RESUMEN
Patients with hypomorphic mutations in the RAG1 or RAG2 gene present with either Omenn syndrome or atypical combined immunodeficiency with a wide phenotypic range. Hematopoietic stem cell transplantation (HSCT) is potentially curative, but data are scarce. We report on a worldwide cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, 78% of whom experienced infections (29% active at HSCT), 72% had autoimmunity, and 18% had granulomas pretransplant. These complications are frequently associated with organ damage. Eight individuals (13%) were diagnosed by newborn screening or family history. HSCT was performed at a median of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and 30% of the patients, respectively. Grafts were T-cell depleted in 15 cases (25%). Overall survival at 1 and 4 years was 77.5% and 67.5% (median follow-up of 39 months). Infection was the main cause of death. In univariable analysis, active infection, organ damage pre-HSCT, T-cell depletion of the graft, and transplant from a mismatched family donor were predictive of worse outcome, whereas organ damage and T-cell depletion remained significant in multivariable analysis (hazard ratio [HR] = 6.01, HR = 8.46, respectively). All patients diagnosed by newborn screening or family history survived. Cumulative incidences of acute and chronic graft-versus-host disease were 35% and 22%, respectively. Cumulative incidences of new-onset autoimmunity was 15%. Immune reconstitution, particularly recovery of naïve CD4+ T cells, was faster and more robust in patients transplanted before 3.5 years of age, and without organ damage. These findings support the indication for early transplantation.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Recién Nacido , Humanos , Donantes de Tejidos , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Diagnóstico Precoz , Costo de Enfermedad , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Donante no Emparentado , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multidisciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-vs.-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines were divided into two parts: PART I covers Cutaneous T-cell lymphoma, chronic graft-vs.-host disease and acute graft-vs.-host disease, while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatric patients, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.
Asunto(s)
Dermatología , Enfermedad Injerto contra Huésped , Linfoma Cutáneo de Células T , Fotoféresis , Neoplasias Cutáneas , Niño , Humanos , Linfoma Cutáneo de Células T/terapiaRESUMEN
INTRODUCTION OR BACKGROUND: For many primary immunodeficiencies (PIDs), haematopoietic stem cell transplantation (HSCT) offers treatment to cure disease. However, patients with PID present a unique set of challenges when considering HSCT. SOURCES OF DATA: Review of recent literature. AREAS OF AGREEMENT: The most significant recent impact on successful outcome is introduction of newborn screening programmes for diagnosis of severe combined immunodeficiency-wider adoption of screening in an increasing number of countries will see further improvements. Other PIDs have better outcomes when treated earlier, before development of co-morbidities-early referral for consideration of HSCT is important. Evolution of conditioning regimens is improving short- and long-term toxicities-targeted busulfan and low-toxicity myeloablative treosulfan regimens deliver good survival with reduced short-term toxicities. AREAS OF CONTROVERSY: The most radical development, still in clinical trials, is the use of mono-antibody-based conditioning, which eliminates the requirement for chemotherapy and is likely to become much more important in HSCT for non-malignant disease in the future. GROWING POINTS: Multidisciplinary working for optimum care is essential. AREAS TIMELY FOR DEVELOPING RESEARCH: International collaborations are important to learn about rare presentations and complications, and to formulate the most effective and safe treatment strategies.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Niño , Humanos , Acondicionamiento PretrasplanteRESUMEN
BACKGROUND: Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T-cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi-disciplinary setting. It has confirmed recognition in well-known documented conditions such as graft-versus-host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. MATERIALS AND METHODS: In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. RESULTS AND CONCLUSION: These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T-cell lymphoma, chronic graft-versus-host disease and acute graft-versus-host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.
