Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an ultra-rare, progressive genetic disease, characterised by immune deficiency and dysregulation, affecting individuals from birth. In a 12-week phase III randomised placebo-controlled trial, leniolisib, a selective PI3Kδ inhibitor, was well-tolerated and met both co-primary endpoints (change from Baseline in log10-transformed sum of product of diameters of index lymph nodes and percentage of naïve/total B cells at Day 85). Here, prespecified subgroup analyses are reported in adolescents aged 12-17 years (leniolisib, n = 8; placebo, n = 4) and adults aged ≥18 (leniolisib, n = 13; placebo, n = 6). In both subgroups, leniolisib reduced lymphadenopathy (least squares mean change versus placebo: adolescents, -0.4 versus -0.1; adults, -0.3 versus 0.1) and increased the percentage of naïve B cells (least squares mean change: adolescents, 44.5 versus -16.5; adults, 28.4 versus -1.1). Leniolisib was well-tolerated in both adolescents and adults. These results show leniolisib is an effective APDS treatment in both subpopulations. PLAIN LANGUAGE SUMMARY: What is activated PI3Kδ syndrome (APDS)? APDS is an ultra-rare disease in which the immune system does not work correctly. People with APDS have a wide range of symptoms, including infections, certain organs associated with the immune system becoming larger, and worse quality of life. These symptoms generally start in childhood. Why was this study carried out? Current treatments only treat the symptoms of APDS, rather than correcting the cause of the problem. These treatments can also have significant side effects. A new medication for APDS called leniolisib aims to treat the underlying cause of the disease. This publication reports results from a clinical trial of leniolisib which compared patients who received leniolisib with patients who received a placebo. The aim of this report was to examine these clinical trial results to understand if leniolisib is effective and safe when treating both adolescents (12-17 years old) and adults (18 years and older) with APDS. What were the results of this study? Leniolisib improved the number of certain immune cells, compared to patients who did not receive leniolisib, in both adolescents and adults with APDS. Leniolisib also reduced the size of the enlarged immune system organs in both adolescents and adults with APDS. There were no major safety concerns for either age group who received leniolisib. What do these results mean? These results show that leniolisib can help the immune system to work in a way that is closer to those without APDS. This new treatment is effective and generally well-tolerated for both adolescents and adults. These results indicate that people with APDS are able to start treatment with leniolisib during adolescence, which may slow the build-up of symptoms and may also have a positive impact on the quality of their lives.

• MeSH
• B-lymfocyty imunologie   účinky léků   MeSH
• dítě MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• fosfatidylinositol-3-kinasy třídy I * genetika   antagonisté a inhibitory   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• primární imunodeficience * farmakoterapie   genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH

• MeSH
• granulom etiologie   diagnóza   MeSH
• lidé MeSH
• syndrom Nijmegen breakage * genetika   MeSH
• těžká kombinovaná imunodeficience * terapie   komplikace   diagnóza   MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• dopisy MeSH
• kazuistiky MeSH

BACKGROUND: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. OBJECTIVE: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. METHODS: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. RESULTS: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P = .004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. CONCLUSIONS: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. CLINICALTRIALS: gov identifier: NCT02859727.

• MeSH
• dospělí MeSH
• fosfatidylinositol-3-kinasy třídy I genetika   MeSH
• fosfatidylinositol-3-kinasy genetika   MeSH
• kvalita života MeSH
• lidé MeSH
• lymfadenopatie * komplikace   MeSH
• mladý dospělý MeSH
• mutace MeSH
• syndromy imunologické nedostatečnosti * genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Intramural MeSH

Juvenile idiopathic arthritis (JIA) is a multifactorial autoimmune disease with involvement of adaptive and also innate immunity. The biological therapy (IL-1ß, IL-6 and TNFa inhibitors) revolutionized patient care, but there is still substantial variability in response to these drugs among JIA patients. Predictors for good clinical outcome are still missing and moreover, the therapy might bring complications such as drug-induced autoimmune diseases or increased susceptibility to infections. Neutrophils have an important role in pathology of these adverse effects, therefore we plan to focus on neutrophil functions in JIA patients during biological therapy. Our approach will include detailed phenotyping, functional tests, neutrophil extracellular trap formation and an effect on other immune cells. Subsequently, we will investigate especially neutrophils from the synovial fluid by mass cytometry and transcriptomics to obtain their complex characteristics. We believe that, our work will help to define neutrophil-related biomarker that could help to improve clinical decision-making.

