Research

Front Immunol. 2025 Oct 1;16:1681763. doi: 10.3389/fimmu.2025.1681763. eCollection 2025.

ABSTRACT

Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE-its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor-associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety-particularly of gene-based therapies-is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care.

PMID:41103407 | PMC:PMC12521201 | DOI:10.3389/fimmu.2025.1681763

J Hum Immun. 2025 Jul 7;1(2). doi: 10.70962/jhi.20250014. Epub 2025 Jun 4.

ABSTRACT

Genetic defects that result in the absence of all T cells, including both αβ and γδ T cells, are classified as severe combined immunodeficiency (SCID), a life-threatening condition requiring immediate hematopoietic stem cell transplantation (HSCT) in affected newborns. Previously, patients with a homozygous c.*+1G>A splice variant in the constant chain (TRAC) of the T cell receptor (TCR) α were found to lack only αβ T cells and demonstrated longer survival compared to SCID patients lacking both αβ and γδ T cells. This observation suggested that γδ T cells might partially compensate for the absence of αβ T cells. Here, we describe two children with biallelic premature stop codons in TRAC. These mutations result in a complete loss of TCRαβ expression on the cell surface and an absence of αβ T cells, leading to severe immunodeficiency and early death. Additionally, we demonstrate that the previously reported c.*+1G>A TRAC variant retains partial activity in vitro, enabling low-level expression of functional TCRαβ. This residual expression likely explains the milder phenotype and extended survival observed in patients carrying this variant. In conclusion, we clarify the non-redundant role of αβ T cells in humans. Our findings show that complete TCRα deficiency causes a SCID-like clinical presentation, whereas partial TCRα deficiency is associated with milder clinical outcomes and longer survival.

PMID:41103553 | PMC:PMC12526356 | DOI:10.70962/jhi.20250014

J Allergy Clin Immunol. 2025 Oct 16:S0091-6749(25)00985-6. doi: 10.1016/j.jaci.2025.09.021. Online ahead of print.

NO ABSTRACT

PMID:41105067 | DOI:10.1016/j.jaci.2025.09.021

J Clin Med. 2025 Oct 7;14(19):7070. doi: 10.3390/jcm14197070.

ABSTRACT

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a broad and varied clinical presentation. In the absence of definite diagnostic criteria, establishing an SLE diagnosis remains challenging. This case series illustrates that other diseases, such as primary immunodeficiencies and monogenic interferonopathies, can closely mimic SLE, even in the presence of its typical serological markers. Recognizing these disease mimickers is crucial to avoid premature conclusions in clinical evaluation and to ensure the initiation of appropriate therapy. Especially in cases of atypical presentation, unusual disease progression, or resistance to standard therapy, alternative diagnoses should be considered. In this overview, we discuss the diagnostic approach for patients with SLE-like manifestations and provide a comprehensive review of diseases that may mimic SLE.

PMID:41096150 | DOI:10.3390/jcm14197070

Int J Mol Sci. 2025 Sep 23;26(19):9302. doi: 10.3390/ijms26199302.

ABSTRACT

The expanded newborn screening (NBS) program in the Russian Federation, launched in 2023, includes the detection of severe forms of T- and B-cell immunodeficiencies via TREC/KREC quantification. We report a rare case of a male infant having multiple congenital anomalies and lymphopenia identified through this program. Genetic testing revealed a 25.8 Mb terminal deletion spanning 13q31.2-qter, consistent with 13q deletion syndrome. Initial NBS revealed reduced TREC levels, prompting further evaluation. The patient exhibited a complex phenotype, including central nervous system malformation (alobar holoprosencephaly), severe congenital heart disease, renal hypoplasia, limb and genitourinary anomalies, and facial dysmorphism. Postnatal complications included pneumonia, pleuritis, and chylothorax. Flow cytometry demonstrated mild T- and B-cell lymphopenia. The genomic defect was characterized using long-read third-generation sequencing, enabling precise breakpoint identification and accurate mapping of deleted genes. The deletion was confirmed via subtelomeric FISH analysis. The patient died at 7 months of age due to the progression of underlying congenital anomalies and associated complications. Our findings broaden the clinical characterization of distal 13q deletion syndrome and demonstrate the value of long-read sequencing in structural chromosomal analysis. They further highlight the difficulties of caring for neonates having complex malformations and immune dysfunction. Given the potential for both primary and secondary immune disturbances, comprehensive immunological evaluation should be considered in patients having 13q deletion syndrome to improve diagnostic accuracy and inform appropriate clinical management.

