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

Cíl: Zaměřili jsme se na stanovení prevalence infekce SARS-CoV-2 se symptomatickým nebo asymptomatickým průběhem a na identifikaci prediktorů symptomatické nebo asymptomatické infekce SARS-CoV-2 u pacientů během sedmi měsíců následujících po transplantaci alogenních hematopoetických kmenových buněk (alo-HSCT) v období cirkulace varianty omikron. Metody: Prevalence proběhlé infekce SARS-CoV-2 byla detekována u pacientů během sedmi měsíců po allo-HSCT v omikronovém období pomocí buněčné a humorální imunitní odpovědi proti nukleoproteinu SARS-CoV-2 (NCP). Výsledky: Pozitivní markery prodělané infekce byly identifikovány u 45,2 % pacientů (n = 42). Infekce byla asymptomatická u 68,4 % pacientů s anti-NCP pozitivitou. Hledání rizikových faktorů pro symptomatickou infekci SARS-CoV-2 u příjemců alo-HSCT odhalilo, že nízká úroveň rekonstituce B buněk byla jediným signifikantně souvisejícím rizikovým faktorem. Závěr: Vysoký podíl příjemců alo-HSCT, kteří byli asymptomaticky infikováni do sedmi měsíců po transplantaci v letech 2022–2023, přestože byli imunokompromitovaní a neočkovaní, ukazuje na oslabení cirkulujícího viru a může signalizovat pro pacienty po transplantaci menší riziko onemocnění SARS-CoV-2 v omikronovém období. Ukázalo se, že očkování těchto pacientů proti SARS- -CoV-2 je spojeno s nízkým, ale významným rizikem exacerbace vyléčené chronické reakce štěpu proti hostiteli (GVHD – Graft Versus Host Disease) a s rizikem de novo GVHD. Nízká úroveň rekonstituce B-buněk byla jediným významným rizikovým faktorem pro symptomatickou infekci SARS-CoV-2 u příjemců alo-HSCT.

Aim: We aimed to determine the prevalence of SARS-CoV-2 infection, including both symptomatic and asymptomatic courses, and to identify predictors of asymptomatic or symptomatic SARS-CoV-2 infection in patients within seven months after allo-HSCT (allogenic hematopoietic stem cell transplantation) in the Omicron period. Methods: Prevalence of the past SARS-CoV-2 infection was determined in patients within seven months after allo-HSCT in the Omicron period using the cellular and humoral immune response against the SARS-CoV-2 nucleoprotein (NCP). Results: Positive markers of past infection were identified in 45.2% of patients (n = 42). The infection was asymptomatic in 68.4% of anti-NCP positive patients. The search for risk factors for symptomatic SARS-CoV-2 infection in allo-HSCT recipients revealed that a low level of B cell reconstitution was the only significantly associated risk factor. Conclusion: A high proportion of allo-HSCT recipients who were asymptomatically infected within up to seven months after transplantation from 2022 to 2023 despite being immunosuppressed and unvaccinated indicates an attenuation of the circulating virus and may signal less risk for transplanted patients from SARS-CoV-2 infection in the Omicron period. Vaccination of these patients against SARS-CoV-2 was shown to be associated with a low but significant risk of exacerbation of cured chronic GVHD (graft versus host disease) and the risk of de novo GVHD. The low level of B-cell reconstitution was the only significant risk factor for symptomatic SARS-CoV-2 infection in HSCT recipients.

• Klíčová slova
• Omikron,
• MeSH
• asymptomatické infekce * epidemiologie   MeSH
• B-lymfocyty imunologie   mikrobiologie   transplantace   MeSH
• COVID-19 * komplikace   mikrobiologie   MeSH
• homologní transplantace MeSH
• kohortové studie MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli etiologie   imunologie   MeSH
• rizikové faktory MeSH
• SARS-CoV-2 patogenita   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• vakcíny proti COVID-19 škodlivé účinky   MeSH
• Check Tag
• lidé MeSH

Simian virus 40 (SV40) is a monkey virus with tumorigenic potential in rodents and is associated with several types of human cancers, including lymphomas. A related Merkel cell polyomavirus causes carcinoma in humans by expressing truncated large tumor antigen (LT), with truncations caused by APOBEC family of cytidine deaminase-induced mutations. AID (activation-induced cytidine deaminase), a member of the APOBEC family, is the initiator of the antibody diversification process known as somatic hypermutation and its aberrant expression and targeting is a frequent source of lymphomagenesis. In this study, we investigated whether AID could cause mutations in SV40 LT. We demonstrate that the SV40 enhancer has strong somatic hypermutation targeting activity in several cell types and that AID-induced mutations accumulate in SV40 LT in B cells and kidney cells and cause truncated LT expression in B cells. Our results argue that the ability of the SV40 enhancer to target somatic hypermutation to LT is a potential source of LT truncation events that could contribute to tumorigenesis in various cell types, thereby linking SV40 infection with malignant development through a novel mutagenic pathway.

