Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers.

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic.

Inborn errors of immunity: manifestation, treatment, and outcome - an ESID registry 1994-2024 report on 30,628 patients.

The patient registry (ESID-R), established in 1994, is one of the world's largest databases on inborn errors of immunity (IEI). IEI are genetic disorders predisposing patients to infections, autoimmunity, inflammation, allergies and malignancies. Treatments include antimicrobial therapy, immunoglobulin replacement, immune modulation, stem cell transplantation and gene therapy.

Inhibition of lysosomal degradation increases expression of mutant ADA2 in DADA2 monocytes.

Background: Deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity causing vasculitis and bone marrow failure. Bone marrow failure is mostly unresponsive to TNF-α inhibitors. The limited understanding of the pathomechanisms driving the disease impedes the development of new treatment options.

Long-term effects of COVID-19 in patients with primary immunodeficiency: An IPOPI worldwide survey.

Background: During the coronavirus disease 2019 (COVID-19) pandemic, many individuals developed persistent symptoms after COVID-19. The data on these long-term effects in the primary immunodeficiency (PID) community are limited.

Objective: This study aimed to understand long-term symptoms after COVID-19 in patients with PID, focusing on prevalence, risk factors, viral persistence, and the impact of COVID-19 on their health-related quality of life (HR-QoL).

Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure.

Inherited bone marrow failure syndromes (IBMFSs) encompass a diverse group of hematological disorders characterized by a progressive single-lineage cytopenia or pancytopenia. Despite their heterogeneity, these syndromes often result from genetic errors affecting key biological mechanisms, including telomere maintenance, DNA repair and chromosomal stability, and ribosome assembly, generally leading to accelerated apoptosis of hematopoietic cells. Nevertheless, a genetic diagnosis remains elusive in more than half of the cases.

IRF2BP2 deficiency: An important form of common variable immunodeficiency with inflammation.

Background: IRF2BP2 is a transcription factor that plays an important role in regulating immune pathways, angiogenesis, apoptosis, and cell differentiation. Defects in this gene have been implicated in immunodeficiency.

Objectives: To deepen the understanding of the clinical implications of IRF2BP2 variants, we sought to clinically characterize and functionally test 34 individuals with IRF2BP2 variants.

Getting to know adenosine deaminase 2 deficiency inside and out.

Ten years after the description of the first cohorts of patients with adenosine deaminase (ADA2) deficiency (DADA2), the pathomechanisms underlying the disease on a cellular level remain poorly understood. With the establishment of the lysosomal localization of the ADA2 protein and its involvement in nucleic acid sensing, the pathophysiologic focus has shifted to the inside of the cell. At the same time, extracellular (serum) ADA2 enzyme activity continues to be the diagnostic reference standard in patients with suspected DADA2.

Long-term safety of dexamethasone sodium phosphate encapsulated in autologous erythrocytes in pediatric patients with ataxia telangiectasia.

Background: Dexamethasone sodium phosphate (DSP) encapsulated in autologous erythrocytes (EryDex) was developed as an alternative to standard glucocorticoids in an effort to eliminate chronic steroid toxicity while preserving efficacy. The primary objective of this report is to describe the safety of long-term use of EryDex in treatment of pediatric patients with ataxia telangiectasia.

Methods: This is a post-hoc analysis of patients treated with EryDex for a minimum of 24 months in two prospective clinical trials.

Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.

IKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features.

Multiomics dissection of human RAG deficiency reveals distinctive patterns of immune dysregulation but a common inflammatory signature.

Human recombination-activating gene (RAG) deficiency can manifest with distinct clinical and immunological phenotypes. By applying a multiomics approach to a large group of -mutated patients, we aimed at characterizing the immunopathology associated with each phenotype. Although defective T and B cell development is common to all phenotypes, patients with hypomorphic variants can generate T and B cells with signatures of immune dysregulation and produce autoantibodies to a broad range of self-antigens, including type I interferons.

Dominant negative mutations cause ADA2 deficiency in heterozygous carriers.

Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype which encompasses vasculopathy including livedo racemosa and lacunar strokes, as well as hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the gene. DADA2 carriers harbor a single pathogenic variant in and are mostly considered healthy and asymptomatic.

A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations.

We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense (MS) mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a MS COPZ1 mutation had isolated neutropenia.

Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 IL-9-expressing cells.

Background: CD4 T cells play essential roles in adaptive immunity. Distinct CD4 T-cell subsets-T1, T2, T17, T22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing T9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity.

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.

Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive.

Successful Haematopoietic Stem Cell Transplantation for LRBA Deficiency with Fludarabine, Treosulfan, and Thiotepa-Based Conditioning.

