MEDNIK syndrome is a rare autosomal recessive disease characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma, and caused by variants in the adaptor-related protein complex 1 subunit sigma 1 (AP1S1) gene. This gene encodes the σ1A protein, which is a subunit of the adaptor protein complex 1 (AP-1), a key component of the intracellular protein trafficking machinery. Previous work identified three AP1S1 nonsense, frameshift and splice-site variants in MEDNIK patients predicted to encode truncated σ1A proteins, with consequent AP-1 dysfunction. However, two AP1S1 missense variants (c.269 T > C and c.346G > A) were recently reported in patients who presented with severe enteropathy but no additional symptoms of MEDNIK. This condition was described as a novel non-syndromic form of congenital diarrhea caused specifically by the AP1S1 missense variants. In this study, we report two patients with the same c.269 T > C variant, who, contrary to the previous cases, presented as complete MEDNIK syndrome. These data substantially revise the presentation of disorders associated with AP1S1 gene variants and indicate that all the identified pathogenic AP1S1 variants result in MEDNIK syndrome. We also provide a series of functional analyses that elucidate the impact of the c.269 T > C variant on σ1A function, contributing to a better understanding of the molecular pathogenesis of MEDNIK syndrome. KEY MESSAGES: A missense AP1S1 c.269 T > C (σ1A L90P) variant causes full MEDNIK syndrome. The σ1A L90P variant is largely unable to assemble into the AP-1 complex. The σ1A L90P variant fails to bind [DE]XXXL[LI] sorting motifs. The σ1A L90P variant results in loss-of-function of the protein.
- MeSH
- adaptorový proteinový komplex - sigma-podjednotky * genetika MeSH
- adaptorový proteinový komplex 1 * genetika MeSH
- genetická predispozice k nemoci MeSH
- lidé MeSH
- mentální retardace genetika MeSH
- missense mutace * MeSH
- průjem genetika MeSH
- syndrom MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Intramural MeSH
BACKGROUND: Common variable immunodeficiency (CVID) is characterized by an impaired postvaccination response, high susceptibility to respiratory tract infections, and a broad spectrum of noninfectious complications. Thus, patients with CVID may be at high risk for COVID-19, and vaccination's role in prevention is questionable. OBJECTIVE: We evaluated the clinical outcomes, safety, and dynamics of humoral and T-cell immune responses induced by the mRNA vaccine BNT162b2 in CVID. METHODS: This prospective observational cohort study focused on the clinical outcomes (proportion of infected patients and disease severity), safety (incidences of adverse events and changes in laboratory parameters), and dynamics of humoral (specific postvaccination and virus-neutralizing antibody assessment) and T-cell immune responses (anti-SARS-CoV-2-specific T-cell detection) in 21 patients with CVID after a two-dose administration of BNT162b2. The patients were observed for 6 months. RESULTS: Humoral response was observed in 52% of patients (11 of 21) at month 1 after vaccination but continuously decreased to 33.3% at month 6 (five of 15). Nevertheless, they had a remarkably lower anti-SARS-CoV-2 neutralizing antibody titer compared with healthy controls. The T-cell response was measurable in 46% of patients with CVID (six of 13) at month 1 and persisted over the study period. Mild infection occurred in three patients within the follow-up period (14.3%). The vaccine also exhibited a favorable safety profile. CONCLUSIONS: The BNT162b2 vaccine elicited a measurable antibody response in a high proportion of patients, but it was limited by low titer of virus-neutralizing antibodies and rapid waning of anti-receptor-binding domain SARS-CoV-2-specific antibodies. T-cell response was detected in one-third of patients and remained stable within the follow-up period. Vaccination has favorable safety and clinical-related outcomes in preventing severe COVID-19.
- MeSH
- běžná variabilní imunodeficience * MeSH
- COVID-19 * prevence a kontrola MeSH
- lidé MeSH
- neutralizující protilátky MeSH
- primární imunodeficience * MeSH
- prospektivní studie MeSH
- protilátky blokující MeSH
- protilátky virové MeSH
- SARS-CoV-2 MeSH
- vakcína BNT162 MeSH
- vakcíny * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- pozorovací studie MeSH
- práce podpořená grantem MeSH
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Primární imunodeficience (PID) je skupina geneticky podmíněných poruch imunitního systému, u které již bylo popsáno více než 300 kauzálních mutací. Negativním prognostickým faktorem pacientů s PID je tzv. dysregulace imunitního systému, projevující se autoreaktivními a autoinflamatorními komplikacemi. Zavedením sekvenování nové generace do klinického hodnocení je rychle rozšiřován rozsah monogenních poruch odpovědných za rozvoj PID. Značná část takto nalezených genetických variant ale není popsána v literatuře ani v dostupných databázích, a je proto bez předchozího testování nemožné posoudit jejich vliv na patogenezi a progresi onemocnění. Proto navrhujeme vyvinout a zavést do klinického hodnocení i metody podrobné imunofenotypizace leukocytů, doplněné o funkční hodnocení jejich reakcí na ex vivo stimuly. Souběžně budeme sekvenovat repertoár T a B buněčných receptorů pro identifikaci jejich restrikce, která se může podílet na projevech dysregulace. Souhrnné poznatky o změnách ve fenotypu, signalizaci a imunitním repertoáru pomůžou vybrat a v čase monitorovat vhodnou léčbu PID.; Primary Immunodeficiency Diseases (PIDD) are a group of disorders of the immune system, with over 300 causal mutations described to date. Immune dysregulation manifesting as autoimmunity and autoinflammation was described as a negative prognostic factor for patients with PIDD. Implementation of next generation sequencing into the clinical evaluation of affected individuals widens the range of identified monogenic errors rapidly. However, uncovering new variants previously undescribed in the literature and available databases makes impossible to assess their impact on the pathogenesis and progression of the disease. Therefore we propose to develop and implement methods for detailed immunophenotypic description of leukocytes, complemented with functional assessment of responses to ex vivo stimuli. In parallel, we will sequence a repertoire of T cell and B cell receptors in search for skewed patterns explaining deficiency and dysregulation. These insights into cellular, signaling and repertoire changes will enable us to select and monitor proper therapy in patients with PIDD.