• MeSH
• antigeny transformující polyomavirové genetika   metabolismus   MeSH
• antigeny virové nádorové genetika   metabolismus   MeSH
• B-lymfocyty virologie   metabolismus   imunologie   MeSH
• buněčné linie MeSH
• cytidindeaminasa * genetika   metabolismus   MeSH
• infekce onkogenními viry genetika   virologie   MeSH
• karcinogeneze genetika   MeSH
• lidé MeSH
• mutace MeSH
• opičí virus SV40 * genetika   MeSH
• polyomavirové infekce genetika   virologie   MeSH
• somatická hypermutace imunoglobulinových genů genetika   MeSH
• zesilovače transkripce * genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The establishment of long-lasting immunity against pathogens is facilitated by the germinal center (GC) reaction, during which B cells increase their antibody affinity and differentiate into antibody-secreting cells (ASC) and memory cells. These events involve modifications in chromatin packaging that orchestrate the profound restructuring of gene expression networks that determine cell fate. While several chromatin remodelers were implicated in lymphocyte functions, less is known about SMARCA5. Here, using ribosomal pull-down for analyzing translated genes in GC B cells, coupled with functional experiments in mice, we identified SMARCA5 as a key chromatin remodeler in B cells. While the naive B cell compartment remained unaffected following conditional depletion of Smarca5, effective proliferation during B cell activation, immunoglobulin class switching, and as a result GC formation and ASC differentiation were impaired. Single-cell multiomic sequencing analyses revealed that SMARCA5 is crucial for facilitating the transcriptional modifications and genomic accessibility of genes that support B cell activation and differentiation. These findings offer novel insights into the functions of SMARCA5, which can be targeted in various human pathologies.

• MeSH
• adenosintrifosfatasy MeSH
• aktivace lymfocytů imunologie   MeSH
• B-lymfocyty * metabolismus   imunologie   MeSH
• buněčná diferenciace * MeSH
• chromozomální proteiny, nehistonové * metabolismus   genetika   MeSH
• myši inbrední C57BL MeSH
• myši MeSH
• přesmyk imunoglobulinových tříd genetika   MeSH
• restrukturace chromatinu * MeSH
• zárodečné centrum lymfatické uzliny * imunologie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

A proliferation-inducing ligand (APRIL) is a key member of the tumor necrosis factor superfamily of cytokines and plays a central role in B-cell survival, proliferation, and Ig class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B-cell activating factor in several glomerular diseases, because of their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B-cell function and responses to vaccination, in contrast to B-cell-depleting strategies. In this review, we describe the physiological roles of APRIL in B-cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

• MeSH
• B-lymfocyty * imunologie   účinky léků   MeSH
• glomerulus imunologie   patologie   účinky léků   MeSH
• IgA nefropatie * imunologie   farmakoterapie   MeSH
• lidé MeSH
• protein TALL-2 * antagonisté a inhibitory   imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Detailed knowledge of human B-cell development is crucial for the proper interpretation of inborn errors of immunity and malignant diseases. It is of interest to understand the kinetics of protein expression changes during development, but also to properly interpret the major and possibly alternative developmental trajectories. We have investigated human samples from healthy individuals with the aim of describing all B-cell developmental trajectories. We validated a 30-parameter mass cytometry panel and demonstrated the utility of "vaevictis" visualization of B-cell developmental stages. We used the trajectory inference tool "tviblindi" to exhaustively describe all trajectories leading to all developmental ends discovered in the data. Focusing on Natural Effector B cells, we demonstrated the dynamics of expression of nuclear factors (PAX-5, TdT, Ki-67, Bcl-2), cytokine and chemokine receptors (CD127, CXCR4, CXCR5) in relation to the canonical B-cell developmental stage markers. We observed branching of the memory development, where follicular memory formation was marked by CD73 expression. Lastly, we performed an analysis of two example cases of abnormal B-cell development caused by mutations in RAG-1 and Wiskott-Aldrich syndrome gene in patients with primary immunodeficiency. In conclusion, we developed, validated, and presented a comprehensive set of tools for the investigation of B-cell development in the bone marrow compartment.