LRBA deficiency is an inborn error of immunity defined by autoimmunity, lymphoproliferation, recurrent infections, cytopenia, and inflammatory bowel disease. Despite recent advances in managing this disease with targeted biologic therapy, haematopoietic stem cell transplant (HSCT) remains the only cure. However, great variability exists between protocols used to transplant patients with LRBA deficiency.

Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Background: Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia.

Charting a course for global progress in PIDs by 2030 - proceedings from the IPOPI global multi-stakeholders' summit (September 2023).

The International Patient Organisation for Primary Immunodeficiencies (IPOPI) held its second Global Multi-Stakeholders' Summit, an annual stimulating and forward-thinking meeting uniting experts to anticipate pivotal upcoming challenges and opportunities in the field of primary immunodeficiency (PID). The 2023 summit focused on three key identified discussion points: (i) How can immunoglobulin (Ig) therapy meet future personalized patient needs? (ii) Pandemic preparedness: what's next for public health and potential challenges for the PID community? (iii) Diagnosing PIDs in 2030: what needs to happen to diagnose better and to diagnose more? Clinician-Scientists, patient representatives and other stakeholders explored avenues to improve Ig therapy through mechanistic insights and tailored Ig preparations/products according to patient-specific needs and local exposure to infectious agents, amongst others. Urgency for pandemic preparedness was discussed, as was the threat of shortage of antibiotics and increasing antimicrobial resistance, emphasizing the need for representation of PID patients and other vulnerable populations throughout crisis and care management.

SARS-CoV-2 brainstem encephalitis in human inherited DBR1 deficiency.

Inherited deficiency of the RNA lariat-debranching enzyme 1 (DBR1) is a rare etiology of brainstem viral encephalitis. The cellular basis of disease and the range of viral predisposition are unclear. We report inherited DBR1 deficiency in a 14-year-old boy who suffered from isolated SARS-CoV-2 brainstem encephalitis.

Clinical efficacy of SARS-CoV-2 Omicron-neutralizing antibodies in immunoglobulin preparations for the treatment of agammaglobulinemia in patients with primary antibody deficiency.

Immunocompromised individuals are at significantly elevated risk for severe courses of coronavirus disease 2019 (COVID-19). In addition to vaccination, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (nAbs) have been applied throughout the pandemic, with time of treatment onset and potency against the currently prevailing virus variant identified as relevant factors for medical benefit. Using data from the European Society for Immunodeficiencies (ESID) registry, the present study evaluated COVID-19 cases in three groups of patients with inborn errors of immunity (IEI; 981 agammaglobulinemia patients on immunoglobulin replacement therapy (IGRT); 8960 non-agammaglobulinemia patients on IGRT; 14 428 patients without IGRT), and the neutralizing capacity of 1100 immunoglobulin lots against SARS-CoV-2 ("Wuhan" and Omicron strains), throughout 3 years.

The HyperPed-COVID international registry: Impact of age of onset, disease presentation and geographical distribution on the final outcome of MIS-C.

Objectives: The aim of the study was to establish an international multicenter registry to collect data on patients with Multisystem Inflammatory Syndrome in Children (MIS-C), in order to highlight a relationship between clinical presentation, age of onset and geographical distribution on the clinical outcome.

Study Design: Multicenter retrospective study involving different international societies for rare immunological disorders.1009 patients diagnosed with MIS-C between March and September 2022, from 48 centers and 22 countries were collected.

Pneumococcal antibody response in children with recurrent respiratory tract infections: A descriptive study.

Background: The pneumococcal antibody response after vaccination with unconjugated pneumococcal vaccine can be evaluated as part of the diagnostic work-up of children with recurrent respiratory tract infections to detect an underlying polysaccharide antibody deficiency. Little is known about the prevalence of polysaccharide antibody deficiency in this population and its therapeutic consequences.

Objectives: This study aimed to investigate the prevalence of polysaccharide antibody deficiency in children with recurrent respiratory tract infections and to correlate polysaccharide responsiveness with clinical severity.

Development of EBV Related Diffuse Large B-cell Lymphoma in Deficiency of Adenosine Deaminase 2 with Uncontrolled EBV Infection.

Deficiency of Adenosine Deaminase 2 (DADA2) patients presenting with primary immunodeficiency are at risk of uncontrolled EBV infection and secondary malignancies including EBV-related lymphoproliferative disorders (LPD). This paper describes the first case of EBV related diffuse large B-cell lymphoma in a patient with DADA2 and uncontrolled EBV infection. Consideration should be given to monitoring for EBV viraemia and to preventative EBV specific therapy in DADA2 and patients with at risk primary immunodeficiencies.