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Cell Death Dis. 2024 Dec 1;15(11):871. doi: 10.1038/s41419-024-07180-w.

ABSTRACT

DOCK8 deficiency has been shown to affect the migration, function, and survival of immune cells in innate and adaptive immune responses. The immunological mechanisms underlying autosomal recessive (AR) hyper-IgE syndrome (AR-HIES) caused by DOCK8 mutations remain unclear, leading to a lack of specific therapeutic options. In this study, we used CRISPR/Cas9 technology to develop a mouse model with a specific DOCK8 point mutation in exon 45 (c.5846C>A), which is observed in patients with AR-HIES. We then investigated the effect of this mutation on B cell development, cell metabolism, and function in a mouse model with Dock8 gene mutation. The results demonstrated that Dock8 gene mutation inhibited splenic MZ and GC B cell development and crippled BCR signaling. In addition, it resulted in enhanced glycolysis in B cells. Mechanistically, the reduced BCR signaling was related to decreased B cell spreading, BCR clustering, and signalosomes, mediated by inhibited activation of WASP. Furthermore, the DOCK8 mutation led to increased expression of c-Myc in B cells, which plays an important role in glycolysis. As such, GC B cells’ formation and immune responses were disturbed in LCMV-infected mice. These findings will provide new insights into the immunological pathogenesis of primary immunodeficiency disorder caused by DOCK8 mutation.

PMID:39616183 | DOI:10.1038/s41419-024-07180-w

J Clin Immunol. 2024 Dec 2;45(1):52. doi: 10.1007/s10875-024-01844-0.

ABSTRACT

Hereditary pulmonary alveolar proteinosis (hPAP) is a rare lung-related primary immunodeficiency. In hPAP, variants of genes encoding the heterodimeric GM-CSF receptor alpha or beta-chains (CSF2Rα, CSF2Rβ) lead to perturbations in GM-CSF signalling. These perturbations impair the scavenging function of pulmonary alveolar macrophages leading to accumulation of surfactant proteins and lipids within the alveoli. The replacement of defective pulmonary alveolar macrophages can be achieved with allogeneic hematopoietic stem cell transplantation. However, previous reports highlight undesirable pulmonary outcomes associated with this therapeutic approach. We report a 4-year-old developmentally normal girl born of second-degree consanguineous marriage diagnosed with severe form of CSFRα-deficient PAP. She required recurrent whole lung lavage and hence was treated with allogeneic hematopoietic stem cell transplantation. A reduced toxicity treosulfan-based myeloablative regimen with alemtuzumab serotherapy was used for conditioning. Ciclosporin, mycophenolate mofetil and FAM (fluticasone inhaler, azithromycin, montelukast) were used to prevent graft-versus-host disease and immune-related complications of lung. Her post-transplant course was uneventful with full donor chimerism and complete resolution of symptoms. We demonstrate for the first time in a case of severe CSF2Rα-deficient PAP, the successful use of hematopoietic stem cell transplantation as a primary curative treatment, restoring normal lungs both anatomically and functionally. The case report provides evidence for considering allogeneic hematopoietic stem cell transplant in severe forms of CSF2R-deficient PAP.

PMID:39621143 | DOI:10.1007/s10875-024-01844-0

Pediatrics. 2024 Dec 1;154(Suppl 4):S53-S54. doi: 10.1542/peds.2024-069114NC.

NO ABSTRACT

PMID:39620788 | DOI:10.1542/peds.2024-069114NC

Front Immunol. 2024 Nov 15;15:1476218. doi: 10.3389/fimmu.2024.1476218. eCollection 2024.

ABSTRACT

BACKGROUND: The use of next-generation sequencing in inborn errors of immunity (IEI) has considerably increased the identification of novel gene variants, many of which are identified in patients without the described clinical phenotype or with variants of uncertain pathogenic significance in previously described genes. Properly designed functional and cellular assays, many necessarily accomplished by research-based laboratories, reveal the pathogenic consequences of the gene variants and contribute to diagnosis. Activated PI3Kδ syndrome (APDS) is a rare disease that can be divided into APDS1, caused by gain of function (GOF) mutations in PIK3CD gene, and APDS2, with loss of function (LOF) variants in the PIK3R1 gene. Both entities present hyperactivation of the PI3K pathway, which can be analyzed through Akt and S6 phosphorylation status.

METHODS: Our objective was to perform an accurate, robust, and reproducible functional assay to analyze the phosphorylation status of proteins in the PI3K-Akt-S6 pathway by flow cytometry, to contribute to diagnosis, to monitor treatments, and to establish intra-assay standardization.

RESULTS: We illustrate the robustness and reproducibility of our experimental procedure in patients with APDS who had high Akt and/or S6 phosphorylation levels at baseline, and after anti-IgM stimulation in B cells. We show the relevance of an appropriate cohort of samples from healthy donors, processed within the same conditions as the suspected samples, in particular the time frame for sample processing once blood is collected.

DISCUSSION: We highlight the importance of B cell stimulation through B cell receptor signaling, which is highly recommended, especially for samples that would be processed more than 24 hours after blood extraction. Also, having a defined experimental procedure is important, including the cytometer setup, which allows cytometer reproducibility for a period of time, enabling the comparison of a sample at different times.

PMID:39620215 | PMC:PMC11604744 | DOI:10.3389/fimmu.2024.1476218

Front Pediatr. 2024 Nov 15;12:1448176. doi: 10.3389/fped.2024.1448176. eCollection 2024.

ABSTRACT

Autoinflammatory diseases (AIDs) are a group of immunodysregulatory disorders resulting in the increased release or signaling of pro-inflammatory cytokines. Patients with AIDs present systemic inflammation in sterile conditions, which are mainly caused by defects in the innate immune system. Fever is one of the typical symptoms of this derailed immune signaling. In addition, autoinflammatory diseases manifest with varying other symptoms during flare-ups and interphasic periods. The diagnosis of these rare diseases poses numerous challenges. This paper provides an overview of AIDs that arise in childhood and in which fever commonly presents as a symptom. It outlines clinical signs, pathophysiology, diagnosis, and management for each syndrome. Additionally, we discuss a comprehensive diagnostic approach for children where an AID is suspected.

PMID:39618694 | PMC:PMC11605516 | DOI:10.3389/fped.2024.1448176

Cancer Rep (Hoboken). 2024 Dec;7(12):e70068. doi: 10.1002/cnr2.70068.

ABSTRACT

BACKGROUND: Germline GATA2-deficiency usually manifests as immunodeficiencies and myeloid neoplasms and sometimes with dermatological diseases, including warts, panniculitis, and skin cancers.

CASE: We report a 36-year-old woman with germline GATA2-deficiency who developed Merkel cell carcinoma followed by acute myeloid leukemia. Molecular analysis revealed a germline GATA2 S447R variant, not reported from the previous reported case, suggesting a potential association with Merkel cell carcinoma.

CONCLUSION: This case broadens the spectrum of solid cancers linked to GATA2-deficiency, emphasizing the need for considering primary immunodeficiency in young patients with myeloid neoplasms or rare skin cancers, facilitating early detection and treatments.

PMID:39614632 | DOI:10.1002/cnr2.70068

Nat Commun. 2024 Nov 28;15(1):10344. doi: 10.1038/s41467-024-54732-x.

ABSTRACT

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency, marked by hypogammaglobulinemia, poor antibody responses, and increased infection susceptibility. The COVID-19 pandemic provided a unique opportunity to study the effects of prolonged viral infections on the immune responses of CVID patients. Here we use single-cell RNA-seq and spectral flow cytometry of peripheral blood samples before, during, and after SARS-CoV-2 infection showing that COVID-19 CVID patients display a persistent type I interferon signature at convalescence across immune compartments. Alterations in adaptive immunity include sustained activation of naïve B cells, increased CD21^low B cells, impaired Th1 polarization, CD4⁺ T central memory exhaustion, and increased CD8⁺ T cell cytotoxicity. NK cell differentiation is defective, although cytotoxicity remains intact. Monocytes show persistent activation of inflammasome-related genes. These findings suggest the involvement of intact humoral immunity in regulating these processes and might indicate the need for early intervention to manage viral infections in CVID patients.

PMID:39609471 | DOI:10.1038/s41467-024-54732-x

Front Med. 2024 Nov 29. doi: 10.1007/s11684-024-1106-2. Online ahead of print.

ABSTRACT

Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient’s peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.

PMID:39609360 | DOI:10.1007/s11684-024-1106-2

Front Immunol. 2024 Nov 13;15:1472957. doi: 10.3389/fimmu.2024.1472957. eCollection 2024.

ABSTRACT

Inborn errors of immunity (IEI) encompass a broad range of disorders with heterogeneous clinical presentations, often leading to challenges in early diagnosis. This study presents a case of a Brazilian patient with a T-B+NK- severe combined immunodeficiency (SCID) diagnosed at the age of 6 months when was admitted to the hospital due to multiple infectious diseases. Despite undergoing hematopoietic stem cell transplantation (HSCT), the patient had recurrent infections, requiring constant hospital care, including IgG infusions and several antibiotic treatments for the following months. One year after HSCT, presenting mixed chimerism, the patient tested positive for SARS-CoV-2 in nasopharyngeal, duodenum, and intestine samples, with persistent positive tests over a six-month period. Whole exome sequencing identified a private homozygous missense variant (c.1202T>C; p.Leu401Pro) in the Janus Kinase 3 (JAK3) gene. This substitution is located in a highly conserved position, and different bioinformatic variant effect predictors classified the variant as damaging. In silico structural analysis suggested that the variant led to increased structural instability, disrupting the hydrophobic interactions within the SH2 domain, thereby influencing the neighboring residues and potentially altering the interaction between JAK3 and gamma chain (γc) intracellular receptors. This study provides evidence for the novel pathogenicity classification of the variant and highlights the importance of the JAK3 and SH2 domain modulating protein function and their contribution to the SCID pathogenesis.

PMID:39611146 | PMC:PMC11603356 | DOI:10.3389/fimmu.2024.1472957

J Ayub Med Coll Abbottabad. 2024 Apr-Jun;36(2):454-458. doi: 10.555/JAMC-02-12731.

ABSTRACT

ABSTRACT: Chediak Higashi syndrome (CHS), a rare form of autosomal recessive disorder has been reported globally in less than 500 cases over the past two decades. It clinically manifests as repeated episodes of infection, haemorrhagic sequelae, partial albinism, photosensitivity and late neurological signs (neuropathy, cognitive impairment etc). The pathognomonic morphological finding is the presence of abnormally large intra-cytoplasmic granules, particularly in leucocytes. Almost 85% of CHS cases advance into an accelerated phase, characterized by cytopenias and hemophagocytosis, leading to multi-organ failure.

PRESENTATION: The child in the present case had consanguinity and a positive family history of recurrent infections. She had repeated episodes of bacterial infections. She also had a history of photosensitivity. CBC reported cytopenias. Peripheral smear showed neutrophils with characteristic large sized abnormal intra-cytoplasmic granules. Bone marrow biopsy was performed which also showed similar granules in leucocytes along with hemophagocytosis. Other clinical and biochemical markers also pointed towards hemophagocytic lymphohistiocytosis (HLH), thus patient was diagnosed as CHS in an accelerated phase. She received eight doses of chemotherapy but eventually expired.

CONCLUSIONS: The definitive treatment is hematopoietic stem cell transplantation which improves the hematological and immune aspects of CHS but not the neurological. Steps should be taken for early diagnosis and to prevent advancement into the accelerated phase.

PMID:39610002 | DOI:10.555/JAMC-02-12731