Congenital athymia is a life-limiting disorder due to rare inborn errors of immunity causing impaired thymus organogenesis or abnormal thymic stromal cell development and function. Athymic infants have a T-lymphocyte-negative, B-lymphocyte-positive, natural killer cell-positive immunophenotype with profound T-lymphocyte deficiency and are susceptible to severe infections and autoimmunity. Patients variably display syndromic features. Expanding access to newborn screening for severe combined immunodeficiency and T lymphocytopenia and broad genetic testing, including next-generation sequencing technologies, increasingly facilitate their timely identification. The recommended first-line treatment is allogeneic thymus transplantation, which is a specialized procedure available in Europe and the United States. Outcomes for athymic patients are best with early diagnosis and thymus transplantation before the development of infectious and inflammatory complications. These guidelines on behalf of the European Society for Immunodeficiencies provide a comprehensive review for clinicians who manage patients with inborn thymic stromal cell defects; they offer clinical practice recommendations focused on the diagnosis, investigation, risk stratification, and management of congenital athymia with the aim of improving patient outcomes.
- MeSH
- lidé MeSH
- management nemoci MeSH
- novorozenec MeSH
- syndromy imunologické nedostatečnosti * terapie diagnóza imunologie MeSH
- thymus imunologie MeSH
- Check Tag
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- směrnice pro lékařskou praxi MeSH
- Geografické názvy
- Evropa MeSH
- MeSH
- extrakty z thymu farmakologie izolace a purifikace klasifikace terapeutické užití MeSH
- thymopentin farmakologie terapeutické užití MeSH
- thymopoetiny farmakologie terapeutické užití MeSH
- thymosin farmakologie terapeutické užití MeSH
- thymové hormony * farmakologie klasifikace terapeutické užití MeSH
- thymus imunologie metabolismus MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Newborn screening (NBS) programs for severe combined immunodeficiency facilitate early diagnosis of severe combined immunodeficiency and promote early treatment with hematopoietic stem cell transplantation, resulting in improved clinical outcomes. Infants with congenital athymia are also identified through NBS because of severe T-cell lymphopenia. With the expanding introduction of NBS programs, referrals of athymic patients for treatment with thymus transplantation have recently increased at Great Ormond Street Hospital (GOSH) (London, United Kingdom). OBJECTIVE: We studied the impact of NBS on timely diagnosis and treatment of athymic infants with thymus transplantation at GOSH. METHODS: We compared age at referral and complications between athymic infants diagnosed after clinical presentation (n = 25) and infants identified through NBS (n = 19) who were referred for thymus transplantation at GOSH between October 2019 and February 2023. We assessed whether age at time of treatment influences thymic output at 6 and 12 months after transplantation. RESULTS: The infants referred after identification through NBS were significantly younger and had fewer complications, in particular fewer infections. All deaths occurred in the group of those who did not undergo NBS, including 6 patients before and 2 after thymus transplantation because of preexisting infections. In the absence of significant comorbidities or diagnostic uncertainties, timely treatment was achieved more frequently after NBS. Treatment when younger than age 4 months was associated with higher thymic output at 6 and 12 months after transplantation. CONCLUSION: NBS contributes to earlier recognition of congenital athymia, promoting referral of athymic patients for thymus transplantation before they acquire infections or other complications and facilitating treatment at a younger age, thus playing an important role in improving their outcomes.
- MeSH
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- novorozenecký screening MeSH
- syndromy imunologické nedostatečnosti * MeSH
- těžká kombinovaná imunodeficience * diagnóza terapie MeSH
- thymus MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- novorozenec MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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
Hrudní chirurgie je stále více ovlivňována rozvojem miniinvazivních přístupů, jež ovlivnily i chirurgii v oblasti předního mediastina. Dříve standardně používaný přístup k thymu cestou parciální sternotomie byl ve většině případů postupně nahrazen přístupem videothorakoskopickým. V posledních letech se celosvětově i v této oblasti začíná prosazovat roboticky asistovaná chirurgie. Cílem našeho sdělení je vytvořit ucelený přehled o výkonech v oblasti thymu včetně jejich indikací a dále se podělit o naše první zkušenosti s roboticky asistovanou chirurgií thymu. Na III. chirurgické klinice bylo od zahájení programu roboticky asistované chirurgie thymu provedeno tímto přístupem 23 thymektomií, z toho 17 výkonů pro thymom, 3 pro myasthenia gravis a 3 pro adenom příštítného tělíska lokalizovaný ve tkáni thymu. Z našich zkušeností i dostupných dat vyplývá, že doba hospitalizace, míra komplikací a výsledný efekt roboticky asistovaných výkonů jsou srovnatelné s VTS výkony, umožňují však miniinvazivní ošetření i u pacientů výrazně obézních a u pacientů s pokročilým nádorem thymu, kteří by byli jinak indikováni k otevřené thymektomii.
