seven novel variants, each displaying distinct phenotypic features, we recorded clinical, immunological, and laboratory data of patients and evaluated the impact of various factors on prognosis.

RESULTS: 67% of patients (n=6) exhibited symptoms during the first month of life, while one demonstrated symptom onset after six months. 78% of patients (n=7) presented with diarrhea, of whom all exhibited vomiting, failure to thrive, hypoalbuminemia, and hypogammaglobulinemia, as the advent of PLE. Patients with reduced CD4⁺ T-cell frequency (n=2) exhibited severe infections with unexpected bacteria during the follow-up. Despite administering immunoglobulin replacement therapy (IgRT), 45% of patients (n=4) passed away from infective complications. A decreased CD4⁺/CD8⁺ T-cell ratio was observed in all deceased patients who showed marked inflammation or apoptosis in colon biopsy samples. Early fat-restricted nutrition extended survival, whereas early symptom onset, recurrent severe infections, and reduced CD4⁺/CD8⁺ T-cell ratio were associated with less favorable outcomes.

CONCLUSIONS: Our findings advocate early fat restriction as a critical therapeutic strategy. Given the heightened risk of severe infections, antibiotic prophylaxis can be recommended in addition to IgRT for DGAT1-deficient patients exhibiting lymphopenia or diminished CD4⁺ T cells.

PMID:40154740 | DOI:10.1016/j.jaip.2025.03.026

Nutrition. 2025 Mar 1;134:112733. doi: 10.1016/j.nut.2025.112733. Online ahead of print.

ABSTRACT

Vitamin C is a versatile nutrient with essential antioxidant properties and roles in amino acid metabolism, collagen promotion, and hormone synthesis. It has long been regarded as benefitting infectious disease management, although its specific roles remain uncertain. The dominant view is that this efficacy not only stems from its redox regulation in the body but also from its profound impact on the immune system. This review provides a comprehensive overview of Vitamin C’s effects on redox regulation and shows how the vitamin influences various immune cells and cell-intrinsic innate immunity signaling pathways, thereby updating and expanding our previous perspectives. Clinically, though some studies and case series have suggested potential benefits of Vitamin C in preventing and (or) treating respiratory tract infections and sepsis and septic shock, the evidence remains controversial. The current data is insufficient to support the routine clinical use of Vitamin C in managing these diseases and requires further rigorous evaluation to establish definitive efficacy and safety profiles. This review thoroughly examines current clinical research progress on Vitamin C, summarizes the primary controversies and their underlying causes, and proposes directions for future clinical research. Furthermore, preclinical evidence shows potential roles for Vitamin C in the supplementary treatment of the “Big Three” infectious diseases: acquired immunodeficiency syndrome (AIDS), tuberculosis, and malaria; however, systematic clinical studies in these areas are lacking. We examine related in vitro and animal studies, as well as clinical trials, and discuss potential roles for Vitamin C as a treatment and (or) adjuvant therapy.

PMID:40154019 | DOI:10.1016/j.nut.2025.112733

Front Biosci (Landmark Ed). 2025 Mar 17;30(3):36795. doi: 10.31083/FBL36795.

NO ABSTRACT

PMID:40152395 | DOI:10.31083/FBL36795

Case Reports Immunol. 2025 Mar 19;2025:9988821. doi: 10.1155/crii/9988821. eCollection 2025.

ABSTRACT

In recent years, due to the widespread use of advanced molecular diagnostic methods, it has become clear that individuals in particular born from consanguineous marriages may be carriers of different genetic diseases. For this reason, cases where diseases related to inborn errors of immunity (IEI) and metabolism errors are detected in the same patient are encountered more frequently. In patients affected by different genetic defects, the pathophysiology is more complex, and disease management is more difficult. In this article, we aimed to draw attention to this complex genetic carrier state in a male with primary immunodeficiency (PID). In the patient who presented with recurrent lower respiratory tract infections, bronchiectasis, asthma and nasal polyps, and antibody deficiencies as well as cellular immunodeficiency findings were detected in the immunological analyses. In the whole exome sequencing (WES) study, three different variants were detected, two in genes related to PIDs (DCLRE1C and TNFRSF13B) and one in the gene related to phenylalanine metabolism (phenylalanine hydroxylase (PAH)). In the light of the current findings, the patient was evaluated as having leaky severe combined immunodeficiency (SCID) with immune phenotype T-B-natural killer (NK)+ and hyperphenylalaninemia (HPA). This case showed us that metabolic diseases may accompany a delay in the diagnosis of SCID and patients should be evaluated with a multidisciplinary approach.

PMID:40151380 | PMC:PMC11944794 | DOI:10.1155/crii/9988821

Curr Pediatr Rev. 2025 Mar 26. doi: 10.2174/0115733963325523250320065040. Online ahead of print.

ABSTRACT

The literature review presents data from a limited number of available studies conducted over the last two decades on immunological deficiency in congenital heart defects (CHDs), which is the cause of frequent infectious complications before and after cardiac surgery. Several studies based on screenings at various levels indicate the presence of primary and secondary immunodeficiency in CHDs, in particular about 13 genetic syndromes in which CHD is combined with immunodeficiency. The available data suggests a greater severity of immunological disorders in patients with critical CHDs, cyanotic CHDs, and conotruncal defects with T-cell dysfunction and deficiency of immunoglobulins (especially the IgG class, mainly IgG4) than in patients with shunts and obstructive defects. To identify defects in the T- and B-cell components of the immune system, quantification of the DNA of T-cell receptor excision circles (TRECs) and K-deleting recombination excision circles (KRECs)-by-products of the maturation of T- and B-cell receptors- has proven helpful in the world practice of neonatal screening. It allows the evaluation of a number of functionally mature T- and B-cells. In Russia, however, its widespread use started only in 2023. Data on the use of this assay in infants with CHDs are represented by isolated case reports. In Russia, a combination of CHD and primary immunodeficiency was found in 37% of cases in the Sverdlovsk Region. We conducted our own study of 200 children with CHD; 5% of cases were syndromic forms of CHD. 48.5% of children were admitted to the cardiac surgery clinic in critical condition. A decrease in the TREC level was detected in 23.5% of cases, including all children with syndromic CHD. In the group of patients with immunological disorders, there were significantly more children with cyanotic CHD, children admitted in critical condition, and children with conotruncal defects. Infectious complications in the postoperative period (sepsis, pneumonia, tracheobronchitis, postoperative wound infection) were observed significantly more often in 47 children with reduced TREC levels compared to children with normal TREC levels (P = .00000, in 36% and 3.6%, respectively). The analysis of publications confirms the prognostic value of TREC and KREC screening for targeted preoperative preparation to reduce postoperative complications and decrease the risk of mortality in CHDs.

PMID:40148298 | DOI:10.2174/0115733963325523250320065040

J Allergy Clin Immunol Pract. 2025 Mar 25:S2213-2198(25)00272-7. doi: 10.1016/j.jaip.2025.03.022. Online ahead of print.

ABSTRACT

BACKGROUND: Cluster of differentiation 3 (CD3) subunit deficiency (CD3SD) causes combined immunodeficiency (CID) and severe CID (SCID).

OBJECTIVE: To elucidate the clinical, laboratory, and genetic features of patients with different CD3SD subtypes.

METHODS: We evaluated the data of five patients with CD3ε (two), CD3γ (two), and CD3δ (one) deficiencies from our institution. In addition, we reviewed the medical literature for cases of CD3SD.

RESULTS: We identified two novel homozygous CD3 variants. In addition, we identified 44 CD3SD cases in the literature. In total, we analyzed the results of 49 patients. Our review of the medical literature revealed 11, 12, 18, and three patients with CD3ε, CD3γ, CD3δ, and CD3ζ deficiency, respectively. Of the 49 patients, 40 had an SCID profile, whereas nine with CD3γ variants had a CID profile. The patients with SCID presented with typical symptoms, including recurrent infections (18/40, 45%), diarrhea (13/40, 33%), and candidiasis (12/40, 30%). Recurrent sinopulmonary infections (4/9, 45%), thyroiditis (4/9, 45%), and bronchiectasis (4/9, 45%) were common in patients with CID. Almost 70% of patients with SCID (27/40) underwent hematopoietic stem cell transplantation (HSCT).

CONCLUSION: Our results show that patients with CD3δ, CD3ε, and CD3ζ deficiencies typically present with a classic SCID phenotype. In contrast, patients with CD3γ deficiency may either show a SCID phenotype or a milder, less severe CID phenotype. Importantly, autoimmunity may be the sole manifestation of CD3γ deficiency.

PMID:40147628 | DOI:10.1016/j.jaip.2025.03.022

J Clin Immunol. 2025 Mar 27;45(1):84. doi: 10.1007/s10875-025-01873-3.

ABSTRACT

PURPOSE: The safety and tolerability of elapegademase (elapegademase-lvlr; Revcovi^®) a PEGylated recombinant adenosine deaminase (ADA), were demonstrated in two Phase 3 clinical trials in the U.S. and Japan in patients with ADA-deficient severe combined immunodeficiency (ADA-SCID). Elapegademase replaced Adagen^® (pegademase, a PEGylated bovine ADA) in 2018. This registry study (NCT03878069) was conducted as a post-marketing requirement to bolster the limited safety and effectiveness data on elapegademase in patients with ADA-SCID and to study patients starting on enzyme replacement therapy (ERT) de novo.

METHODS: Patients were managed by routine clinical care and treating physicians’ judgement from September 2019 to January 2023. Primary endpoints included trough plasma ADA activity and total trough erythrocyte deoxyadenosine nucleotides (dAXP). Secondary outcomes included lymphocyte counts, hospitalizations, infections, and safety outcomes.

RESULTS: Thirty-two patients were grouped as ERT-naïve (n = 7; infants and children with no prior ERT [EN]); pegademase-transitioning (n = 21; from pegademase to elapegademase [PT]); and patients who had participated in the Phase 3 clinical trial (n = 4; STP-2279-002; [STP]). The EN group maintained optimal plasma ADA activity, increased lymphocyte counts, had manageable infections, and had no mortality for up to 30 months while on elapegademase. The STP group and 66.7% of the PT group continued to maintain satisfactory levels of both ADA and dAXP with stable rates of infections and hospitalizations and stable lymphocyte counts for up to 48.6 months. Variability on all measures was seen, but overall, patients did not deteriorate while on elapegademase.

CONCLUSION: Effectiveness of elapegademase was maintained up to 4 years of use and with no new safety concerns.

PMID:40140214 | DOI:10.1007/s10875-025-01873-3

Hum Pathol. 2025 Mar 23:105763. doi: 10.1016/j.humpath.2025.105763. Online ahead of print.

ABSTRACT

OBJECTIVE: Very early-onset inflammatory bowel disease (VEO-IBD) is a clinical umbrella term referring to IBD-like symptoms arising in children before 6 years of age, encompassing ‘pure’ IBD (Crohn’s Colitis/Ulcerative Colitis)/non IBD colitis, and monogenic diseases (MDs), the latter often related to primary immunodeficiency disorders. A multidisciplinary approach is imperative for correct therapeutic management, as endoscopy and histology are not always completely informative. In this setting, the study aims to describe the extent/features of histologic lesions in both endoscopically damaged mucosa and otherwise endoscopically healthy (normal/near normal) mucosa.

METHODS: Endoscopic data were retrospectively recorded, and histologic slides were collegially re-evaluated in a 93 VEO-IBD multicenter cohort, 76 (76/93 – 81,7%) of which with complete endoscopic/histologic data.

RESULTS: At endoscopy, lesions were reported by the clinician in 66/76 (86,8%) cases. When endoscopic lesions were reported, histologic damage was also seen. Interestingly, histologic mucosal damage was also documented in 43,3% (13/30) of cases with endoscopically healthy/nearly healthy mucosa. This misalignment between endoscopy and pathology was seen in about a third of (29,1% – 7/24) ‘true’ IBD and all MDs (100% – 6/6) (p=0.0029).

CONCLUSION: In VEO-IBD, histologic lesions can be present in endoscopically ‘healthy’ intestinal mucosa. This finding is more frequent in MDs, suggesting the need to accurately sample all the mucosal tract in VEO-IBD patients, even when no endoscopic lesions are seen at endoscopy.

PMID:40132689 | DOI:10.1016/j.humpath.2025.105763