RESUMEN
Genetic variants in cell division cycle 42 (CDC42) can manifest with dysmorphic features, autoinflammation, hemophagocytic lymphohistiocytosis, and thrombocytopenia, whereas defective thymopoiesis is a rare disease manifestation. We report a novel CDC42 missense variant (c.46A > G, p.Lys16Glu) resulting in infection and HPV-driven carcinogenesis in the mosaic mother and impaired thymopoiesis and profound T cell lymphopenia in the heterozygous daughter identified through newborn screening for SCID. We found that surface expression of IL-7Rα (CD127) was decreased, consistent with reduced IL-7-induced STAT5 phosphorylation and accelerated apoptotic T cell death. Consistent with the vital role of IL-7 in regulating thymopoiesis, both patients displayed reduced T cell receptor CDR3 repertoires. Moreover, the CDC42 variant prevented binding to the downstream effector, p21-activated kinase (PAK)1, suggesting this impaired interaction to underlie reduced IL-7Rα expression and signaling. Here, we provide the first report of severely compromised thymopoiesis and perturbed IL-7Rα signaling caused by a novel CDC42 variant and presenting with diverging clinical and immunological phenotypes in patients.
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Interleucina-7 , Quinasas p21 Activadas , Humanos , Recién Nacido , Apoptosis , Interleucina-7/genética , Receptores de Antígenos de Linfocitos T/genética , Transducción de SeñalRESUMEN
OBJECTIVES: The aim of the study was to create a simple assay for microchimerism detection independent of sex and without HLA genotyping. METHODS: The method is based on detection of insertion or deletions utilizing a multiplex PCR followed by fragment analysis by capillary electrophoresis, and probe-based qPCR assays. A total of 192 samples, taken either before pregnancy, during 1st trimester, or either during 2nd trimester or at miscarriage, obtained from a cohort of 97 female patients with either primary or secondary recurrent pregnancy loss, were screened for fetal microchimerism by the indel panel as well as an existing assay based on detection of the Y-chromosome marker; DYS14. RESULTS: The overall prevalence of DYS14 positive samples was 29% (55/192) whereas 32% (61/192) tested positive by the indel method. There was an overall agreement of 64% (122/192) between the results obtained by the two methods. A Fisher's Exact test showed no statistic significant difference in the prevalence of microchimerism detected by the two methods at any of the three times of sampling. The distribution of the number of positive wells detected by both methods were compared by a Mann-Whitney U test, which showed no statistically significant difference at any of the three times of sampling. CONCLUSION: The data indicates that microchimerism can be detected efficiently by the indel method. This makes it possible to detect both female and male cells without the need of HLA-genotyping. Furthermore, the indel method has potential to be implemented as a routine analysis. This will remove the sex bias in future explorations of the role microchimerism plays in health and disease.
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Quimerismo , Mutación INDEL , Femenino , Feto , Marcadores Genéticos , Humanos , Masculino , Embarazo , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
OBJECTIVE: Aberrant pyrin inflammasome activity triggers familial Mediterranean fever (FMF) pathogenesis, but the exact mechanism remains elusive and an obstacle to efficient treatment. We undertook this study to identify pyrin inflammasome-specific mechanisms to improve FMF treatment and diagnostics in the future. METHODS: Pyrin-specific protein secretion was assessed by proteome analysis in U937-derived macrophages, and specific findings were confirmed in pyrin inflammasome-activated monocytes from healthy blood donors and patients with FMF, stratified according to MEFV genotype categories corresponding to a suspected increase in FMF disease severity. RESULTS: Proteome data revealed a differential secretion pattern of interleukin-1 receptor antagonist (IL-1Ra) from pyrin- and NLRP3-activated U937-derived macrophages, which was verified by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. Moreover, pyrin activation significantly reduced IL1RN messenger RNA expression (P < 0.001) and IL-1Ra secretion (P < 0.01) in healthy donor and FMF monocytes, respectively. Independent of MEFV genotype, unstimulated FMF monocytes from colchicine-treated patients secreted lower amounts of IL-1Ra compared to healthy donors (P < 0.05) and displayed decreased ratios of IL-1Ra:IL-1ß (P < 0.05), suggesting a reduced antiinflammatory capacity. CONCLUSION: Our data show an inherent lack of IL-1Ra expression specific to pyrin inflammasome activation, suggesting a new mechanism underlying FMF pathogenesis. The reduced IL-1Ra levels in FMF monocytes suggest a diminished antiinflammatory capacity that potentially leaves FMF patients sensitive to proinflammatory stimuli, regardless of receiving colchicine therapy. Thus, considering the potential clinical consequence of reduced monocyte IL-1Ra secretion in FMF patients, we suggest further investigation into IL-1Ra dynamics and its potential implications for FMF treatment in the future.
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Fiebre Mediterránea Familiar/metabolismo , Inflamasomas/metabolismo , Proteína Antagonista del Receptor de Interleucina 1/metabolismo , Pirina/metabolismo , Línea Celular , Fiebre Mediterránea Familiar/genética , Humanos , Proteína Antagonista del Receptor de Interleucina 1/genética , Macrófagos/metabolismo , Monocitos/metabolismo , Proteoma , Pirina/genéticaRESUMEN
Objectives: To study Epstein-Barr virus (EBV) antibody patterns in twin individuals with rheumatoid arthritis (RA) and their healthy co-twins, and to determine the heritability of antibody responses against the EBV encoded EBNA1 protein. Methods: Isotypes of EBNA1 antibodies were measured in 137 RA affected- and 150 healthy twin pairs. We estimated the effect of RA and RA predisposition, anti-citrullinated antibodies (ACPA), IgM rheumatoid factor (RF), the shared epitope (SE) and the PTPN22-T allele (PTPN22) on the level of EBNA1 antibodies. We also determined the heritability of EBNA1 antibody levels. Results: IgA-EBNA1 antibody levels were increased in twins from RA discordant twin pairs irrespective of RA, ACPA or IgM-RF status. The IgG-EBNA1 antibody level was elevated in healthy co-twins from RA discordant twin pairs but not in RA affected twins. The IgM-EBNA1 antibody level was elevated in both RA twins and their healthy co-twins. The effect of RA on the IgA-EBNA1 antibody level was reversed when SE was present and with no effect of PTPN22. The heritability of IgA-, IgG- and IgM-EBNA1 antibody level was 40.6, 65.5, and 54.3%, with no effect of environment shared by the twins. Conclusion: EBNA1 antibody levels are distinctively different between patients with RA and healthy subjects but also between relatives of RA strongly predisposed to RA and healthy subjects. The high level of IgA EBNA1 antibodies associated with RA and a family predisposition to RA is attributable to both genetics incl. the shared epitope and environmental variation.
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Formación de Anticuerpos/inmunología , Artritis Reumatoide/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Estudios en Gemelos como Asunto , Adolescente , Adulto , Anciano , Artritis Reumatoide/genética , Artritis Reumatoide/virología , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Antígenos Nucleares del Virus de Epstein-Barr/inmunología , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Voluntarios Sanos , Herpesvirus Humano 4/fisiología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Adulto JovenRESUMEN
OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
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Presentación de Antígeno/genética , Inmunidad Innata/genética , Interferón Tipo I/inmunología , Lupus Eritematoso Sistémico/genética , Linfopoyesis/genética , Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/genética , Estudios de Casos y Controles , Análisis por Conglomerados , Activación de Complemento/genética , Femenino , Humanos , Quinasas Janus/genética , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Factores de Transcripción STAT/genética , Análisis de Secuencia de ADN , Transducción de Señal/genética , Suecia , Población Blanca , Adulto JovenRESUMEN
BACKGROUND: Reduced D antigen on red blood cells (RBCs) may be due to "partial" D phenotypes associated with loss of epitope(s) and risk for alloimmunization or "weak" D phenotypes that do not lack major epitopes with absence of clinical complications. Genotyping of samples with weak and discrepant D typing is recommended to guide transfusion and RhIG prophylaxis. The goal was to compare the impact of RHD genotyping on transfusion practice in two centers serving different populations. STUDY DESIGN AND METHODS: Fifty-seven samples from Denmark and 353 from the United States with weak or discrepant D typing were genotyped. RBC typing was by multiple methods and reagents. DNA isolated from white blood cells was tested with RBC-Ready Gene D weak or CDE in Denmark or RHD BeadChip in the United States. RHD was sequenced for those unresolved. RESULTS: Of Caucasian samples from Denmark, 90% (n = 51) had weak D types 1, 2, or 3; two had other weak D, two partial D, and two new alleles. In diverse ethnic U.S. samples, 44% (n = 155) had weak D types 1, 2, or 3 and 56% (n = 198) had other alleles: uncommon weak D (n = 13), weak 4.0 (n = 62), partial D (n = 107), no RHD (n = 9), and new alleles (n = 7). CONCLUSION: Most samples with weak or variable D typing from Denmark had alleles without risk for anti-D. In U.S. samples, 48% could safely be treated as D+, 18% may require consideration if pregnancy possible, and 34% could potentially benefit from being treated as D-. Black and multiracial ethnicities were overrepresented relative to population.
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Transfusión Sanguínea/métodos , Eritrocitos/metabolismo , Sistema del Grupo Sanguíneo Rh-Hr/genética , Globulina Inmune rho(D)/genética , Adulto , Alelos , Antígenos de Grupos Sanguíneos , Transfusión Sanguínea/estadística & datos numéricos , Dinamarca/etnología , Eritrocitos/inmunología , Femenino , Genotipo , Técnicas de Genotipaje/métodos , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Embarazo , Globulina Inmune rho(D)/inmunología , Globulina Inmune rho(D)/uso terapéutico , Estados Unidos/etnologíaRESUMEN
BACKGROUND: STK4 deficiency due to homozygous mutations in the STK4 gene encoding the STK4/MST1 kinase was first described in 2012. STK4/MST1 kinase regulates cell proliferation, survival, differentiation, and immune responses through canonical and non-canonical Hippo signaling pathways. OBJECTIVE: We describe an 11-year-old girl with a clinical presentation consisting of severe recurrent herpes zoster, chronic warts, and recurrent pneumonias, as well as a somatic phenotype with hypothyroidism and low stature. Whole exome sequencing revealed STK4 deficiency due to homozygosity for a novel frameshift variant in STK4, c.523dupA, p.(L174fsTer45), resulting in a premature stop codon within the kinase domain. METHODS: We performed a thorough investigation of the genetics and innate and adaptive immunological abnormalities in STK4 deficiency. RESULTS: We show significantly impaired type I, II, and III interferon (IFN) responses and partly reduced proinflammatory cytokine responses to ligands of Toll-like receptor (TLR)3, TLR9, and the cytosolic RNA and DNA sensors as well as to microorganisms. Impaired IFN responses could be attributed to reduced phosphorylation of TBK1 and IRF3. Moreover, virus infection induced enhanced cell death by apoptosis. Importantly, autophagy pathways were slightly disturbed, with enhanced LC3B-Ito LCB3-II conversion at the single cell level but normal overall formation of LCB3 punctae. Finally, the patient displayed some indicators of impaired adaptive immunity in the form of insufficient vaccination responses, T cell lymphopenia, and reduced Treg fractions, although with largely normal T cell proliferation and normal IFNg production. CONCLUSION: Here, we demonstrate disturbances in various immune cell populations and pathways involved in innate immune responses, cell death, autophagy, and adaptive immunity in a patient homozygous for a novel STK4 frameshift mutation.
Asunto(s)
Inmunidad Innata/genética , Factor 3 Regulador del Interferón/metabolismo , Interferones/biosíntesis , Péptidos y Proteínas de Señalización Intracelular/deficiencia , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Inmunidad Adaptativa , Alelos , Autofagia , Diferenciación Celular , Proliferación Celular , Supervivencia Celular/genética , Citocinas/biosíntesis , Femenino , Genotipo , Vía de Señalización Hippo , Humanos , Huésped Inmunocomprometido , Inmunofenotipificación , Infecciones/etiología , Infecciones/metabolismo , Activación de Linfocitos , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Mutación , Neutrófilos/inmunología , Neutrófilos/metabolismo , Linaje , Fenotipo , Linfocitos T/inmunología , Linfocitos T/metabolismoRESUMEN
OBJECTIVES: To carry out genetic and serological analyses of a Swiss blood donor and a Danish patient carrying an aberrant ABO phenotype with weak A expression. BACKGROUND: ABO is the most clinically important blood group system but also one of the most complex. The system antigens are determined by carbohydrate structures generated by A and B glycosyltransferases encoded by the ABO gene. Genetic variants of ABO may encode a glycosyltransferase with reduced activity, leading to weak expression of A antigen. METHODS: Samples from two individuals were examined using genetic testing and extended immunohaematological evaluation, including standard serological methods, flow cytometry and analysis of plasma glycosyltransferase activity. RESULTS: Both individuals were serologically determined to be Aweak B. Genetic testing revealed that both were heterozygous for a novel ABO*A1.01-like allele with an in-frame duplication of 21 nucleotides in exon 7 (c.543_563dup), leading to the insertion of seven amino acids (QDVSMRR). Flow cytometric testing of native red blood cells (RBCs) showed very weak A antigen expression. This was in accordance with the enzyme activity test. CONCLUSION: In summary, we describe a novel A allele with a duplication of 21 nucleotides in exon 7 that significantly decreases the enzyme activity and leads to very weak expression of A antigen. (200 words).
Asunto(s)
Sistema del Grupo Sanguíneo ABO , Alelos , Eritrocitos/metabolismo , Exones , Heterocigoto , Sistema del Grupo Sanguíneo ABO/biosíntesis , Sistema del Grupo Sanguíneo ABO/genética , Anciano , Dinamarca , Humanos , Masculino , SuizaAsunto(s)
Antígenos CD18/sangre , Síndrome de Deficiencia de Adhesión del Leucocito/diagnóstico , Vacunas/inmunología , Antígenos CD18/genética , Antígenos CD18/inmunología , Humanos , Lactante , Recién Nacido , Síndrome de Deficiencia de Adhesión del Leucocito/inmunología , Síndrome de Deficiencia de Adhesión del Leucocito/terapia , Masculino , MutaciónRESUMEN
Low mitochondrial DNA copy number (mtDNA CN) has been associated with e.g. cancer, cardiovascular and autoimmune diseases. We aimed to study a potential association between mtDNA CN and rheumatoid arthritis (RA). The relative quantity of mitochondrial DNA compared to nuclear DNA was measured in peripheral white blood cells from 149 RA affected twin pairs and 1321 non-affected twin pairs. Multiple regression analysis including RA discordant twin pairs was performed in order to separate specific effects of RA and familial RA predisposition using non-RA affected twin pairs as reference group. In addition, we performed a twin pair level analysis including only RA discordant twin pairs evaluating the effect of cell type, auto antibodies and RA genetic risk factors. Both the RA twins and their non-affected co-twins had significantly lower mtDNA CN than non-affected twins (-28.7 and -23.1 mtDNA CN, respectively). Adjusting for cell count attenuated these differences (-23.1 mtDNA CN and -20.1 mtDNA CN respectively). Within RA discordant twin pairs PTPN22(T) positive RA twins had a significantly lower amount than their co-twins (-16.3 mtDNA CN). PTPN22(T) had no effect among twins from non-affected twin pairs. MtDNA CN is significantly lower in persons with established RA and in predisposed non-affected RA co-twins suggesting that mitochondrial variation may be involved in the RA disease pathways. Our results also suggest that the RA associated genetic risk factor, PTPN22(T), further decreases the mtDNA CN, but only in carriers with established RA.
Asunto(s)
Artritis Reumatoide/genética , ADN Mitocondrial/genética , Genotipo , Leucocitos/fisiología , Proteína Tirosina Fosfatasa no Receptora Tipo 22/genética , Adulto , Anciano , Artritis Reumatoide/epidemiología , Variaciones en el Número de Copia de ADN , Dinamarca/epidemiología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Factores de RiesgoRESUMEN
BACKGROUND: Reliability of noninvasive prenatal RHD genotype test (NIP RHD) depends on having sufficient amounts of cell-free fetal DNA (cffDNA) in the maternal plasma sample. The fraction of cffDNA in maternal plasma is inversely related to maternal body mass index (BMI), suggesting that high maternal BMI may limit the test's accuracy. This study determined the effect of maternal BMI on the accuracy of NIP RHD. STUDY DESIGN AND METHODS: Results from NIP RHD performed in Gestation Week 25 were correlated to maternal BMI in Week 12. The accuracy of NIP RHD result was determined by correlation with serologic RhD types of the neonates. RESULTS: A total of 1618 pregnancies in 1588 D- women were included. Median BMI in these pregnancies was 24.2 (10%-90%, 20.1-32.4), and in 261 of 1618 (16%) pregnancies BMI was 30 or more (median BMI in this group was 33.6; 10th-90th percentiles, 30.5-41.1). NIP RHD was positive in 987 of 1618 (61%), negative in 582 of 1618 (36%), and inconclusive in 49 of 1618 (3.0%). Compared to the neonate's serologic RhD type, nine of 987 (0.9%) positive NIP RHD results were false positive, and four of 582 (0.7%) negative NIP RHD results were false negative (FN). In five of 49 (10%) inconclusive NIP RHD results, the neonatal RhD type was positive. There was no difference in median BMI between individuals who tested inconclusive or FN compared to those with true positive or true negative results (p = 0.80). CONCLUSION: The accuracy of NIP RHD testing performed in Gestation Week 25 does not depend on maternal BMI in the 12th gestation week.
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Índice de Masa Corporal , Edad Gestacional , Diagnóstico Prenatal/métodos , Sistema del Grupo Sanguíneo Rh-Hr/sangre , Adulto , Ácidos Nucleicos Libres de Células/sangre , Femenino , Genotipo , Humanos , Recién Nacido , Embarazo , Adulto JovenRESUMEN
BACKGROUND: With a potentially early onset, hereditary angioedema (HAE) requires special knowledge also in infancy and early childhood. In children from families with HAE, the diagnosis should be confirmed or refuted early, which can be difficult. Studies of childhood HAE and the diagnostic approaches are limited. Our aim was to investigate the entire Danish cohort of children with HAE and non-HAE children of HAE patients for diagnostic approaches and clinical characteristics. RESULTS: We included 41 children: 22 with HAE and 19 non-HAE. Of the HAE children, 14 were symptomatic-median age at onset was 4 [1-11] years. The first attack was peripheral in 8/14 children and abdominal in 6/14 children, i.e. no one had their first attacks in the upper airways. Most children had less than one attack per month. All of the symptomatic children had been treated with tranexamic acid and/or C1 inhibitor concentrate. Unlike in other countries, androgens were not used in our pediatric cohort. Home therapy with C1 inhibitor concentrate was established in 9 cases: 6 children were trained in self-administration and 3 children were treated by parents. Of the children, 10 had been diagnosed by symptoms, including 3 without family history-median age of diagnosis among these children was 5.35 [2-13.2] years. In 31 children, HAE was diagnosed or refuted before symptoms by blood samples. In 23 of these children, complement values were investigated, and in 9 cases genetic testing was added to the complement measurements. In 8 children recently investigated, genetic testing was first choice. Cord blood was used for complement measurements in 9 children and for genetic testing in 4 children. Results of complement measurements were equivocal in several cases, especially in the cord blood samples, and the sensitivity of low complement C4 for the diagnosis of HAE was 75%. CONCLUSIONS: We investigated clinical characteristics in all Danish children with HAE. The rate of home therapy was high and androgens had been avoided. Complement values were often equivocal, especially in cord blood samples. Consequently, we have changed diagnostic practice to early genetic testing in children where the family mutation is known.
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Angioedemas Hereditarios/diagnóstico , Pruebas Genéticas/métodos , Angioedemas Hereditarios/tratamiento farmacológico , Angioedemas Hereditarios/genética , Niño , Preescolar , Complemento C4/genética , Femenino , Humanos , Lactante , Masculino , Ácido Tranexámico/uso terapéuticoRESUMEN
A 2-month-old female infant, born to consanguineous parents, presented with infections in skin and upper respiratory tract. She was notable for delayed umbilical cord detachment, partial albinism, and neurological irritability. Giant granules were present in white blood cells. The intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient with 82% and 8% perforin-containing CD8 T cells at active and nonactive hemophagocytic lymphohistiocytosis (HLH) disease, respectively. HLH was confirmed by hemophagocytosis in bone marrow and absent natural killer cell activity. The patient carried a homozygous G>A mutation in the 3' splice site of intron 24 of the LYST/CHS1 gene, leading to the use of an alternative YAG splice site located in exon 25, introducing a premature STOP codon (L2355fsX2370; NP_000072.2). The early-onset accelerated phase in this severe phenotype of Chediak-Higashi syndrome was probably induced by rotaviral infection. Interestingly, the intracellular perforin content in CD8 T cells seems to correlate to the immune activation state of the patient. Late separation of the umbilical cord in concordance with clinical symptoms should lead to evaluation of a possible neutrophil dysfunction including Chediak-Higashi syndrome before onset of HLH.
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Síndrome de Chediak-Higashi/genética , Diarrea , Linfohistiocitosis Hemofagocítica/etiología , Mutación/genética , Cordón Umbilical/cirugía , Proteínas de Transporte Vesicular/genética , Síndrome de Chediak-Higashi/complicaciones , Preescolar , Femenino , Humanos , PronósticoRESUMEN
We report an infant of consanguineous parents of Turkish decent with a novel immunodeficiency associated with homozygosity for a nonsense mutation of the gene encoding Inhibitor of nuclear factor kappa-B (NF-κB) kinase subunit beta (IKKß). At five months, she presented with respiratory insufficiency and Pneumocystis jirovecii pneumonia which was successfully treated. At nine months, iatrogenic systemic infection with Mycobacterium bovis was found and eventually led to her death at age 14 months. Laboratory findings were reminiscent of hyper-IgM syndrome, but genetic testing gave no explanation before whole exome sequencing revealed a novel mutation abrogating signaling through the canonical NF-κB pathway.
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Codón sin Sentido , Quinasa I-kappa B/genética , Síndromes de Inmunodeficiencia/genética , Resultado Fatal , Femenino , Humanos , Síndromes de Inmunodeficiencia/complicaciones , Lactante , Mycobacterium bovis , Pneumocystis carinii , Neumonía por Pneumocystis/complicaciones , Insuficiencia Respiratoria/complicaciones , Tuberculosis/complicaciones , Tuberculosis/patología , Vacunación/efectos adversosRESUMEN
BACKGROUND: The RhD antigen is very immunogenic and is a significant cause of hemolytic disease of the newborn (HDN). The RHD-CE(8-9)-D hybrid allele is commonly associated with a D- phenotype. Here, we report a case of high-titer maternal anti-D and late onset of HDN in a newborn carrying a RHD-CE(9)-D variant supposedly encoding the same partial D antigen as the RHD-CE(8-9)-D allele, but with significant expression of D antigen. STUDY DESIGN AND METHODS: To elucidate the blood group antigen background of the case, we carried out serologic, flow cytometric, and genetics studies of the newborn and his father. CONCLUSION: Individuals carrying the RHD-CE(9)-D allele do express D antigen, but do so at significantly lower levels than those carrying the more common D+ phenotypes (e.g., DCe/dce). It may mitigate and delay otherwise severe HDN in pregnancies complicated by high-titer anti-D.
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Eritroblastosis Fetal/inmunología , Isoanticuerpos/efectos adversos , Sistema del Grupo Sanguíneo Rh-Hr/inmunología , Adulto , Factores de Edad , Eritroblastosis Fetal/sangre , Femenino , Humanos , Recién Nacido , Isoanticuerpos/sangre , Masculino , Datos de Secuencia Molecular , Embarazo , Globulina Inmune rho(D) , Índice de Severidad de la EnfermedadRESUMEN
Here we describe a patient with hyper-IgE syndrome presenting with recurrent staphylococcal abscesses, pneumonia, and chronic mucocutaneous candidiasis, and report the identification of a novel STAT3 mutation at amino acid position 621, which has not previously been described. In addition, we review the immunological, infectious, and genetic features of hyper-IgE syndrome.
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Síndrome de Job/genética , Mutación , Factor de Transcripción STAT3/genética , Absceso/genética , Absceso/inmunología , Candidiasis Mucocutánea Crónica/genética , Candidiasis Mucocutánea Crónica/inmunología , Femenino , Humanos , Síndrome de Job/microbiología , Persona de Mediana Edad , Infecciones Cutáneas Estafilocócicas/genética , Infecciones Cutáneas Estafilocócicas/inmunologíaRESUMEN
BACKGROUND: X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the common cytokine-receptor gamma chain (gamma(c)), resulting in disruption of development of T lymphocytes and natural-killer cells. B-lymphocyte function is also intrinsically compromised. Allogeneic bone-marrow transplantation is successful if HLA-matched family donors are available, but HLA-mismatched procedures are associated with substantial morbidity and mortality. We investigated the application of somatic gene therapy by use of a gibbon-ape-leukaemia-virus pseudotyped gammaretroviral vector. METHODS: Four children with SCID-X1 were enrolled. Autologous CD34-positive haemopoietic bone-marrow stem cells were transduced ex vivo and returned to the patients without preceding cytoreductive chemotherapy. The patients were monitored for integration and expression of the gamma(c) vector and for functional immunological recovery. FINDINGS: All patients have shown substantial improvements in clinical and immunological features, and prophylactic medication could be withdrawn in two. No serious adverse events have been recorded. T cells responded normally to mitogenic and antigenic stimuli, and the T-cell-receptor (TCR) repertoire was highly diverse. Where assessable, humoral immunity, in terms of antibody production, was also restored and associated with increasing rates of somatic mutation in immunoglobulin genes. INTERPRETATION: Gene therapy for SCID-X1 is a highly effective strategy for restoration of functional cellular and humoral immunity.