PMID:41096571 | DOI:10.3390/ijms26199302

Int J Mol Sci. 2025 Oct 1;26(19):9590. doi: 10.3390/ijms26199590.

ABSTRACT

T cell receptor (TCR) profiling using next-generation sequencing (NGS) enables high-throughput, in-depth analysis of repertoire diversity, offering numerous clinical applications. We developed a DNA-based strategy to analyse the TCRβ-chain using NGS and established reference values for T cell repertoire characteristics in 74 healthy donors, including 44 adults, 20 paediatrics, and 10 cord blood units (CBUs). Additionally, four paediatric patients with combined immunodeficiency (CID) or severe CID (SCID) due to deleterious mutations in recombination activating genes (RAG) were analysed. The developed strategy demonstrated high specificity, reproducibility, and sensitivity, and all functional variable and joining genes were detected with minimal PCR bias. All donors had a Gaussian-like distribution of complementary-determining region 3 length, with lower presence of non-templated nucleotides and higher proportion of non-functional clonotypes in CBUs. Both CBUs and paediatrics showed greater convergence and TCRβ diversity was significantly lower in adults and donors with cytomegalovirus-positive serostatus. Finally, an analysis of paediatric patients with RAG-SCID/CID showed significantly shorter CDR3 region length and lower repertoire diversity compared to healthy paediatrics. In summary, we developed a reliable and feasible TCRβ sequencing strategy for application in the clinical setting, and established reference values that could assist in the diagnosis and monitoring of pathological conditions affecting the T cell repertoire.

PMID:41096855 | DOI:10.3390/ijms26199590

J Clin Immunol. 2025 Oct 16;45(1):143. doi: 10.1007/s10875-025-01949-0.

ABSTRACT

Hypogammaglobulinemia (HG) predisposes patients to gastrointestinal Campylobacter infections. This prospective study determined the prevalence of Campylobacter in stool samples from patients with immunoglobulin (Ig)-substituted HG at Bordeaux University Hospital. 73 patients (42 women, median age: 61) receiving Ig substitution therapy were enrolled from July 2022 to July 2024. Stool samples were analysed with culture, PCR, faecal calprotectin levels, and immune profiles were also assessed. A second stool sample was collected from 38 patients after 6-12 months, totalling 111 samples. 53 patients had primary HG (32 common variable immunodeficiency, 7 IgG subclass deficiencies, 4 Bruton’s agammaglobulinemias) and 20 had secondary HG (7 drug-induced, 8 lymphoid hemopathy-related, 5 mixed). Campylobacter were detected in 11 patients (15.1%), with species identified as Campylobacter jejuni, Campylobacter coli, and Aliarcobacter butzleri. Diarrhea was reported in 42% of Campylobacter-positive patients versus 15% of negative patients. Campylobacter-positive patients exhibited higher median faecal calprotectin levels (255 µg/g vs. 52 µg/g). Among positive patients, 44% (versus 34% in negative patients) had non-infectious complications such as immune complications. Mean residual IgG levels were similar between groups, although IgA and IgM were lower in Campylobacter-positive patients (0 vs. 0.36 g/L and 0.17 vs. 0.40 g/L, respectively). The mean CD4/CD8 ratio was also lower in the positive group (1.71 ± 0.85 vs. 2.06 ± 1.18). This study reveals a high prevalence of Campylobacter in HG patients despite receiving Ig therapy. Elevated faecal levels of calprotectin in symptomatic patients suggests active infection. Screening for Campylobacter should be considered in HG patients presenting with digestive symptoms.

PMID:41099909 | DOI:10.1007/s10875-025-01949-0

PLoS One. 2025 Oct 15;20(10):e0333341. doi: 10.1371/journal.pone.0333341. eCollection 2025.

ABSTRACT

BACKGROUND: Activated phosphoinositide 3-kinase delta syndrome (APDS) is an ultra-rare, underrecognized inborn error of immunity. This study aimed to identify outcomes important in evaluating APDS treatment effectiveness and percent change in specific outcomes indicating a clinically meaningful benefit.

METHODS: In this e-Delphi panel study, 28 globally based APDS experts used a 5-point Likert scale (Strongly Disagree to Strongly Agree) to indicate level of agreement that an outcome was an important measure of APDS treatment effectiveness in adult and pediatric patients at 3 and 6 months after treatment initiation. A threshold of ≥75% responding with “Agree” or “Strongly Agree” was considered consensus. Percent meaningful improvement in 6 outcomes was assessed and applied to APDS trial data (NCT02435173).

RESULTS: Twenty-four panelists participated; e-Delphi rounds 1-5 were completed by 23, 21, 18, 17, and 16 panelists, respectively. Outcomes with the highest degree of consensus included lymph node size/volume, clinician overall impression of disease activity, antibiotic use, patient/caregiver-reported social outcomes and patient quality of life, hospitalizations, thrombocytopenia, spleen volume, lymphopenia, and anemia. Panelists indicated within-patient clinically meaningful improvements in adult patients ranged from median values of 20%-25% in lymph nodes, naïve B-cell to total B-cell ratio, spleen volume, hemoglobin, platelets, and lymphocytes at 3 months, and 25%-30% at 6 months. Panelists indicated within-patient clinically meaningful improvements in pediatric patients ranged from median values of 20%-27.5% at 3 months and 22.5%-45% at 6 months in the same 6 outcomes. In an application of responder thresholds, treatment with leniolisib resulted in significant and meaningful improvements in disease hallmarks, including lymph node size, spleen volume, and naïve B-cell ratio.

CONCLUSION: This study provides expert consensus on outcomes important in assessing APDS treatment effectiveness and improvement thresholds in 6 treatment outcomes indicative of a clinically meaningful benefit. These outcomes may help optimize APDS treatment in the clinic.

PMID:41091701 | DOI:10.1371/journal.pone.0333341

N Engl J Med. 2025 Oct 16;393(15):1486-1497. doi: 10.1056/NEJMoa2502754.

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a life-threatening inborn error of immunity for which lentiviral gene therapy has been investigated in clinical trials.

METHODS: Between 2012 and 2019, we treated patients who had ADA-SCID with busulfan nonmyeloablative conditioning followed by transplantation with autologous CD34+ hematopoietic stem cells transduced ex vivo with a lentiviral vector encoding human ADA. The primary efficacy end points were overall survival and event-free survival (defined as survival free from rescue allogeneic hematopoietic stem-cell transplantation, reinitiation of enzyme-replacement therapy, and additional gene therapy). Secondary end points included no receipt of immunoglobulin-replacement therapy, the presence of protective titers to tetanus or pneumococcal vaccines, and sustained discontinuation of fungal or viral prophylaxis. We now report the long-term results from this cohort representing 474 patient-years of follow-up, with a median follow-up of 7.5 years.

RESULTS: We treated 62 patients with ADA-SCID in the United States (33 patients) and the United Kingdom (29 patients). Overall survival was 100%, and event-free survival was 95% (59 of 62 patients). All 59 patients who had successful gene-marked engraftment at 6 months have continued not to receive enzyme-replacement therapy and have had stable gene marking, ADA enzyme activity, metabolic detoxification, and immune reconstitution through the last follow-up; 58 of these patients (98%) discontinued IgG replacement therapy and have evidence of a robust response to vaccinations. None of the patients had a leukoproliferative event or clonal expansion.

CONCLUSIONS: These long-term findings in a large patient cohort show the sustained clinical efficacy and safety of autologous CD34+ hematopoietic stem-cell lentiviral gene therapy for ADA-SCID, indicating that it is a curative treatment. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT04049084.).

PMID:41092330 | DOI:10.1056/NEJMoa2502754

Clin Otolaryngol. 2025 Oct 14. doi: 10.1111/coa.70045. Online ahead of print.

ABSTRACT

OBJECTIVE: Chronic rhinosinusitis (CRS) is prevalent and causes a great negative impact on quality of life. Primary antibody deficiency (PAD) is highly prevalent with CRS compared to the background population. There are efficient treatment options to consider when CRS is a symptom of PAD. The condition seems to be underdiagnosed.

DESIGN: A prospective cohort study investigating adults with CRS for PAD.

RESULTS: One hundred and thirty-eight patients were included in the study. Mean age was 49 years. Twenty-nine (21%) had hypogammaglobulinemia. Nine of 83 (11%) patients had insufficient response to pneumovax polysaccharide vaccine, but insufficient clinical history for diagnosis of Specific Antibody Deficiency (SPAD). Four patients met the clinical criteria for PAD; one had Common Variable Immune Deficiency (CVID), one had IgA deficiency, and two had IgG subclass deficiency. No clinical characteristic was predictive of PAD, and severity of CRS was not indicative of hypogammaglobulinemia or insufficient vaccine response.

CONCLUSION: Immunoglobulin testing should be a routine part of the diagnostic work-up in chronic rhinosinusitis before considering biologics, as primary antibody deficiency is an under-recognised but treatable cause of refractory disease.

PMID:41087302 | DOI:10.1111/coa.70045