Juvenilní idiopatická artritida (JIA) je multifaktoriální autoimunitní onemocnění zahrnující jak adaptivní tak i přirozenou imunitu. I přes revoluční přínos biologické léčby při péči o pacienty, je stále velká variabilita u JIA pacientů v odpovídavosti na léčbu. Predikátory dobrého klinického vývoje se stále hledají a terapie také může přinést řadu komplikací, jako například indukci autoimunitních onemocnění nebo náchylnost k infekcím. Jelikož je známo, že se neutrofily se podílejí na patologii těchto nežádoucích účinků, plánujeme se zaměřit na funkční vlastnosti neutrofilů u JIA pacientů během biologické léčby (IL-1ß, IL-6, TNFa inhibitory). Projekt bude zahrnovat detailní fenotypizaci, funkční testy, tvorbu neutrofilních extracelulárních pastí a interakce s ostatními imunitními buňkami. Komplexní chatakteristiku doplníme detekcí neutrofilů v synoviální tekutině, jejich fenotypizací pomocí hmotnostní cytometrie a RNA sekvenace. Věříme, že tato práce poslouží k podrobnějšímu definování netrofilů jako biomarkerů, které napomohou nasměrovat klinická rozhodnutí a zlepší péči o pacienty.

• Klíčová slova
• synoviální tekutina, synovial fluid, biologická léčba, neutrofily, neutrophils, dendritické buňky, dendritic cells, juvenilní idiopatická artritida, juvenile idiopathic arthritis, CyTOF, RNA-seq, biologic therapy, RNA-seq, CyTOF,

• NLK Publikační typ
• závěrečné zprávy o řešení grantu AZV MZ ČR

Severe combined immunodeficiency (SCID) screening je souhrnný název pro nástroj časné detekce řady závažných vrozených poruch imunity. Současná kvantifikace excizních DNA molekul TREC a KREC umožňuje časně diagnostikovat závažné buněčné i protilátkové vrozené defekty imunity. Do dvouletého pilotního programu screeningu se v letech 2022–2023 v České republice zapojilo > 90 % novorozenců (vyšetřeno bylo 198 675 vzorků). Diagnostikováni byli 2 pacienti se SCID na podkladě CD3 epsilon deficience a atypického kompletního DiGeorgova syndromu a dalších 17 pacientů s jinými vrozenými poruchami imunity, z toho 9 s agamaglobulinemií. U dvou pacientů se SCID umožnil screening časnou kauzální terapii, tj. transplantaci hematopoetických buněk / thymu, u non-SCID pacientů vedla časná znalost jejich diagnózy k zavedení adekvátních režimových a profylaktických opatření za účelem snížení jejich následné morbidity. Od 1. ledna 2024 byl screening závažných vrozených poruch imunity spolu se spinální muskulární atrofií integrován do celoplošného novorozeneckého laboratorního screeningu.

Severe Combined Immunodeficiency (SCID) screening is a collective term for an early detection tool for a range of serious inborn errors of immunity. The quantification of excision DNA molecules TREC and KREC allows for early diagnosis of severe cellular and antibody immune defects. The recently concluded Czech pilot screening program (2022-2023) included over 90% of newborns (with 198,675 samples examined). Two patients with SCID were diagnosed based on CD3 epsilon deficiency and atypical complete DiGeorge syndrome, and another 17 patients were found to have other inborn errors of immunity, including 9 agammaglobulinemia. Screening enabled early causal therapy, i.e., hematopoietic cell/thymus transplantation, for two SCID patients, while early diagnosis in non-SCID patients led to the implementation of appropriate regimen and prophylactic measures to reduce subsequent morbidity. As of January 1, 2024, screening for severe inborn errors of immunity, along with screening for spinal muscular atrophy, becomes integral part of the national laboratory newborn screening program.

