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Immunogenetics. 2025 Nov 14;77(1):32. doi: 10.1007/s00251-025-01388-6.

ABSTRACT

The present study aimed to evaluate lymphoid defects in patients with specific IEIs (n = 28) using a 12-antibody 9-color single-tube flow cytometry assay. The lymphoid defects (lymphocyte counts below the reference range) were significantly higher in XLA patients (p-0.0002), CVID patients (p-0.00022), WAS patients (p- < 0.001), HIES patients (p- < 0.001), CHS patients (p < 0.001), and CGD patients (p < 0.0002) than age-matched controls. The lymphoid defects (lymphocyte counts above the reference range) were significantly higher in LAD-1 than age-matched controls (p < 0.001). In patients with XLA, the NK cells were reduced in 50% and naïve Tc cells in 33.3% of patients. The patients with CVID showed reduced CD4 + T cell subset in 75% and increased memory Tc cells in 50% of patients. In WAS, absolute B cell, naïve B cell, switched memory B cell, CD4 + T cell, and naïve Th cell counts were decreased in 100% of patients. In HIES, the CD4 + T cell and memory Th cell count was reduced in 100% of patients. In CGD, reduced absolute count of T cells, CD4 + T cells, CD8 + T cells, naïve Th cells, memory Th cells, naïve Tc cells and γδ T cells and increased B-cell counts were noted in 67% of cases. Both B- and T-cell defects were identified in HIGM, MHC-II deficiency, LAD-1, CHS, CARD-11, and STXBP2 defects. No significant difference was observed between routine and single-tube panel results by paired T-test.

PMID:41238939 | DOI:10.1007/s00251-025-01388-6

BMC Immunol. 2025 Nov 12;26(1):89. doi: 10.1186/s12865-025-00774-9.

ABSTRACT

BACKGROUND: Severe combined immunodeficiency (SCID) is a congenital immunodeficiency characterized by significant numerical or functional defects in T lymphocytes and is often accompanied by B lymphocyte dysfunction. It presents early in life with severe, recurrent opportunistic infections. Early diagnosis and hematopoietic stem cell transplantation (HSCT) are vital for patient survival. Cernunnos/XLF deficiency is an autosomal recessive form of SCID caused by mutations in the NHEJ1 gene, which plays a critical role in repairing DNA double-strand breaks. First described in 2006, this condition remains exceedingly rare, with only about 55 cases reported to date. This study aimed to describe a novel infant with Cernunnos/XLF deficiency and to review previously reported patients carrying the same variant, thereby expanding the clinical spectrum of this rare disease.

METHODS: With written informed consent, we retrospectively evaluated a pediatric patient with Cernunnos/XLF deficiency followed at our clinic. Demographic, clinical, laboratory, and radiological findings were reviewed. The diagnosis was based on clinical and immunological features and confirmed via clinical exome sequencing. A literature review was conducted to compare the genotype-phenotype correlations of previously reported patients carrying the same NHEJ1 variant.

RESULTS: We report an infant who was hospitalized at 6.5 months of age with a preliminary diagnosis of meningitis and was subsequently diagnosed with Cernunnos/XLF deficiency. The patient exhibited microcephaly, growth retardation, recurrent infections, prolonged SARS-CoV-2 PCR positivity, and localized BCGitis following live Bacillus Calmette-Guérin (BCG) vaccination. Immunological evaluation revealed T- and B-cell lymphopenia and hypogammaglobulinemia. Genetic testing confirmed a homozygous nonsense mutation in NHEJ1. HSCT from a matched sibling donor was performed.

CONCLUSION: This study describes a rare case of Cernunnos/XLF deficiency diagnosed in early infancy, underscoring the value of early recognition and the critical role of genetic testing and HSCT. It also expands the clinical spectrum of the disease and provides a comparative perspective with previously reported patients carrying the same mutation. In infants presenting with unexplained infections or complications related to live vaccines, inborn errors of immunity should be considered. Our findings emphasize the importance of timely diagnosis and comprehensive, multidisciplinary follow-up, particularly in patients with additional complications.

PMID:41225329 | DOI:10.1186/s12865-025-00774-9

Cureus. 2025 Oct 12;17(10):e94410. doi: 10.7759/cureus.94410. eCollection 2025 Oct.

ABSTRACT

A man in his 50s develops signs of immune dysfunction (recurrent chest infections and new-onset chronic diarrhoea), alongside a history of multiple distinct malignancies and nail dystrophy. Immunological testing reveals T-cell lymphopenia and hypogammaglobulinaemia. Whole genome sequencing reveals a heterozygous c.1465del mutation in the FOXN1 (forkhead box N1) gene. This case suggests that previously healthy carriers of heterozygous FOXN1 mutations may be at risk of developing immune dysfunction in later life. Potential reasons for the severe and delayed phenotype include a dominant-negative effect of the resultant protein (p.Gln489ArgfsTer61), age-related involution of the thymus and previous chemoradiotherapy. Further studies on heterozygous FOXN1 mutations are required to clarify their clinical significance and inform evidence-based management approaches.

PMID:41230284 | PMC:PMC12604831 | DOI:10.7759/cureus.94410

Rev Med Virol. 2025 Nov;35(6):e70081. doi: 10.1002/rmv.70081.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency, characterised by impaired antibody production, immune dysregulation, and a broad spectrum of clinical manifestations. Gastrointestinal involvement is frequent, affecting up to 20% of patients and significantly contributing to morbidity and mortality. Among infectious triggers, norovirus plays a particularly important role, as persistent infection may drive chronic inflammation and contribute to the development of CVID-associated enteropathy, a severe non-infectious complication marked by chronic diarrhoea, malabsorption, and weight loss. The pathogenesis is multifactorial, involving impaired humoural immunity, absent mucosal IgA, and aberrant T- and B-cell interactions, resulting in defective viral clearance and sustained mucosal injury. Although viral eradication has been shown to induce clinical and histological improvement, no standardized therapeutic strategy currently exists. Intravenous or subcutaneous immunoglobulin replacement fails to adequately protect against gastrointestinal infections, and off-label antivirals such as ribavirin, nitazoxanide, or interferon alpha have yielded inconsistent results. Oral administered immunoglobulin preparations have shown variable efficacy in case reports, reflecting differences in viral genotypes, host susceptibility, and donor antibody repertoires. In this review, we summarise current knowledge on the epidemiology, pathogenesis, clinical features, and diagnostic considerations of CVID-associated enteropathy linked to chronic norovirus infection, with a special focus on therapeutic aspects. We also present our experience with a patient successfully treated with immunoglobulin therapy administered via nasogastric tube, leading to clinical remission, nutritional recovery, and viral clearance. Recognising norovirus as a key etiological factor in CVID enteropathy emphasises the need to conduct systematic studies and evidence-based therapeutic approaches.

PMID:41229388 | DOI:10.1002/rmv.70081

Allergol Immunopathol (Madr). 2025 Nov 1;53(6):32-37. doi: 10.15586/aei.v53i6.1472. eCollection 2025.

ABSTRACT

INTRODUCTION: Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency, yet its clinical presentation ranges from asymptomatic cases to individuals suffering from recurrent infections, allergic manifestations, and autoimmune disorders. Limited data exist regarding the immunological and clinical profiles of pediatric patients with sIgAD in Türkiye.

METHODS: We conducted a retrospective analysis of 45 pediatric patients (20 females and 25 males) diagnosed with sIgAD and followed at two tertiary care centers. Demographic features, allergic and autoimmune comorbidities, and immunological parameters were evaluated. Lymphocyte subset analyses and immunoglobulin subclass levels were recorded. Associations between IgG3/IgG4 subclass deficiencies and infection frequency were assessed using the Mann-Whitney U test.

RESULTS: The median current age was 102 months (range: 48-204), with a median age of symptom onset at 24 months (range: 1-186), referral at 88 months (range: 6-199), and diagnosis at 87 months (range: 48-192). A history of at least one allergic disease, including asthma, allergic rhinitis, and/or atopic dermatitis, was present in 66.7% of patients. Autoimmune conditions were identified in 13.3%, including Hashimoto’s thyroiditis, vitiligo, and immune thrombocytopenic purpura. No statistically significant differences in the frequencies of upper respiratory tract infections, pneumonia, otitis, or viral infections were observed between patients with low versus normal/high IgG3 or IgG4 levels (all P > 0.05).

CONCLUSION: Our findings highlight the high prevalence of allergic diseases and the clinical heterogeneity of sIgAD in children. Moreover, isolated IgG3 or IgG4 subclass deficiencies may not independently influence infection susceptibility. Longitudinal studies are warranted to better define the prognostic role of immunoglobulin subclasses in pediatric sIgAD.

PMID:41229040 | DOI:10.15586/aei.v53i6.1472

Cancers (Basel). 2025 Oct 30;17(21):3504. doi: 10.3390/cancers17213504.

ABSTRACT

BACKGROUND: The main type of treatment of unresectable NSCLC is chemoradiotherapy, which has a relatively high toxicity. One option allowing to reduce the toxicity of this approach may be immunocorrective therapy. The appointment of this type of treatment should be warranted in terms of patient’s immune system response. This confirms the importance of verifying systemic immune disorders in primary patients with NSCLC.

GOAL: To assess the features of the population of immune cells in peripheral blood in patients with stage IIIB, IIIC primary NSCLC and to identify any signs of secondary immunodeficiency in this cohort.

METHODS: We analyzed the frequencies of circulating T cells (CD3+, CD4+, CD8+), B-cells (CD19+), NK-cells (CD3-CD16+CD56+ cell), and NKT-cells (CD3+CD56+ cells) within CD45+ cells (lymphocytes) in 80 patients with stage IIIB-IIIC NSCLC, and in 40 healthy controls using eight-color flow cytometry.

RESULTS: In patients with stages IIIB-IIIC primary NSCLC, changes within immunocompetent blood cells were found. Moreover, it was unveiled that quantitative changes affected all major immunocompetent cells. A decrease in the proportion of CD4+ T cells and B lymphocytes and an increase in the number of NK and NKT cells were found. Also, an increase in the number of double-positive CD4+CD8+ T cells was revealed, as well as a significant increase in the proportion of B1a (CD5+CD19+) cells among B lymphocytes (qualitative disorders).

CONCLUSION: The revealed multidirectional changes among immunocompetent peripheral blood cells in patients with locally advanced NSCLC (stages IIIB-IIIC) can be beyond doubt considered as signs of systemic immune disorders in this cohort (secondary immunodeficiency).

PMID:41228297 | DOI:10.3390/cancers17213504

Transplant Cell Ther. 2025 Nov 10:S2666-6367(25)01558-1. doi: 10.1016/j.jtct.2025.11.006. Online ahead of print.

ABSTRACT

BACKGROUND: Inflammatory bowel disease (IBD) is a phenotype of patients with inborn errors of immunity (IEI). Allogeneic hematopoietic cell transplantation (HCT) is an established curative treatment for IEI; however, the effect of IBD on HCT outcomes is unclear.

OBJECTIVE: We evaluated the impact of IBD on post-HCT prognosis in pediatric patients with IEI.

STUDY DESIGN: We used the Japanese transplant registry database to retrospectively analyze the medical records of 625 patients with pediatric IEI who underwent allogeneic HCT between 2007 and 2022 to evaluate the clinical impact of IBD on these patients.

RESULTS: Sixty-six (10.6%) patients had concurrent IBD before HCT. Compared with patients without IBD, those with IBD did not show inferior overall survival, transplant-related mortality (TRM), or neutrophil and platelet engraftment. Moreover, no significant differences were observed in the incidence of acute or chronic graft-versus-host disease (GVHD) between the two groups. However, the IBD group had a higher incidence of acute gastrointestinal GVHD. These findings remained consistent even after propensity score matching, accounting for the identified risk factors, including age at HCT, performance status, total HCT-specific comorbidity index score, HLA mismatch, era of HCT, and underlying disease classification.

CONCLUSION(S): IBD has a limited effect on HCT outcomes in patients with pediatric IEI, despite the higher incidence of acute gastrointestinal GVHD. Nevertheless, in this study, we included patients with heterogeneous and complex disease backgrounds, indicating the need for further investigation to confirm the findings.

PMID:41224146 | DOI:10.1016/j.jtct.2025.11.006

Int J Dermatol. 2025 Nov 12. doi: 10.1111/ijd.70147. Online ahead of print.

NO ABSTRACT

PMID:41222135 | DOI:10.1111/ijd.70147

Ann Lab Med. 2025 Nov 12. doi: 10.3343/alm.2025.0241. Online ahead of print.

ABSTRACT

BACKGROUND: Current reference intervals for lymphocyte subpopulations are primarily based on Western populations, with limited data available for Korean children, particularly for extended subsets. We determined absolute cell counts and percentages of lymphocyte subpopulations in Korean children, according to age and sex.

METHODS: Samples from 92 children-stratified into two age groups, groups 1 (5-9 yrs) and 2 (10-17 yrs)-were obtained. Immunophenotyping was performed via flow cytometry using the Primary Immunodeficiency Orientation Tube (PIDOT) panel, primarily classifying the cells into T, B, and natural killer cell populations. T lymphocytes were divided into CD4⁺, CD8⁺, and CD4^–CD8^– subsets; T and B cells were further subdivided according to their maturation stage.

RESULTS: Children in group 1 exhibited higher absolute counts of total B cells, unswitched memory B cells/plasma cells, total T cells, CD4⁺ naïve cells, and TCRγδ⁺ T cells than those in group 2. In contrast, Group 2 children showed higher absolute counts of CD4⁺ effector memory (EM) T cells. Males had higher absolute counts of total B cells, particularly pregerminal center B cells, CD4⁺ EM cells, and CD8⁺ terminally differentiated T cells, whereas females showed higher proportions of CD4⁺, CD4⁺ naïve, and CD8⁺ central memory/transitional memory T cells.

CONCLUSIONS: To the best of our knowledge, this study is the first to establish reference values for extended lymphocyte subsets in Korean children using the PIDOT panel. Age, sex, and laboratory-related factors influenced lymphocyte subset distributions. These findings may serve as reference data for immune disorders and immunotherapy in pediatric populations.

PMID:41220249 | DOI:10.3343/alm.2025.0241

J Clin Immunol. 2025 Nov 12;45(1):159. doi: 10.1007/s10875-025-01960-5.

ABSTRACT

Haploinsufficiency of cytotoxic T-lymphocyte associated protein 4 (CTLA4), a known cause of inborn errors of immunity, can lead to autoimmunity, inflammation, neoplasia and infections. A previously undescribed CTLA4 variant was identified in a patient who presented with life-threatening cutaneous infection caused by Pseudomonas aeruginosa, severe VZV infection, and Evans syndrome. Our aim was to assess the pathogenicity of the previously undescribed c.379T > G variant in the CTLA4 gene and explore its phenotypic presentation in relatives. We employed genetic and protein-based in silico analyses to evaluate the potential role of the c.379T > G variant in the CTLA4 gene. We subsequently studied CTLA4 expression ex vivo, analyzed the clinical presentation of affected carriers and compared the biological status across affected individuals, healthy carriers and noncarriers. In silico analyses revealed that the c.379T > G mutation, which is located within the ligand binding area of CTLA4, is highly pathogenic. Its clinical manifestations, which are sometimes fatal, include multiple infections, autoimmunity, inflammation of the central nervous system, lymphoproliferation and thymoma with Good’s syndrome. Compared with its expression in healthy donors, the expression of CTLA4 following stimulation in memory regulatory T cells was decreased in affected individuals. Immunophenotyping revealed an increased proportion of immature and double-negative B cells in affected patients compared with their nonmutated relatives. Additionally, a reduction in naive T cells and an increase in CD4 + CD25-Foxp3 + cells were observed in carriers compared with controls. The c.379T > G variant of CTLA4, resulting in a p.Tyr127Asp substitution, is pathogenic and contributes to the development of a CTLA4 haploinsufficiency phenotype. This finding highlights the heterogeneous presentations of the disease, including oncological and neurological manifestations.

PMID:41219619 | DOI:10.1007/s10875-025-01960-5