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Semin Pediatr Neurol. 2024 Dec;52:101169. doi: 10.1016/j.spen.2024.101169. Epub 2024 Nov 19.

ABSTRACT

Ataxia telangiectasia (AT) is a rare neurocutaneous syndrome that results from biallelic pathogenic variants in the ataxia telangiectasia mutated (ATM) gene, named for its characteristic cerebellar ataxia in the early toddler years and variable oculocutaneous telangiectasias in the school age years. While its name only hints at neurologic and cutaneous manifestations, this multisystemic disorder also has important immunologic, oncologic, respiratory, and endocrinologic implications. This article will review the function of the ATM gene, the neurologic manifestations of AT, non-neurologic complications, mimickers of AT (including other disorders of defective DNA repair), and the realm of therapeutic research for AT.

PMID:39622612 | DOI:10.1016/j.spen.2024.101169

Semin Pediatr Neurol. 2024 Dec;52:101168. doi: 10.1016/j.spen.2024.101168. Epub 2024 Nov 8.

ABSTRACT

Chedíak-Higashi Syndrome (CHS) is a rare autosomal recessive disorder caused by mutations in the Lysosomal Trafficking Regulator (LYST) gene, leading to defective lysosomal function in immune cells, melanocytes, and neurons. Clinically, CHS is characterized by a spectrum of symptoms, including immunodeficiency, partial oculocutaneous albinism, bleeding tendencies, neurodevelopmental deficits and progressive neurodegenerative symptoms. The severity of CHS correlates with the type of LYST mutation: the classic form, linked to nonsense or frameshift mutations, presents early in childhood with severe immune dysfunction, recurrent infections, and a high risk of hemophagocytic lymphohistiocytosis (HLH), a life-threatening hyperinflammatory state. Without timely treatment, including hematopoietic stem cell transplantation (HSCT), prognosis is poor, with high mortality in early life. Atypical forms, associated with missense mutations, manifest later with milder immunologic symptoms but inevitably progress to neurological impairment, including cognitive decline and motor dysfunction. Diagnosing CHS is complex due to its rarity, phenotypic variability, and overlap with other disorders. A thorough approach, incorporating clinical evaluation, peripheral blood smear for giant granules in leukocytes, and genetic testing for LYST mutations, is crucial for accurate diagnosis. Management of CHS requires a multidisciplinary approach, focusing on HSCT for immunologic and hematologic stabilization and symptomatic and supportive care for neurological symptoms. Even those patients who undergo stabilizing HSCT eventually develop neurological difficulties. This review provides an in-depth exploration of CHS, covering its epidemiology, clinical presentation, molecular genetics, diagnostic challenges, and current management strategies, while emphasizing the necessity of a comprehensive, multidisciplinary approach to improve patient outcomes.

PMID:39622608 | DOI:10.1016/j.spen.2024.101168

J Allergy Clin Immunol. 2024 Nov 30:S0091-6749(24)01282-X. doi: 10.1016/j.jaci.2024.11.030. Online ahead of print.

ABSTRACT

BACKGROUND: Inborn errors of immunity (IEIs) are more than 500 different rare congenital disorders of the immune system characterized by susceptibility to infections and immune dysregulation. The significant overlap of the clinical features among the different forms may lead to diagnostic delay. High throughput sequencing techniques may allow a timely genetic definition. Guidelines for the use and the interpretation of genetic testing produced by the American College of Medical Genetics and Genomics (ACMG) and the European Society of Human Genetics (ESHG) do not cover specificities for the application to IEIs.

OBJECTIVE: The aim of this consensus study is to define the best approach to genetic testing for IEIs.

METHODS: A panel of experts in the context of the Italian Primary Immunodeficiency Network (IPINet) composed a list of statements that were evaluated using Delphi method.

RESULTS: The experts recommend that genetic testing for IEIs should be offered to selected patients with warning signs for IEIs and highlight the crucial role of thorough phenotyping and functional tests for the conclusive diagnosis of IEI. Comprehensive educational programs targeted to health care professionals and the public should be developed to increase IEIs awareness and reduce the diagnostic delay. Ethical issues should be pondered over the diagnostic advantages of genetic tests requested for diagnostic purposes.

CONCLUSION: Adherence to the guidelines on the use and interpretation of genetic testing for the diagnosis of IEIs should help limiting the inappropriate use of these techniques and reduce the risk of misdiagnosis and apprehension for inconclusive genetic results.

PMID:39622296 | DOI:10.1016/j.jaci.2024.11.030

J Allergy Clin Immunol. 2024 Nov 30:S0091-6749(24)01283-1. doi: 10.1016/j.jaci.2024.11.031. Online ahead of print.

ABSTRACT

BACKGROUND: CD4⁺ T cells play essential roles in adaptive immunity. Distinct CD4⁺ T cell subsets – Th1, Th2, Th17, Th22, T follicular helper and regulatory T cells – have been identified and their contributions to host defence and immune regulation are increasingly well-defined. IL-9 producing Th9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human Th9 cells remain incompletely defined.

OBJECTIVE: Define signalling pathways that regulate IL-9 production by human CD4⁺ T cells.

METHODS: Human naive and memory CD4⁺ T cells were cultured under different conditions and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4⁺ T cells from a broad range of patients (n=92) with pathogenic variants in key immune genes (n=21) to differentiate into IL-9⁺ cells.

RESULTS: We identified two culture conditions that yielded IL-9-expressing cells from naïve CD4⁺ T cells, and amplified IL-9 production by in vivo-generated memory CD4⁺ T cells: TGFβ plus IL-4 (i.e. Th9 polarising condition), and the combination of IL-21, IL-23, IL-6, IL-1β and TGFβ (i.e. Th17 polarising condition). Combining these conditions had a synergistic effect in generating IL-9⁺CD4⁺ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signalling via the TCR and STAT5. Importantly, IL-9 induction was restrained by IFNγ/STAT1 and IL-10.

CONCLUSIONS: Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4⁺ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease.

PMID:39622295 | DOI:10.1016/j.jaci.2024.11.031

Vox Sang. 2024 Dec 1. doi: 10.1111/vox.13769. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVES: Intravenous polyvalent immunoglobulins (IVIG) for prophylaxis in patients with primary immunodeficiency disorders (PIDs) exposes them to life-threatening infections and debilitating diseases. To improve access to IVIG in lower middle-income countries, the WHO recommends a stepwise approach for the local production of purified and virus-inactivated plasma immunoglobulins by national blood transfusion services using new technologies and medical devices. One new technology relies on single-use sterile medical devices for the purification of plasma immunoglobulin G (IgG), as well as lipid-enveloped virus inactivation from mini-pools of recovered plasma separated from whole blood (mini-pool IVIG [MP-IVIG]). This study aimed to compare the safety and efficacy of MP-IVIG to standard IVIG (STD-IVIG).

MATERIALS AND METHODS: In this prospective crossover clinical study, we investigated the safety and efficacy of MP-IVIG for STD-IVIG preparations as a replacement therapy in a cohort of 21 paediatric patients with PID.

RESULTS: Both MP-IVIG and STD-IVIG were effective in reducing the frequency of severe bacterial infections and hospital admissions in patients with PID. Mild side effects have been observed in seven patients (6.2%) with PID who received MP-IVIG and five patients (5.3%) who received STD-IVIG. No moderate or severe side effects or haemolytic transfusion reactions were reported. The mortality rates were also comparable and were not related to the study products.

CONCLUSION: MP-IVIG presented no safety issues and was as effective as STD-IVIG in IgG replacement in patients with PID. Due to the small numbers, the results have to be addressed with caution.

PMID:39617397 | DOI:10.1111/vox.13769

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