Thoracic surgery is increasingly influenced by the development of minimally invasive approaches which have also influenced surgery in the area of the anterior mediastinum. The previously standard approach to the thymus via partial sternotomy was gradually replaced by the videothoracoscopic approach in most cases. In recent years, robotically assisted surgery has been gaining ground worldwide in this area, as well. The aim of our paper is to provide a comprehensive overview of procedures in the field of the thymus, including their indications, and to share our first experience with robot-assisted thymus surgery. At the 3rd Department of Surgery, since the start of the robot-assisted thymus surgery program, 23 thymectomies have been performed using this approach, of which 17 were performed for thymoma, 3 for myasthenia gravis, and 3 for parathyroid adenoma localized in thymus tissue. From our experience and the available data, it follows that the length of hospitalization, the rate of complications and the resulting effect of robot-assisted procedures is comparable to VTS procedures; however, the robot-assisted surgery also allows for mini-invasive treatment even in significantly obese patients and in patients with advanced thymic tumors who would otherwise be indicated for open thymectomy.
- MeSH
- lidé MeSH
- myasthenia gravis diagnóza imunologie patologie terapie MeSH
- nádory brzlíku chirurgie klasifikace MeSH
- roboticky asistované výkony * metody statistika a číselné údaje MeSH
- statistika jako téma MeSH
- stupeň závažnosti nemoci MeSH
- terapie metody statistika a číselné údaje MeSH
- thymektomie * metody MeSH
- thymom chirurgie diagnostické zobrazování MeSH
- thymus chirurgie patologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Since its discovery, Aire has been the topic of numerous studies in its role as a transcriptional regulator in the thymus where it promotes the "promiscuous" expression of a large repertoire of tissue-restricted antigens (TRAs) that are normally expressed only in the immune periphery. This process occurs in specialized medullary thymic epithelial cells (mTECs) and mediates the elimination of self-reactive T cells or promotes their conversion to the Foxp3+ regulatory T cell lineage, both of which are required for the prevention of autoimmunity. In recent years, there has been increasing interest in the role of extrathymic Aire expression in peripheral organs. The focus has primarily been on the identification of the cellular source(s) and mechanism(s) by which extrathymic AIRE affects tolerance-related or other physiological processes. A cadre of OMICs tools including single cell RNA sequencing and novel transgenic models to trace Aire expression to perform lineage tracing experiments have shed light on a phenomenon that is more complex than previously thought. In this chapter, we provide a deeper analysis of how extrathymic Aire research has developed and progressed, how cellular sources were identified, and how the function of AIRE was determined. Current data suggests that extrathymic AIRE fulfills a function that differs from what has been observed in the thymus and strongly argues that its main purpose is to regulate transcriptional programs in a cell content-dependent manner. Surprisingly, there is data that also suggests a non-transcriptional role of extrathymic AIRE in the cytoplasm. We have arrived at a potential turning point that will take the field from the classical understanding of AIRE as a transcription factor in control of TRA expression to its role in immunological and non-immunological processes in the periphery.
Patients with autoimmune polyendocrinopathy syndrome type 1 (APS-1) caused by autosomal recessive AIRE deficiency produce autoantibodies that neutralize type I interferons (IFNs)1,2, conferring a predisposition to life-threatening COVID-19 pneumonia3. Here we report that patients with autosomal recessive NIK or RELB deficiency, or a specific type of autosomal-dominant NF-κB2 deficiency, also have neutralizing autoantibodies against type I IFNs and are at higher risk of getting life-threatening COVID-19 pneumonia. In patients with autosomal-dominant NF-κB2 deficiency, these autoantibodies are found only in individuals who are heterozygous for variants associated with both transcription (p52 activity) loss of function (LOF) due to impaired p100 processing to generate p52, and regulatory (IκBδ activity) gain of function (GOF) due to the accumulation of unprocessed p100, therefore increasing the inhibitory activity of IκBδ (hereafter, p52LOF/IκBδGOF). By contrast, neutralizing autoantibodies against type I IFNs are not found in individuals who are heterozygous for NFKB2 variants causing haploinsufficiency of p100 and p52 (hereafter, p52LOF/IκBδLOF) or gain-of-function of p52 (hereafter, p52GOF/IκBδLOF). In contrast to patients with APS-1, patients with disorders of NIK, RELB or NF-κB2 have very few tissue-specific autoantibodies. However, their thymuses have an abnormal structure, with few AIRE-expressing medullary thymic epithelial cells. Human inborn errors of the alternative NF-κB pathway impair the development of AIRE-expressing medullary thymic epithelial cells, thereby underlying the production of autoantibodies against type I IFNs and predisposition to viral diseases.