• MeSH
• algoritmy * MeSH
• B-lymfocyty * imunologie   MeSH
• buněčná diferenciace * imunologie   genetika   MeSH
• homeodoménové proteiny * genetika   metabolismus   MeSH
• lidé MeSH
• mutace MeSH
• Check Tag
• lidé 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

Multiple myeloma (MM) is an incurable malignancy of plasma cells. Epidemiological studies indicate a substantial heritable component, but the underlying mechanisms remain unclear. Here, in a genome-wide association study totaling 10,906 cases and 366,221 controls, we identify 35 MM risk loci, 12 of which are novel. Through functional fine-mapping and Mendelian randomization, we uncover two causal mechanisms for inherited MM risk: longer telomeres; and elevated levels of B-cell maturation antigen (BCMA) and interleukin-5 receptor alpha (IL5RA) in plasma. The largest increase in BCMA and IL5RA levels is mediated by the risk variant rs34562254-A at TNFRSF13B. While individuals with loss-of-function variants in TNFRSF13B develop B-cell immunodeficiency, rs34562254-A exerts a gain-of-function effect, increasing MM risk through amplified B-cell responses. Our results represent an analysis of genetic MM predisposition, highlighting causal mechanisms contributing to MM development.

• MeSH
• B-lymfocyty imunologie   metabolismus   MeSH
• celogenomová asociační studie * MeSH
• genetická predispozice k nemoci * MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• maturační antigen B-buněk * genetika   MeSH
• mendelovská randomizace MeSH
• mnohočetný myelom * genetika   MeSH
• receptor TACI genetika   MeSH
• studie případů a kontrol MeSH
• telomery genetika   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. METHODS: For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation. FINDINGS: This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. INTERPRETATION: Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. FUNDING: CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).

• MeSH
• aktivace komplementu MeSH
• autoprotilátky * krev   imunologie   MeSH
• B-lymfocyty metabolismus   imunologie   MeSH
• dospělí MeSH
• fenotyp * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myasthenia gravis * krev   diagnóza   imunologie   metabolismus   MeSH
• proteom MeSH
• proteomika * metody   MeSH
• receptory cholinergní * imunologie   metabolismus   MeSH
• senioři MeSH
• shluková analýza MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

V článku sa uvádza prehľad súčasného stavu poznatkov o imunoterapii spektra ochorení neuromyelitis optica (NMOSD, neuromyelitis optica spectrum disorders). Zneschopnenie pri NMOSD je následkom atakov a relapsov choroby, na ktoré sa sústreďuje liečba. Diagnostickým biomarkerom ochorenia sú autoprotilátky proti aquaporínu 4 (AQP4-IgG), ktoré zohrávajú dôležitú úlohu v patogenéze poškodenia astrocytov. Nedávny pokrok v chápaní NMOSD viedol k vývoju nových terapií a overeniu ich účinnosti v randomizovaných kontrolovaných štúdiách. Pre pacientov s pozitívnymi protilátkami proti AQP4 boli schválené nové imunoterapie, ktoré majú potenciál znížiť aktivitu ochorenia redukciou relapsov, sú to ekulizumab, ravulizumab, inebilizumab a satralizumab.

The article provides an overview of the current state of knowledge about neuromyelitis optica spectrum disorder (NMOSD) immunotherapy. Therapy focuses on the relapses that determine disability in NMOSD. Autoantibodies against aquaporin 4 (AQP4-IgG) are a diagnostic biomarker of the disease and have an important role in the pathogenesis of damage to astrocytes. Recent advances in the understanding of NMOSD have led to the development of new therapies and validation of their effectiveness in randomized controlled trials. New immunotherapies have been approved for patients with positive AQP4-igG antibodies, with the potential to reduce the number of relapses, namely eculizumab, ravulizumab, inebilizumab and satralizumab.

• MeSH
• akvaporin 4 imunologie   MeSH
• B-lymfocyty účinky léků   MeSH
• imunosupresiva farmakologie   klasifikace   škodlivé účinky   terapeutické užití   MeSH
• imunoterapie klasifikace   metody   MeSH
• inhibitory interleukinu-6 farmakologie   klasifikace   terapeutické užití   MeSH
• inhibitory komplementu farmakologie   klasifikace   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• lidé MeSH
• lymfocytární deplece metody   MeSH
• monoklonální protilátky farmakologie   klasifikace   terapeutické užití   MeSH
• neuromyelitis optica * farmakoterapie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH