Journal of Clinical Immunology最新文献

Purpose: B-cell expansion with nuclear factor kappa B and T-cell anergy (BENTA) is an inborn error of immunity characterized by congenital polyclonal B-cell lymphocyte expansion. In this report, we present a case of a girl diagnosed with BENTA carrying a novel CARD11 germline mutation, aiming to clarify the clinical presentation of BENTA by conducting a literature review.

Methods: Genetic analysis, including whole-exome sequencing, was performed using genomic DNA extracted from the patient's peripheral blood, oral mucosa, and fingernails. Additionally, a comprehensive literature review of cases with BENTA was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines.

Results: A p.Leu251Pro germline variant in the CARD11 gene was identified in an 18-month-old girl with a genetic diagnosis of BENTA. She required adenoidectomy and tonsillectomy due to airway obstruction causing wheezing. Her symptoms improved with prednisolone and sirolimus. The literature review we conducted identified a total of 34 cases of BENTA. Among these cases, 15 were either asymptomatic or showed improvement without requiring any specific treatment. However, all six reported deaths were diagnosed before the age of 3 years, with two attributed to refractory hemophagocytic syndrome and four caused by opportunistic infections.

Conclusion: We present a case of BENTA with life-threatening respiratory symptoms caused by a novel CARD11 germline mutation. The patient showed a positive response to immunosuppressive therapy, including sirolimus. While BENTA is typically regarded as a benign disorder, a literature review revealed that infants with BENTA are at high risk of severe outcomes and require therapeutic intervention.

Purpose: GATA2 deficiency, a rare inborn error of immunity, presents with highly variable phenotypes. Bone marrow (BM) changes such as hypocellularity and myelodysplastic syndrome (MDS) are common, with hematopoietic stem cell transplantation being the only curative option due to the risk of progression to acute myeloid leukemia. Although traditional markers like cytogenetic abnormalities and somatic mutations (e.g., ASXL1) identify the risk of leukemic transformation, efforts to identify novel predictors of disease evolution are needed. CD8+ T cells are known to play a key role in MDS immune surveillance, but their specific involvement in GATA2 deficiency remains poorly defined.

Methods: In this case report, we report on a young adult with GATA2 deficiency who underwent longitudinal monitoring of both peripheral and BM lymphocyte subsets, with a focus on CD8+ T-cell evolution in relation to MDS progression.

Results: The patient exhibited typical GATA2-deficient immune-hematological findings, including monocytopenia, B- and NK-cell deficiency, but had no history of severe infections and remained transfusion-independent. While peripheral CD8+ T-cell levels remained stable over time, a notable reduction in BM CD8+ T cells was observed in association with MDS progression.

Conclusion: Providing a long-term follow-up of one GATA2-deficient patient, we suggest that a decrease in BM CD8+ T cells may serve as an early marker of immune surveillance escape and disease progression. These findings underscore the need for further investigation into the role of BM CD8+ T cells in GATA2 deficiency and MDS evolution, potentially offering new insights for follow-up and therapeutic intervention.

Deficiency in ELF4, X-linked (DEX) is a newly identified monogenic autoinflammatory disease. Most reported cases are male, leading to the recognition of DEX being primarily limited to male patients. Here we described 3 pediatric female patients with DEX from 3 unrelated families, who are all heterozygous for ELF4 mutations (c.320_c.321insA, c.329delA and c.685 A > G). Similar to reported male DEX patients, the main clinical features include recurring oral ulcers, abdominal pain and diarrhea with colonoscopy showing ulcers in the colon. Meanwhile, novel and effective treatment strategies, such as the use of the biologic vedolizumab and exclusive enteral nutrition (EEN), have provided additional options for the treatment of DEX. Finally, we observed skewed X chromosome inactivation patterns in all three female patients, with over-inactivation of the X chromosome carrying the wild-type allele confirmed in two of them.

Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially resulting in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as an influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with RS.

Reticular dysgenesis (RD) is a rare inborn error of immune cell formation defined by severe combined immunodeficiency, agranulocytosis and sensorineural deafness. We report a case of successful haploidentical maternal hematopoietic stem cell transplantation (HSCT) in a boy with RD detected by TREC newborn screening. The patient was admitted to our hospital at 2 weeks of age and was kept in laminar-air flow / hepa-filtered isolation until HSCT was performed at 8 weeks of age with a busulfan, fludarabine conditioning regime. Except few episodes of acute skin graft-versus-host disease (aGVHD) the peritransplant period was uneventful. The patient was discharged 7 weeks post-HSCT. At 18 months of age cochlear implants were placed. The patient was thriving well, showed full donor chimerism and a T cell count > 1000 TCRab + CD3 + cells/µl after one year. Our case highlights that severely immune-compromised patients with RD benefit from early diagnosis by newborn screening, immediate isolation to prevent infections, and early haploidentical HSCT to overcome neonatal neutropenia and establish protective immunity.

Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of STAT3 NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers' peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers' PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37* STAT3 mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.