Asunto(s)
Dermatología , Enfermedad Injerto contra Huésped , Linfoma Cutáneo de Células T , Fotoféresis , Neoplasias Cutáneas , Niño , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Linfoma Cutáneo de Células T/terapiaRESUMEN
PURPOSE OF REVIEW: Hematopoietic cell transplantation (HCT) is an established curative treatment for children with primary immunodeficiencies. This article reviews the latest developments in conditioning regimens for primary immunodeficiency (PID). It focuses on data regarding transplant outcomes according to newer reduced toxicity conditioning regimens used in HCT for PID. RECENT FINDINGS: Conventional myeloablative conditioning regimens are associated with significant acute toxicities, transplant-related mortality, and late effects such as infertility. Reduced toxicity conditioning regimens have had significant positive impacts on HCT outcome, and there are now well-established strategies in children with PID. Treosulfan has emerged as a promising preparative agent. Use of a peripheral stem cell source has been shown to be associated with better donor chimerism in patients receiving reduced toxicity conditioning. Minimal conditioning regimens using monoclonal antibodies are in clinical trials with promising results thus far. Reduced toxicity conditioning has emerged as standard of care for PID and has resulted in improved transplant survival for patients with significant comorbidities.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedades de Inmunodeficiencia Primaria/terapia , Acondicionamiento Pretrasplante/métodos , Busulfano/análogos & derivados , Busulfano/farmacocinética , Busulfano/uso terapéutico , Humanos , Inmunosupresores/farmacocinética , Inmunosupresores/uso terapéutico , Enfermedades de Inmunodeficiencia Primaria/metabolismo , Vidarabina/análogos & derivados , Vidarabina/farmacocinética , Vidarabina/uso terapéuticoRESUMEN
Acute graft-versus-host disease (aGVHD) complicates allogeneic hematopoietic stem cell transplantation (HSCT), and is treated with topical and/or systemic corticosteroids. Systemic corticosteroids and aGVHD damage thymic tissue. We compared thymopoietic effect of topical steroid therapy, corticosteroids and extracorporeal photopheresis (ECP) in 102 pediatric allogeneic HSCT patients. We categorized patients into 4 groups: - no aGVHD, aGVHD treated with topical or systemic steroid, or ECP. Naïve CD4+CD45RA+CD27+ T-lymphocyte values at 3, 6, 9, 12months post-HSCT were recorded: for ECP patients, values were recorded at 3, 6, 9, 12months during ECP. Differences were compared using the Kruskal-Wallis test. 41 patients had no aGVHD, 23 had aGVHD treated topically or systemically (25), 13 received ECP. Rate of thymopoiesis was significantly different between all groups at all time-points post-transplant (p=0.002, p<0.001, p<0.001, p=0.001 respectively). Even mild aGVHD impairs thymopoiesis. Worst recovery was in ECP patients. Earlier institution of ECP may speed thymic recovery.
Asunto(s)
Corticoesteroides/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Enfermedad Injerto contra Huésped/inmunología , Trasplante de Células Madre Hematopoyéticas , Inmunosupresores/uso terapéutico , Timo/inmunología , Enfermedad Aguda , Niño , Preescolar , Estudios de Cohortes , Femenino , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Hematopoyesis , Humanos , Lactante , Antígenos Comunes de Leucocito/metabolismo , Masculino , Fotoféresis , Estudios Retrospectivos , Trasplante Homólogo , Miembro 7 de la Superfamilia de Receptores de Factores de Necrosis Tumoral/metabolismoRESUMEN
This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.
Asunto(s)
Monitoreo Epidemiológico , Síndromes de Inmunodeficiencia/epidemiología , Sistema de Registros/estadística & datos numéricos , Femenino , Humanos , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/terapia , Masculino , Reino Unido/epidemiologíaRESUMEN
This report summarizes the establishment of the first national online registry of primary immune deficency in the United Kingdom, the United Kingdom Primary Immunodeficiency (UKPID Registry). This UKPID Registry is based on the European Society for Immune Deficiency (ESID) registry platform, hosted on servers at the Royal Free site of University College, London. It is accessible to users through the website of the United Kingdom Primary Immunodeficiency Network (www.ukpin.org.uk). Twenty-seven centres in the United Kingdom are actively contributing data, with an additional nine centres completing their ethical and governance approvals to participate. This indicates that 36 of 38 (95%) of recognized centres in the United Kingdom have engaged with this project. To date, 2229 patients have been enrolled, with a notable increasing rate of recruitment in the past 12 months. Data are presented on the range of diagnoses recorded, estimated minimum disease prevalence, geographical distribution of patients across the United Kingdom, age at presentation, diagnostic delay, treatment modalities used and evidence of their monitoring and effectiveness.
Asunto(s)
Síndromes de Inmunodeficiencia , Internet , Sistema de Registros , Femenino , Humanos , Síndromes de Inmunodeficiencia/diagnóstico , Síndromes de Inmunodeficiencia/epidemiología , Síndromes de Inmunodeficiencia/terapia , Masculino , Reino Unido/epidemiologíaRESUMEN
Chronic Granulomatous Disease (CGD) is a rare primary immunodeficiency due to a defect in one of the NADPH oxidase complex subunits; 70 % of cases are X-linked, due to a CYBB mutation, resulting in defective production of gp91PHOX. Female carriers of X-linked CGD have previously been considered to be unaffected. It is increasingly recognized that they may suffer from similar problems to CGD patients. This review will examine the literature about clinical manifestations of disease in X-linked carriers of CGD.
Asunto(s)
Enfermedad Granulomatosa Crónica/genética , Enfermedad Granulomatosa Crónica/inmunología , NADPH Oxidasas/deficiencia , Tamización de Portadores Genéticos , Enfermedad Granulomatosa Crónica/patología , Humanos , Lupus Eritematoso Discoide/genética , Lupus Eritematoso Discoide/inmunología , Lupus Eritematoso Discoide/patología , NADPH Oxidasas/genética , Neutrófilos/inmunología , Neutrófilos/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Estallido Respiratorio/genética , Estallido Respiratorio/inmunologíaRESUMEN
In September 2006, the 7-valent pneumococcal conjugate vaccine (PCV7) was added to the UK immunization programme. We aimed to evaluate the impact of PCV7 on the incidence of all-cause community-acquired pneumonia (CAP) in children. A prospective survey was undertaken in 2008-2009 at 11 hospitals in North East England of children aged 0-16 years with radiologically confirmed pneumonia. Data were compared to those from a similar survey undertaken in the same hospitals in 2001-2002. A total of 542 children were enrolled, of which 74% were aged <5 years. PCV7 uptake was 90â7%. The incidence of pneumonia was 11â8/10,000 [95% confidence interval (CI) 10â9-12â9], and the hospitalization rate was 9â9/10,000 (95% CI 9â0-10â9). Compared to 2001, there was a 19% (95% CI 8-29) reduction in the rate of CAP in those aged <5 years, and in those <2 years a 33â1% (95% CI 20-45) reduction in the incidence of CAP and 38â1% (95% CI 24-50) reduction in hospitalization rates. However, for those unvaccinated aged ≥5 years, there was no difference in the incidence of CAP and hospitalization rate between both surveys. Since 2001, the overall reduction in incidence was 17â7% (95% CI 8-26) and for hospitalization 18â5% (95% CI 8-28). For the <5 years age group there was a lower incidence of CAP in PCV7-vaccinated children (25â2/10,000, 95% CI 22â6-28â2) than in those that were not vaccinated (37â4/10,000, 95% CI 29â2-47â1). In conclusion, PCV7 has reduced both incidence and rate of hospitalization of pneumonia in children, particularly in the <2 years age group.
Asunto(s)
Vacunas Neumococicas/uso terapéutico , Neumonía/prevención & control , Preescolar , Infecciones Comunitarias Adquiridas/epidemiología , Infecciones Comunitarias Adquiridas/prevención & control , Inglaterra/epidemiología , Humanos , Incidencia , Lactante , Vacunas Neumococicas/inmunología , Neumonía/epidemiología , Estudios Prospectivos , Streptococcus pneumoniae/fisiología , Vacunas Conjugadas/inmunología , Vacunas Conjugadas/uso terapéuticoRESUMEN
Chromosome 22q11 deletion is the most common chromosomal deletion syndrome and is found in the majority of patients with DiGeorge syndrome and velo-cardio-facial syndrome. Patients with CHARGE syndrome may share similar features. Cardiac malformations, speech delay, and immunodeficiency are the most common manifestations. The immunological phenotype may vary widely between patients. Severe T lymphocyte immunodeficiency is rare-thymic transplantation offers a new approach to treatment, as well as insights into thymic physiology and central tolerance. Combined partial immunodeficiency is more common, leading to recurrent sinopulmonary infection in early childhood. Autoimmunity is an increasingly recognized complication. New insights into pathophysiology are reviewed.
Asunto(s)
Síndrome CHARGE/inmunología , Deleción Cromosómica , Cromosomas Humanos Par 22/inmunología , Síndrome de DiGeorge , Síndromes de Inmunodeficiencia/inmunología , Anomalías Múltiples/genética , Anomalías Múltiples/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Síndrome CHARGE/genética , Tolerancia Central , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/inmunología , Humanos , Síndromes de Inmunodeficiencia/genética , Linfocitos T/inmunología , Linfocitos T/metabolismo , Timo/crecimiento & desarrollo , Timo/inmunología , Timo/patologíaRESUMEN
Chronic granulomatous disease (CGD) is an inborn error of immunity due to defects in the transport or function of subunits of nicotinamide adenine dinucleotide phosphate oxidase, the enzyme that generates the phagocyte respiratory burst responsible for intracellular killing of engulfed micro-organisms. Patients present with infectious or inflammatory complications. Common bacterial pathogens include Staphylococcus aureus and Burkholderia cepacia complex. Fungal pathogens include Aspergillus species, particularly Aspergillus fumigatus. Inflammatory complications most commonly manifest as inflammatory bowel disease or lung disease. Granulomata are the distinguishing histological feature. Haematopoietic stem cell transplantation (HSCT) was first considered for CGD in the early 1970's. Since then, refinements in transplant technique, donor selection, conditioning regimens, and graft engineering have widened the option of HSCT to most patients with CGD. This review charts the progress made in HSCT for CGD.
RESUMEN
INTRODUCTION: Hematopoietic stem cell transplantation is a curative treatment for many inborn errors of immunity (IEI). Incremental improvements and advances in care have led to high rates of >85% survival and cure in many of these diseases. Improvements in HLA-classification and matching have led to increased survival using HLA-matched donors, but survival using T-lymphocyte-depleted mismatched grafts remained significantly worse until fairly recently. Advances in T-lymphocyte depletion methods and graft engineering, although not specific to IEI, have been widely adopted and instrumental in changing the landscape of donor selection, such that a donor should now be possible for every patient. AREAS COVERED: A literature review focusing on T-lymphocyte depletion methodologies and treatment results was performed. The importance of early T-lymphocyte immunoreconstitution to protect against viral infection is reviewed. Two main platforms now dominate the field - immune-magnetic selection of specific cell types and post-transplant chemotherapeutic targeting of rapidly proliferating allo-reactive T-lymphocytes - the emerging literature on these reports, focusing on IEI, is explored, as well as the impact of serotherapy on early immunoreconstitution. EXPERT OPINION: Pharmacokinetic monitoring of serotherapy agents, and use of co-stimulatory molecule blockade are likely to become more widespread. Post-transplant cyclophosphamide or TCR depletion strategies are likely to become the dominant methods of transplantation for nonmalignant diseases.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Virosis , Humanos , Linfocitos T , Trasplante de Células Madre Hematopoyéticas/métodos , Resultado del Tratamiento , Depleción Linfocítica/métodosRESUMEN
In 22q11.2 deletion patients, the normal decrease in T lymphocyte counts after 1-2 years is blunted such that relatively T lymphocyte numbers increase over early childhood, probably via post-thymic expansion of peripheral lymphocytes. This may leave less T lymphocyte receptor (TCR) diversity than when derived from naive thymic emigrants. We analysed TCR Vß repertoire on 27 22q11.2 chromosome deletion patients. No patient had infection at sampling. CD3(+) CD4(+) recent thymic emigrants (RTEs) were identified by CD45RA and CD31 expression. TCR Vß repertoire was determined using four-colour flow cytometry. Patients and controls showed significant TCR Vß family usage differences between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subpopulations. Vß family abnormalities (±3 SD of controls) were identified in 18/27 (67%) patients and 12/47 (25%) controls. In patients, the magnitude of expansions was increased, with some Vß families representing 37% of the cells present in the subpopulations. There was a significant increase in frequency of abnormalities in CD3(+) CD4(+) (P < 0.001) and CD3(+) CD4(-) T lymphocytes (P < 0.05) in patients. A total of 11/16 patients had an abnormal CD4(+) CD25(Bright) TCR Vß repertoire. There was no difference in expansions/contractions between CD4(+) CD25(Bright) and CD4(+) T lymphocyte repertoires (P = 0.575) for individual patients but significant differences in expansions/contractions between CD4(+) CD25(Bright) and CD8(+) T lymphocytes repertoires (P = 0.011). There was bias in Vß usage between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subsets. A total of 67% patients had TCR Vß repertoire abnormalities, with a trend towards increased repertoire abnormalities with fewer RTEs, suggesting thymic output plays an important role in TCR repertoire diversity. There was no correlation between skewed repertoire and symptoms of infection or autoimmunity.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunofenotipificación/métodos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Adolescente , Niño , Preescolar , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/inmunología , Citometría de Flujo , Humanos , Lactante , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Estadísticas no ParamétricasRESUMEN
Cockayne syndrome is an autosomal recessive multisystem disorder characterized principally by neurological and sensory impairment, cachectic dwarfism, and photosensitivity. This rare disease is linked to mutations in the CSB/ERCC6 and CSA/ERCC8 genes encoding proteins involved in the transcription-coupled DNA repair pathway. The clinical spectrum of Cockayne syndrome encompasses a wide range of severity from severe prenatal forms to mild and late-onset presentations. We have reviewed the 45 published mutations in CSA and CSB to date and we report 43 new mutations in these genes together with the corresponding clinical data. Among the 84 reported kindreds, 52 (62%) have mutations in the CSB gene. Many types of mutations are scattered along the whole coding sequence of both genes, but clusters of missense mutations can be recognized and highlight the role of particular motifs in the proteins. Genotype-phenotype correlation hypotheses are considered with regard to these new molecular and clinical data. Additional cases of molecular prenatal diagnosis are reported and the strategy for prenatal testing is discussed. Two web-based locus-specific databases have been created to list all identified variants and to allow the inclusion of future reports (www.umd.be/CSA/ and www.umd.be/CSB/).
Asunto(s)
Síndrome de Cockayne/genética , ADN Helicasas/genética , Enzimas Reparadoras del ADN/genética , Mutación/genética , Factores de Transcripción/genética , Secuencia de Aminoácidos , Síndrome de Cockayne/diagnóstico , ADN Helicasas/química , Enzimas Reparadoras del ADN/química , Bases de Datos Genéticas , Estudios de Asociación Genética , Humanos , Datos de Secuencia Molecular , Proteínas de Unión a Poli-ADP-Ribosa , Polimorfismo Genético , Alineación de Secuencia , Relación Estructura-Actividad , Factores de Transcripción/químicaRESUMEN
Patients with chronic mucocutaneous candidiasis (CMC) have an unknown primary immune defect and are unable to clear infections with the yeast Candida. CMC includes patients with AIRE gene mutations who have autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), and patients without known mutations. CMC patients have dysregulated cytokine production, suggesting that defective expression of pattern recognition receptors (PRRs) may underlie disease pathogenesis. In 29 patients with CMC (13 with APECED) and controls, we assessed dendritic cell (DC) subsets and monocyte Toll-like receptor (TLR) expression in blood. We generated and stimulated monocyte-derived (mo)DCs with Candida albicans, TLR-2/6 ligand and lipopolysaccharide and assessed PRR mRNA expression by polymerase chain reaction [TLR-1-10, Dectin-1 and -2, spleen tyrosine kinase (Syk) and caspase recruitment domain (CARD) 9] in immature and mature moDCs. We demonstrate for the first time that CMC patients, with or without APECED, have normal blood levels of plasmocytoid and myeloid DCs and monocyte TLR-2/TLR-6 expression. We showed that in immature moDCs, expression levels of all PRRs involved in anti-Candida responses (TLR-1, -2, -4, -6, Dectin-1, Syk, CARD9) were comparable to controls, implying that defects in PRR expression are not responsible for the increased susceptibility to Candida infections seen in CMC patients. However, as opposed to healthy controls, both groups of CMC patients failed to down-regulate PRR mRNA expression in response to Candida, consistent with defective DC maturation, as we reported recently. Thus, impaired DC maturation and consequent altered regulation of PRR signalling pathways rather than defects in PRR expression may be responsible for inadequate Candida handling in CMC patients.
Asunto(s)
Candidiasis Mucocutánea Crónica/inmunología , Poliendocrinopatías Autoinmunes/inmunología , Receptores de Reconocimiento de Patrones/sangre , Candida albicans/inmunología , Candidiasis Mucocutánea Crónica/genética , Diferenciación Celular/inmunología , Células Cultivadas , Células Dendríticas/inmunología , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Lipopolisacáridos/inmunología , Masculino , Monocitos/inmunología , Mutación , Poliendocrinopatías Autoinmunes/genética , Reacción en Cadena de la Polimerasa/métodos , ARN Mensajero/genética , Receptores de Reconocimiento de Patrones/biosíntesis , Receptores de Reconocimiento de Patrones/genética , Transducción de Señal/inmunología , Factores de Transcripción/genética , Proteína AIRERESUMEN
BACKGROUND: Immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome) is a rare autosomal recessive disease characterised by facial dysmorphism, immunoglobulin deficiency and branching of chromosomes 1, 9 and 16 after PHA stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients which is explained by mutations in the DNA methyltransferase gene DNMT3B in some, but not all, ICF patients. OBJECTIVE: To obtain a comprehensive description of the clinical features of this syndrome as well as genotype-phenotype correlations in ICF patients. METHODS: Data on ICF patients were obtained by literature search and additional information by means of questionnaires to corresponding authors. RESULTS AND CONCLUSIONS: 45 patients all with proven centromeric instability were included in this study. Facial dysmorphism was found to be a common characteristic (n = 41/42), especially epicanthic folds, hypertelorism, flat nasal bridge and low set ears. Hypo- or agammaglobulinaemia was demonstrated in nearly all patients (n = 39/44). Opportunistic infections were seen in several patients, pointing to a T cell dysfunction. Haematological malignancy was documented in two patients. Life expectancy of ICF patients is poor, especially those with severe infections in infancy or chronic gastrointestinal problems and failure to thrive. Early diagnosis of ICF is important since early introduction of immunoglobulin supplementation can improve the course of the disease. Allogeneic stem cell transplantation should be considered as a therapeutic option in patients with severe infections or failure to thrive. Only 19 of 34 patients showed mutations in DNMT3B, suggesting genetic heterogeneity. No genotype-phenotype correlation was found between patients with and without DNMT3B mutations.
Asunto(s)
Inestabilidad Cromosómica , Anomalías Craneofaciales/genética , Síndromes de Inmunodeficiencia/genética , Adolescente , Adulto , Centrómero/genética , Niño , Preescolar , Anomalías Craneofaciales/patología , ADN (Citosina-5-)-Metiltransferasas/genética , Femenino , Genotipo , Humanos , Lactante , Masculino , Mutación , Fenotipo , Síndrome , ADN Metiltransferasa 3BRESUMEN
Recurrent or persistent infection is the major manifestation of primary immunodeficiency, which also results in atypical infection with opportunistic organisms. Young children are also vulnerable to infection and recurrent infection is common. While most children with recurrent infection have a normal immunity, it is important to recognize the child with an underlying primary immunodeficiency and investigate and treat appropriately and yet not over investigate normal children. Prompt, accurate diagnosis directs the most appropriate treatment, and early and judicious use of prophylactic antibiotics and replacement immunoglobulin can prevent significant end organ damage and improve long-term outlook and quality of life. This paper describes important presenting features of primary immunodeficiency and indicates when further investigation is warranted.
Asunto(s)
Síndromes de Inmunodeficiencia/complicaciones , Síndromes de Inmunodeficiencia/diagnóstico , Infecciones Oportunistas/complicaciones , Adolescente , Edad de Inicio , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Infecciones Oportunistas/inmunología , Infecciones Oportunistas/terapia , Selección de Paciente , RecurrenciaRESUMEN
Evaluation of the T cell receptor (TCR) Vbeta repertoire by flow cytometric analysis has been used for studying the T cell compartments for diseases in which T cells are implicated in the pathogenesis. For the interpretation of these studies information is needed about Vbeta usage in healthy individuals and there are few data for normal usage in paediatric populations. We examined the T lymphocyte (sub)populations in 47 healthy controls (age range: 3 months-16 years). We found non-random Vbeta usage with skewed reactivity of some families towards CD4+ or CD4- T cells. Importantly, there appeared to be no significant change in Vbeta usage according to age group. Some controls showed expansions in some Vbeta families, although incidence of such expansions was low. We went on to examine the repertoire of CD4+CD25(Bright) T regulatory cells in 25 healthy controls. We found overlapping quantitative usage for each of the Vbeta families between CD4+CD25- and CD4+CD25(Bright) T cells. However, there was a significant preferential usage for five Vbeta families and decreased usage of two Vbeta families in the CD4+CD25(Bright) T cells, suggesting that although they overlap there may be subtle but important differences in the TCR repertoire of T regulatory cells.
Asunto(s)
Receptores de Antígenos de Linfocitos T alfa-beta/análisis , Linfocitos T/metabolismo , Adolescente , Envejecimiento/inmunología , Complejo CD3/inmunología , Niño , Preescolar , Femenino , Citometría de Flujo , Humanos , Lactante , Subunidad alfa del Receptor de Interleucina-2/inmunología , Masculino , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismoRESUMEN
There are no epidemiological studies from the British Isles of chronic granulomatous disease, characterized by recurrent, life-threatening bacterial and fungal infections and inflammatory sequelae. Patients were enrolled in a national registry and medical records were analysed. Of 94 subjects, 69 had X-linked disease, 16 had autosomal recessive disease and nine were unknown. Prevalence was 7.5/million for 1990-99 and 8.5/million for 1980-89. Suppurative adenitis, abscesses and pneumonia presented commonly. Twenty-three of 30 patients who underwent high resolution computerized tomography had chronic respiratory disease. Inflammatory sequelae included bowel stricture and urogenital tract granulomata. Growth failure was common; 75% of those measured were below the population mean. All patients received prophylactic antibiotics and 93% anti-fungal prophylaxis. Interferon gamma was used to treat infection, but rarely as prophylaxis. Despite prophylaxis, estimated survival was 88% at 10 years but 55% at age 30 years. Morbidity remains significant, severe infectious complications common. Curative treatments including stem cell transplantation should be considered for patients with frequent or serious complications.