- MeSH
- aktivační mutace MeSH
- autoprotilátky * imunologie MeSH
- COVID-19 genetika imunologie MeSH
- epiteliální buňky štítné žlázy metabolismus patologie MeSH
- genetická predispozice k nemoci * MeSH
- heterozygot MeSH
- interferon typ I * antagonisté a inhibitory imunologie MeSH
- kinasa indukující NF-kappaB MeSH
- lidé MeSH
- mutace ztráty funkce MeSH
- NF-kappa B - podjednotka p52 nedostatek genetika MeSH
- NF-kappa B * nedostatek genetika MeSH
- protein AIRE MeSH
- proteiny I-kappa B nedostatek genetika MeSH
- thymus abnormality imunologie patologie MeSH
- virová pneumonie genetika imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- autoimunitní regulátor,
- MeSH
- antigen prezentující buňky imunologie MeSH
- antigeny imunologie klasifikace MeSH
- autoimunitní polyglandulární syndromy genetika imunologie klasifikace MeSH
- dendritické buňky imunologie MeSH
- imunologická tolerance * imunologie MeSH
- lidé MeSH
- specificita protilátek imunologie MeSH
- T-lymfocyty imunologie klasifikace MeSH
- thymus imunologie růst a vývoj MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Mature T cells are selected for recognizing self-antigens with low to intermediate affinity in the thymus. Recently, the relative differences in self-reactivity among individual T-cell clones were appreciated as important factors regulating their fate and immune response, but the role of self-reactivity in T-cell biology is incompletely understood. We addressed the role of self-reactivity in T-cell diversity by generating an atlas of mouse peripheral CD8+ T cells, which revealed two unconventional populations of antigen-inexperienced T cells. In the next step, we examined the steady-state phenotype of monoclonal T cells with various levels of self-reactivity. Highly self-reactive clones preferentially differentiate into antigen-inexperienced memory-like cells, but do not form a population expressing type I interferon-induced genes, showing that these two subsets have unrelated origins. The functional comparison of naïve monoclonal CD8+ T cells specific to the identical model antigen did not show any correlation between the level of self-reactivity and the magnitude of the immune response.
- MeSH
- autoantigeny MeSH
- buněčné klony MeSH
- CD8-pozitivní T-lymfocyty * MeSH
- interferon typ I * MeSH
- myši MeSH
- thymus MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
The inevitability of evolution of the adaptive immune system with its mechanism of randomly rearranging segments of the T cell receptor (TCR) gene is the generation of self-reactive clones. For the sake of prevention of autoimmunity, these clones must be eliminated from the pool of circulating T cells. This process occurs largely in the thymic medulla where the strength of affinity between TCR and self-peptide MHC complexes is the factor determining thymocyte fate. Thus, the display of self-antigens in the thymus by thymic antigen presenting cells, which are comprised of medullary thymic epithelial (mTECs) and dendritic cells (DCs), is fundamental for the establishment of T cell central tolerance. Whereas mTECs produce and present antigens in a direct, self-autonomous manner, thymic DCs can acquire these mTEC-derived antigens by cooperative antigen transfer (CAT), and thus present them indirectly. While the basic characteristics for both direct and indirect presentation of self-antigens are currently known, recent reports that describe the heterogeneity of mTEC and DC subsets, their presentation capacity, and the potentially non-redundant roles in T cell selection processes represents another level of complexity which we are attempting to unravel. In this review, we underscore the seminal studies relevant to these topics with an emphasis on new observations pertinent to the mechanism of CAT and its cellular trajectories underpinning the preferential distribution of thymic epithelial cell-derived self-antigens to specific subsets of DC. Identification of molecular determinants which control CAT would significantly advance our understanding of how the cellularly targeted presentation of thymic self-antigens is functionally coupled to the T cell selection process.