- Klíčová slova
- sekvenování nové generace, Next generation sequencing, primární imunodeficience, dysregulace, dysregulation, signalizace, imunofenotyp, immunophenotype, signaling, funkční testy, functional assays, repertoár receptorů lymfocytů, lymphocyte receptor repertoire, autoinflamatorní projevy, monogenní poruchy, Primary Immunodeficiency Diseases, autoinflammation, monogenic errors,
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
BACKGROUND: Inborn errors of immunity are genetic disorders characterized by various degrees of immune dysregulation that can manifest as immune deficiency, autoimmunity, or autoinflammation. The routine use of next-generation sequencing in the clinic has facilitated the identification of an ever-increasing number of inborn errors of immunity, revealing the roles of immunologically important genes in human pathologies. However, despite this progress, treatment is still extremely challenging. OBJECTIVE: We sought to report a new monogenic autoinflammatory disorder caused by a de novo activating mutation, p.Tyr515∗, in hematopoietic cell kinase (HCK). The disease is characterized by cutaneous vasculitis and chronic pulmonary inflammation that progresses to fibrosis. METHODS: Whole-exome sequencing, Sanger sequencing, mass spectrometry, and western blotting were performed to identify and characterize the pathogenic HCK mutation. Dysregulation of mutant HCK was confirmed ex vivo in primary cells and in vitro in transduced cell lines. RESULTS: Mutant HCK lacking the C-terminal inhibitory tyrosine Tyr522 exhibited increased kinase activity and enhanced myeloid cell priming, migration and effector functions, such as production of the inflammatory cytokines IL-1β, IL-6, IL-8, and TNF-α, and production of reactive oxygen species. These aberrant functions were reflected by inflammatory leukocyte infiltration of the lungs and skin. Moreover, an overview of the clinical course of the disease, including therapies, provides evidence for the therapeutic efficacy of the Janus kinase 1/2 inhibitor ruxolitinib in inflammatory lung disease. CONCLUSIONS: We propose HCK-driven pulmonary and cutaneous vasculitis as a novel autoinflammatory disorder of inborn errors of immunity.
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an 'experiment of nature' to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal a RAG-dependent 'domino effect' that impacts stringency of tolerance and B cell fate in the periphery.
- MeSH
- B-lymfocyty * MeSH
- buněčná diferenciace MeSH
- DNA vazebné proteiny * nedostatek genetika MeSH
- homeodoménové proteiny * genetika MeSH
- imunologická tolerance MeSH
- jaderné proteiny * nedostatek MeSH
- lidé MeSH
- počet lymfocytů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- MeSH
- aminopyridiny MeSH
- anaplastický velkobuněčný lymfom * farmakoterapie MeSH
- laktamy MeSH
- lidé MeSH
- makrocyklické laktamy MeSH
- pyrazoly terapeutické užití MeSH
- reziduální nádor MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
INTRODUCTION: Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. METHODS: A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. RESULTS: Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. CONCLUSIONS: Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries.
- MeSH
- aktivační mutace * MeSH
- dítě MeSH
- inhibitory Janus kinas * terapeutické užití MeSH
- lidé MeSH
- multicentrické studie jako téma MeSH
- retrospektivní studie MeSH
- transkripční faktor STAT1 * genetika MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Our study presents a novel germline c.1715G>T (p.G572V) mutation in the gene encoding Toll-like receptor 8 (TLR8) causing an autoimmune and autoinflammatory disorder in a family with monozygotic male twins, who suffer from severe autoimmune hemolytic anemia worsening with infections, and autoinflammation presenting as fevers, enteritis, arthritis, and CNS vasculitis. The pathogenicity of the mutation was confirmed by in vitro assays on transfected cell lines and primary cells. The p.G572V mutation causes impaired stability of the TLR8 protein, cross-reactivity to TLR7 ligands and reduced ability of TLR8 to attenuate TLR7 signaling. This imbalance toward TLR7-dependent signaling leads to increased pro-inflammatory responses, such as nuclear factor-κB (NF-κB) activation and production of pro-inflammatory cytokines IL-1β, IL-6, and TNFα. This unique TLR8 mutation with partial TLR8 protein loss and hyperinflammatory phenotype mediated by TLR7 ligands represents a novel inborn error of immunity with childhood-onset and a good response to TLR7 inhibition.
- MeSH
- autoimunitní hemolytická anemie genetika imunologie MeSH
- cytokiny genetika imunologie MeSH
- dvojčata monozygotní MeSH
- HEK293 buňky MeSH
- lidé MeSH
- mutace * MeSH
- posouzení stavu pacienta MeSH
- toll-like receptor 7 genetika imunologie MeSH
- toll-like receptor 8 genetika imunologie MeSH
- zánět genetika imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- studie na dvojčatech MeSH