• MeSH
• agamaglobulinemie diagnóza   farmakoterapie   genetika   MeSH
• kojenec MeSH
• kombinovaná protilátková terapie terapeutické užití   MeSH
• lidé MeSH
• novorozenecký screening MeSH
• předškolní dítě MeSH
• primární imunodeficience * diagnóza   genetika   terapie   MeSH
• těžká kombinovaná imunodeficience diagnóza   genetika   terapie   MeSH
• thymus abnormality   patologie   MeSH
• transplantace hematopoetických kmenových buněk metody   MeSH
• transplantace orgánů MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• mužské pohlaví MeSH
• předškolní dítě MeSH
• Publikační typ
• kazuistiky MeSH

Schimke immuno-osseous dysplasia is a rare multisystemic disorder caused by biallelic loss of function of the SMARCAL1 gene that plays a pivotal role in replication fork stabilization and thus DNA repair. Individuals affected from this disease suffer from disproportionate growth failure, steroid resistant nephrotic syndrome leading to renal failure and primary immunodeficiency mediated by T cell lymphopenia. With infectious complications being the leading cause of death in this disease, researching the nature of the immunodeficiency is crucial, particularly as the state is exacerbated by loss of antibodies due to nephrotic syndrome or immunosuppressive treatment. Building on previous findings that identified the loss of IL-7 receptor expression as a possible cause of the immunodeficiency and increased sensitivity to radiation-induced damage, we have employed spectral cytometry and multiplex RNA-sequencing to assess the phenotype and function of T cells ex-vivo and to study changes induced by in-vitro UV irradiation and reaction of cells to the presence of IL-7. Our findings highlight the mature phenotype of T cells with proinflammatory Th1 skew and signs of exhaustion and lack of response to IL-7. UV light irradiation caused a severe increase in the apoptosis of T cells, however the expression of the genes related to immune response and regulation remained surprisingly similar to healthy cells. Due to the disease's rarity, more studies will be necessary for complete understanding of this unique immunodeficiency.

• MeSH
• apoptóza genetika   MeSH
• arterioskleróza genetika   etiologie   imunologie   MeSH
• dítě MeSH
• DNA-helikasy genetika   MeSH
• lidé MeSH
• metabolické nemoci kostí etiologie   genetika   MeSH
• nefrotický syndrom etiologie   genetika   MeSH
• oprava DNA * genetika   MeSH
• osteochondrodysplazie * genetika   imunologie   MeSH
• plicní embolie genetika   etiologie   MeSH
• poruchy růstu genetika   etiologie   MeSH
• primární imunodeficience * genetika   diagnóza   imunologie   MeSH
• syndromy imunologické nedostatečnosti genetika   imunologie   MeSH
• T-lymfocyty imunologie   MeSH
• ultrafialové záření škodlivé účinky   MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Agammaglobulinemia due to variants in IGLL1 has traditionally been considered an exceedingly rare form of severe B-cell deficiency, with only 8 documented cases in the literature. Surprisingly, the first agammaglobulinemic patient identified by newborn screening (NBS) through quantification of kappa-deleting recombination excision circles harbored variants in IGLL1. OBJECTIVE: We comprehensively reviewed clinical and immunologic findings of patients with B-cell deficiency attributed to variants in IGLL1. METHODS: NBS programs reporting the use of kappa-deleting recombination excision circle assays, the European Society for Immunodeficiencies Registry, and authors of published reports featuring patients with B-cell deficiency linked to IGLL1 variants were contacted. Only patients with (likely) pathogenic variants, reduced CD19+ counts, and no alternative diagnosis were included. RESULTS: The study included 13 patients identified through NBS, 2 clinically diagnosed patients, and 2 asymptomatic siblings. All had severely reduced CD19+ B cells (< 0.1 × 109/L) at first evaluation, yet subsequent follow-up assessments indicated residual immunoglobulin production. Specific antibody responses to vaccine antigens varied, with a predominant reduction observed during infancy. Clinical outcomes were favorable with IgG substitution. Two patients successfully discontinued substitution therapy without developing susceptibility to infections and while maintaining immunoglobulin levels. The pooled incidence of homozygous or compound heterozygous pathogenic IGLL1 variants identified by NBS in Austria, Czechia, and Switzerland was 1.3:100,000, almost double of X-linked agammaglobulinemia. CONCLUSION: B-cell deficiency resulting from IGLL1 variants appears to be more prevalent than initially believed. Despite markedly low B-cell counts, the clinical course in some patients may be milder than reported in the literature so far.

• MeSH
• agamaglobulinemie * genetika   imunologie   diagnóza   MeSH
• B-lymfocyty imunologie   MeSH
• dítě MeSH
• fenotyp * MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• Check Tag
• dítě MeSH
• kojenec MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• předškolní dítě MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• Klíčová slova
• syndrom VEXAS,
• MeSH
• genetické nemoci vázané na chromozom X * diagnóza   genetika   klasifikace   MeSH
• hematopoetické kmenové buňky patologie   MeSH
• lidé MeSH
• příznaky a symptomy MeSH
• vzácné nemoci diagnóza   klasifikace   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• úvodní články MeSH

Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS) is an inborn error of immunity that manifests as immune deficiency and dysregulation; symptoms include frequent infections and lymphoproliferation. In our dose-finding and phase 3 placebo-controlled trials, treatment with the selective PI3Kδ inhibitor leniolisib reduced lymphoproliferation and normalized lymphocyte subsets. Here, we present 6 years of follow-up from the 6 adult patients in the original dose-finding trial receiving leniolisib. We used data from the ongoing open-label extension study, which was supplemented at later time points by investigators, including health-related quality of life (HRQoL) assessed through a clinician-reported questionnaire. We observed improvements in HRQoL: 5 of 6 patients experienced an increase in physical capabilities and socialization, and a decrease in prescribed medications. Immune subsets improved in all patients: mean transitional B-cell levels decreased from 38.17% to 2.47% and the CD4:CD8 T-cell ratio normalized to 1.11. Manifestations seen before and within the first year of leniolisib exposure, such as infections and gastrointestinal conditions, attenuated after year 2, with few new conditions emerging out to year 6. Thrombocytopenia or lymphopenia remained present in half of patients at year 6. Of 83 adverse events through year 5, 90.36% were grade 1; none were grade 4/5 nor deemed leniolisib related. Collectively, we saw an enhancement in HRQoL as well as durable changes in lymphocyte subsets and clinical manifestations, further supporting the use of leniolisib as a long-term therapeutic option for the treatment of APDS. This trial was registered at www.ClinicalTrials.gov as #NCT02859727.

• MeSH
• dospělí MeSH
• fosfatidylinositol-3-kinasy třídy I * antagonisté a inhibitory   MeSH
• inhibitory fosfoinositid-3-kinasy terapeutické užití   farmakologie   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• primární imunodeficience * farmakoterapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The balance between the tumor-necrosis factor α (TNFα) and type-I interferon (T1IFN) pathways is crucial for proper immune function. Dysregulation of either pathway can contribute to autoimmune diseases development. Even though TNFα blockade has shown promising results in various autoimmune diseases, the effect on the balance between TNFα and T1IFN is elusive. We used targeted anti-TNFα therapies in juvenile idiopathic arthritis (JIA) as an experimental approach to study the cross-regulation between TNFα and type-I IFN. We found that TNFα-rich environment affected viral defense through the attenuation of T1IFN responses and affected the phenotype and distribution of myeloid dendritic cells, which are engaged in early viral infections. Anti-TNFα therapy normalized the observed deviations in JIA patients. We hypothesize that the inadequate immune response caused by a high TNFα environment could be projected to more frequent or lengthy viral infections and possibly play a role in the process of JIA disease development.

• MeSH
• dendritické buňky MeSH
• fenotyp MeSH
• interferon typ I * MeSH
• juvenilní artritida * farmakoterapie   MeSH
• lidé MeSH
• nekróza MeSH
• TNF-alfa MeSH
• virové nemoci * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH