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1.
Scand J Immunol ; 91(1): e12811, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31378960

RESUMO

Hypomorphic mutations in the gene encoding Bruton tyrosine kinase (BTK) may result in milder phenotypes and delayed diagnosis of B-cell related immunodeficiencies due to residual BTK function. Newborn screening for kappa-deleting-recombination-excision circles (KRECs) reliably identifies classical X-linked agammaglobulinaemia (XLA) patients with profound B-cell lymphopenia at birth but has not been evaluated in patients with residual BTK function. We aimed to evaluate clinical findings, BTK function and KREC copy numbers in three patients with BTK mutations presenting with impaired polysaccharide responsiveness without agammaglobulinaemia. One patient had an invasive pneumococcal infection at the age of 4 years. All three patients (two brothers) had visible tonsils, normal to slightly decreased immunoglobulin G levels, undetectable pneumococcal antibodies despite pneumococcal conjugate vaccinations, no antibody response after a diagnostic polysaccharide vaccination as well as profound B-cell lymphopenia with residual B-cell differentiation. BTK mutations were identified by Sanger sequencing. BTK staining and phosphorylation assays were performed on peripheral B cells. KREC copy numbers were determined from dried blood spots obtained within the first week of life as well as once at the age of 8, 6 and 3 years, respectively. BTK staining showed residual protein expression. Also, residual BTK activity could be demonstrated. KREC copy numbers from dried blood spots were above the threshold set for detection of patients with profound B-cell lymphopenia. Male patients with impaired polysaccharide responsiveness should be evaluated for B-cell lymphopenia followed by BTK analyses irrespective of immunoglobulin levels or tonsil size.


Assuntos
Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/etiologia , Mutação , Fenótipo , Polissacarídeos/imunologia , Biomarcadores , Criança , Pré-Escolar , Variações do Número de Cópias de DNA , Análise Mutacional de DNA , Seguimentos , Genótipo , Humanos , Imunofenotipagem , Recém-Nascido , Masculino , Triagem Neonatal , /etiologia , Avaliação de Sintomas
2.
EJIFCC ; 30(4): 396-406, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31832054

RESUMO

Newborn screening (NBS) for severe T and/or B cell lymphopenia to identify neonates with severe combined immunodeficiencies (SCID) or agammaglobulinemia rapidly after birth has paved its way into clinical practice. Debate exists on the concept and strategy for rapid verification and stratification of the cellular immune status of positively screened infants. We provide impulses for harmonization of flow cytometric approaches to allow rapid integration in the growing number of immunological laboratories involved in follow-up and subdivision of SCID and non-SCID entities.

3.
Front Immunol ; 10: 1272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379802

RESUMO

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

4.
Sci Transl Med ; 10(452)2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30068569

RESUMO

Immune cell profiles provide valuable diagnostic information for hematologic and immunologic diseases. Although it is the most widely applied analytical approach, flow cytometry is limited to liquid blood. Moreover, either analysis must be performed with fresh samples or cell integrity needs to be guaranteed during storage and transport. We developed epigenetic real-time quantitative polymerase chain reaction (qPCR) assays for analysis of human leukocyte subpopulations. After method establishment, whole blood from 25 healthy donors and 97 HIV+ patients as well as dried spots from 250 healthy newborns and 24 newborns with primary immunodeficiencies were analyzed. Concordance between flow cytometric and epigenetic data for neutrophils and B, natural killer, CD3+ T, CD8+ T, CD4+ T, and FOXP3+ regulatory T cells was evaluated, demonstrating substantial equivalence between epigenetic qPCR analysis and flow cytometry. Epigenetic qPCR achieves both relative and absolute quantifications. Applied to dried blood spots, epigenetic immune cell quantification was shown to identify newborns suffering from various primary immunodeficiencies. Using epigenetic qPCR not only provides a precise means for immune cell counting in fresh-frozen blood but also extends applicability to dried blood spots. This method could expand the ability for screening immune defects and facilitates diagnostics of unobservantly collected samples, for example, in underdeveloped areas, where logistics are major barriers to screening.


Assuntos
Teste em Amostras de Sangue Seco , Epigênese Genética , Testes Imunológicos/métodos , Contagem de Células , Estudos de Coortes , Metilação de DNA/genética , Loci Gênicos , Infecções por HIV/diagnóstico , Infecções por HIV/imunologia , Humanos , Recém-Nascido , Triagem Neonatal , Sulfitos , Subpopulações de Linfócitos T/metabolismo
5.
Scand J Immunol ; : e12699, 2018 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-29943473

RESUMO

T-cell receptor excision circles (TRECs) and κ-deleting recombination excision circles (KRECs) are recently used for detection of T or B cell lymphopenia in neonates based on region-specific cutoff levels. Here, we report cutoffs for TREC and KREC copies useful for newborn screening and/or diagnosis of primary immunodeficiency diseases (PID) in Iran. DNA was extracted from a single 3.2 mm punch of dried blood spots collected from 2160 anonymized newborns referred to two major referral health centers between 2014 and 2016. For refinement of the cutoffs, 51 patients with a definite diagnosis of severe combined immunodeficiency, X-linked agammaglobulinaemia and combined immunodeficiency, including ataxia telangiectasia, human phosphoglucomutase 3 and Janus kinase-3 deficiency, as well as 47 healthy controls were included. Samples from patients with an X-linked hyper-IgM-syndrome, Wiskott-Aldrich syndrome and DNA ligase 4 deficiency were considered as disease controls. Triplex-quantitative real-time PCR was used. Cutoffs were calculated as TRECs < 11 and KRECs < 6 copies with an ACTB > 700 copies with sensitivity of 100% for TREC and 97% for KREC. Among thirty anonymized newborn samples (1.5%) with abnormal results for TREC and/or KREC, only twenty one available cases were retested and shown to be in the normal range except for three samples (0.15%). All of the patients with a definitive diagnosis were correctly identified based on our established TREC/KREC copy numbers. Determining cutoffs for TREC/KREC is essential for correctly identifying children with PID in newborn screening. Early diagnosis of PID patients enables appropriate measures and therapies like stem cell transplantation. This article is protected by copyright. All rights reserved.

6.
Eur J Hum Genet ; 26(9): 1282-1287, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29760432

RESUMO

Recently, variants in DONSON have been reported to cause different disorders of the microcephalic primordial dwarfism spectrum. Using whole-exome sequencing, we identified two novel, compound heterozygous DONSON variants in a pair of siblings, one of whom was previously diagnosed with Fanconi anemia. This occurred because the present cases exhibited clinical findings in addition to those of the microcephalic primordial dwarfism disorder, including severe limb malformations. These findings suggest that the DONSON and Fanconi anemia proteins could have supplementary roles in developmental processes as they have in the maintenance of genomic integrity, resulting in related disease phenotypes.


Assuntos
Proteínas de Ciclo Celular/genética , Nanismo/genética , Deformidades Congênitas dos Membros/genética , Microcefalia/genética , Proteínas Nucleares/genética , Fenótipo , Feto Abortado/patologia , Nanismo/patologia , Feminino , Heterozigoto , Humanos , Lactente , Deformidades Congênitas dos Membros/patologia , Microcefalia/patologia , Mutação , Síndrome
8.
Clin Immunol ; 188: 94-102, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29305966

RESUMO

The CTLA-4 checkpoint regulates the activation of T cells. Individuals with heterozygous mutations in CTLA-4 have a complex phenotype typically characterized by antibody deficiency alongside variable autoimmunity. Despite severe disease in some individuals, others remain largely unaffected with reasons for this variation unknown. We studied a large family carrying a single point mutation in CTLA-4 leading to an amino acid change R75W and compared both unaffected with affected individuals. We measured a variety of features pertaining to T cell and CTLA-4 biology and observed that at the cellular level there was complete penetrance of CTLA-4 mutations. Accordingly, unaffected individuals were indistinguishable from those with disease in terms of level of CTLA-4 expression, percentage of Treg, upregulation of CTLA-4 upon stimulation and proliferation of CD4 T cells. We conclude that the wide variation in disease phenotype is influenced by immune variation outside of CTLA-4 biology.


Assuntos
Antígenos CD28/imunologia , Antígeno CTLA-4/imunologia , Ativação Linfocitária/imunologia , Linfócitos T/imunologia , Antígenos CD28/metabolismo , Antígeno CTLA-4/deficiência , Antígeno CTLA-4/genética , Diarreia/genética , Diarreia/imunologia , Diarreia/metabolismo , Saúde da Família , Feminino , Humanos , Enteropatias/genética , Enteropatias/imunologia , Enteropatias/metabolismo , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto , Linhagem , Índice de Gravidade de Doença , Transdução de Sinais/imunologia , Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
10.
Turk J Haematol ; 34(4): 345-349, 2017 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-28404538

RESUMO

Hematopoietic stem cell transplantation is a promising curative therapy for many combined primary immunodeficiencies and phagocytic disorders. We retrospectively reviewed pediatric cases of patients diagnosed with primary immunodeficiencies and scheduled for hematopoietic stem cell transplantation. We identified 22 patients (median age, 6 months; age range, 1 month to 10 years) with various diagnoses who received hematopoietic stem cell transplantation. The patient diagnoses included severe combined immunodeficiency (n=11), Chediak-Higashi syndrome (n=2), leukocyte adhesion deficiency (n=2), MHC class 2 deficiency (n=2), chronic granulomatous syndrome (n=2), hemophagocytic lymphohistiocytosis (n=1), Wiskott-Aldrich syndrome (n=1), and Omenn syndrome (n=1). Of the 22 patients, 7 received human leukocyte antigen-matched related hematopoietic stem cell transplantation, 12 received haploidentical hematopoietic stem cell transplantation, and 2 received matched unrelated hematopoietic stem cell transplantation. The results showed that 5 patients had graft failure. Fourteen patients survived, yielding an overall survival rate of 67%. Screening newborn infants for primary immunodeficiency diseases may result in timely administration of hematopoietic stem cell transplantation.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Síndromes de Imunodeficiência/terapia , Síndrome de Chediak-Higashi/epidemiologia , Síndrome de Chediak-Higashi/terapia , Criança , Pré-Escolar , Feminino , Rejeição de Enxerto/epidemiologia , Doença Granulomatosa Crônica/epidemiologia , Doença Granulomatosa Crônica/terapia , Humanos , Síndromes de Imunodeficiência/epidemiologia , Lactente , Síndrome da Aderência Leucocítica Deficitária/epidemiologia , Síndrome da Aderência Leucocítica Deficitária/terapia , Linfo-Histiocitose Hemofagocítica/epidemiologia , Linfo-Histiocitose Hemofagocítica/terapia , Masculino , Imunodeficiência Combinada Severa/epidemiologia , Imunodeficiência Combinada Severa/terapia , Análise de Sobrevida , Turquia/epidemiologia , Síndrome de Wiskott-Aldrich/epidemiologia , Síndrome de Wiskott-Aldrich/terapia
11.
J Clin Immunol ; 37(1): 51-60, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27873105

RESUMO

Newborn screening for severe primary immunodeficiencies (PID), characterized by T and/or B cell lymphopenia, was carried out in a pilot program in the Stockholm County, Sweden, over a 2-year period, encompassing 58,834 children. T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) were measured simultaneously using a quantitative PCR-based method on DNA extracted from dried blood spots (DBS), with beta-actin serving as a quality control for DNA quantity. Diagnostic cutoff levels enabling identification of newborns with milder and reversible T and/or B cell lymphopenia were also evaluated. Sixty-four children were recalled for follow-up due to low TREC and/or KREC levels, and three patients with immunodeficiency (Artemis-SCID, ATM, and an as yet unclassified T cell lymphopenia/hypogammaglobulinemia) were identified. Of the positive samples, 24 were associated with prematurity. Thirteen children born to mothers treated with immunosuppressive agents during pregnancy (azathioprine (n = 9), mercaptopurine (n = 1), azathioprine and tacrolimus (n = 3)) showed low KREC levels at birth, which spontaneously normalized. Twenty-nine newborns had no apparent cause identified for their abnormal results, but normalized with time. Children with trisomy 21 (n = 43) showed a lower median number of both TREC (104 vs. 174 copies/µL blood) and KREC (45 vs. 100 copies/3.2 mm blood spot), but only one, born prematurely, fell below the cutoff level. Two children diagnosed with DiGeorge syndrome were found to have low TREC levels, but these were still above the cutoff level. This is the first large-scale screening study with a simultaneous detection of both TREC and KREC, allowing identification of newborns with both T and B cell defects.


Assuntos
Triagem Neonatal , Imunodeficiência Combinada Severa/diagnóstico , Feminino , Testes Genéticos/métodos , Idade Gestacional , Humanos , Recém-Nascido , Masculino , Reação em Cadeia da Polimerase Multiplex , Triagem Neonatal/métodos , Fenótipo , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Antígenos de Linfócitos T/genética , Recombinação Genética , Fatores de Risco , Deleção de Sequência , Imunodeficiência Combinada Severa/genética , Suécia
12.
J Exp Med ; 214(1): 91-106, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28011864

RESUMO

In this study, we describe four patients from two unrelated families of different ethnicities with a primary immunodeficiency, predominantly manifesting as susceptibility to Epstein-Barr virus (EBV)-related diseases. Three patients presented with EBV-associated Hodgkin's lymphoma and hypogammaglobulinemia; one also had severe varicella infection. The fourth had viral encephalitis during infancy. Homozygous frameshift or in-frame deletions in CD70 in these patients abolished either CD70 surface expression or binding to its cognate receptor CD27. Blood lymphocyte numbers were normal, but the proportions of memory B cells and EBV-specific effector memory CD8+ T cells were reduced. Furthermore, although T cell proliferation was normal, in vitro-generated EBV-specific cytotoxic T cell activity was reduced because of CD70 deficiency. This reflected impaired activation by, rather than effects during killing of, EBV-transformed B cells. Notably, expression of 2B4 and NKG2D, receptors implicated in controlling EBV infection, on memory CD8+ T cells from CD70-deficient individuals was reduced, consistent with their impaired killing of EBV-infected cells. Thus, autosomal recessive CD70 deficiency is a novel cause of combined immunodeficiency and EBV-associated diseases, reminiscent of inherited CD27 deficiency. Overall, human CD70-CD27 interactions therefore play a nonredundant role in T and B cell-mediated immunity, especially for protection against EBV and humoral immunity.


Assuntos
Linfócitos B/imunologia , Ligante CD27/deficiência , Infecções por Vírus Epstein-Barr/complicações , Doença de Hodgkin/etiologia , Síndromes de Imunodeficiência/complicações , Adolescente , Adulto , Ligante CD27/genética , Linfócitos T CD8-Positivos/imunologia , Criança , Citotoxicidade Imunológica , Feminino , Herpesvirus Humano 4/imunologia , Humanos , Memória Imunológica , Masculino , Mutação , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia
13.
J Clin Immunol ; 36(1): 73-84, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26604104

RESUMO

PURPOSE: Gain-of-function (GOF) mutations in the signal transducer and activator of transcription 1 (STAT1) result in unbalanced STAT signaling and cause immune dysregulation and immunodeficiency. The latter is often characterized by the susceptibility to recurrent Candida infections, resulting in the clinical picture of chronic mucocutaneous candidiasis (CMC). This study aims to assess the frequency of GOF STAT1 mutations in a large international cohort of CMC patients. METHODS: STAT1 was sequenced in genomic DNA from 57 CMC patients and 35 healthy family members. The functional relevance of nine different STAT1 variants was shown by flow cytometric analysis of STAT1 phosphorylation in patients' peripheral blood cells (PBMC) after stimulation with interferon (IFN)-α, IFN-γ or interleukin-27 respectively. Extended clinical data sets were collected and summarized for 26 patients. RESULTS: Heterozygous mutations within STAT1 were identified in 35 of 57 CMC patients (61%). Out of 39 familial cases from 11 families, 26 patients (67%) from 9 families and out of 18 sporadic cases, 9 patients (50%) were shown to have heterozygous mutations within STAT1. Thirteen distinct STAT1 mutations are reported in this paper. Eight of these mutations are known to cause CMC (p.M202V, p.A267V, p.R274W, p.R274Q, p.T385M, p.K388E, p.N397D, and p.F404Y). However, five STAT1 variants (p.F172L, p.Y287D, p.P293S, p.T385K and p.S466R) have not been reported before in CMC patients. CONCLUSION: STAT1 mutations are frequently observed in patients suffering from CMC. Thus, sequence analysis of STAT1 in CMC patients is advised. Measurement of IFN- or IL-induced STAT1 phosphorylation in PBMC provides a fast and reliable diagnostic tool and should be carried out in addition to genetic testing.


Assuntos
Candidíase Mucocutânea Crônica/diagnóstico , Síndromes de Imunodeficiência/diagnóstico , Leucócitos Mononucleares/imunologia , Mutação/genética , Fator de Transcrição STAT1/metabolismo , Adulto , Candidíase Mucocutânea Crônica/genética , Células Cultivadas , Citocinas/metabolismo , Análise Mutacional de DNA , Feminino , Humanos , Síndromes de Imunodeficiência/genética , Masculino , Linhagem , Fenótipo , Estrutura Terciária de Proteína/genética , Fator de Transcrição STAT1/genética
14.
Pediatr Allergy Immunol ; 27(1): 70-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26498110

RESUMO

BACKGROUND: Early diagnosis of primary immunodeficiency such as severe combined immunodeficiency (SCID) and X-linked agammaglobulinemia (XLA) improves outcome of affected children. T-cell-receptor-excision circles (TRECs) and kappa-deleting-recombination-excision circles (KRECs) determination from dried blood spots (DBS) identify neonates with severe T- and/or B-lymphopenia. No prospective data exist of the impact of gestational age (GA) and birth weight (BW) on TRECs and KRECs values. METHODS: TRECs and KRECs determination using triplex RT-PCR (TRECS-KRECS-ß-actin-Assay) from prospectively collected DBS between 02/2014 and 02/2015 in three hospitals in Seville, Spain. Cut-off levels were TRECs < 6/punch, KRECs < 4/punch and -ß-actin>700/punch. Internal (SCID, XLA, ataxia telangiectasia) and external controls (NBS quality assurance program, CDC) were included. RESULTS: A total of 5160 DBS were tested. Re-punch was needed in 77 samples (1.5%) due to insufficient ß-actin (<700 copies/punch). Pre-term neonates (GA<37 weeks) and neonates with a BW<2500 g showed significantly lower TRECs and KRECs levels (p < 0.001). Due to repeat positive results five neonates were re-called (<0.1%): Fatal chromosomopathy (n = 1; TRECs 1/KRECs 4); extreme pre-maturity (n = 2; TRECs 0/KRECs 0 and TRECs 1/KRECs 20 copies/punch); neonates born to mothers receiving azathioprine during pregnancy (n = 2; TRECs 92/KRECs 1 and TRECs 154/KRECs 3 copies/punch). All internal and external controls were correctly identified. CONCLUSIONS: TRECS-KRECS-ß-actin-Assay correctly identifies T- and B-cell lymphopenias. Pre-maturity and low BW is associated with lower TREC and KREC levels. Extreme pre-maturity and maternal immune suppressive therapy may be a cause for false positive results of TRECs and KRECs values, respectively. To reduce the rate of insufficient samples, DBS extraction and storage need to be improved.


Assuntos
Linfócitos B/imunologia , Teste em Amostras de Sangue Seco , Síndromes de Imunodeficiência/diagnóstico , Reação em Cadeia da Polimerase Multiplex , Triagem Neonatal/métodos , Reação em Cadeia da Polimerase em Tempo Real , Linfócitos T/imunologia , Artefatos , Peso ao Nascer , Estudos de Casos e Controles , Teste em Amostras de Sangue Seco/normas , Reações Falso-Positivas , Feminino , Marcadores Genéticos , Idade Gestacional , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Recém-Nascido de Baixo Peso/sangue , Recém-Nascido de Baixo Peso/imunologia , Recém-Nascido , Recém-Nascido Prematuro/sangue , Recém-Nascido Prematuro/imunologia , Estudos Longitudinais , Masculino , Reação em Cadeia da Polimerase Multiplex/normas , Triagem Neonatal/normas , Valor Preditivo dos Testes , Estudos Prospectivos , Reação em Cadeia da Polimerase em Tempo Real/normas , Reprodutibilidade dos Testes , Fatores de Risco , Índice de Gravidade de Doença , Espanha
15.
Iran J Allergy Asthma Immunol ; 14(4): 457-61, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26547715

RESUMO

Severe combined immunodeficiency (SCID) represents a rare group of primary immunodeficiency disorders (PIDs), with known or unknown genetic alterations. Here, we report a new interleukin 2 receptor, gamma chain (IL-2RG) mutation in an Iranian SCID newborn. The patient was a 6-day old boy with a family history of PID. The child was screened using a molecular-based analysis for the assessment of T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs). Moreover, a complete immunological evaluation and gene sequencing was performed. Results showed undetectable TREC but a high level of KREC copy numbers. Flow cytometric data indicated low numbers of T and NK cells, but elevated number of B cells. A novel substitution in IL2RG: c.675 C>A, leading to p.225 Ser>Arg was found. Based on the functional analysis, the mutation is predicted to be damaging. The patient was diagnosed as a T B+ NK X-linked SCID.


Assuntos
Cadeias kappa de Imunoglobulina/genética , Subunidade gama Comum de Receptores de Interleucina/genética , Mutação , Receptores de Antígenos de Linfócitos T/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , DNA Circular/genética , Humanos , Recém-Nascido , Masculino
16.
Clin Immunol ; 161(2): 103-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26187144

RESUMO

Autosomal recessive human ZAP70 deficiency is a rare cause of combined immunodeficiency (CID) characterized by defective CD4 T cells and profound CD8 T cell lymphopenia. Herein, we report two novel patients that extend the molecular genetics, the clinical and functional phenotypes associated with the ZAP70 deficiency. The patients presented as infant-onset CID with severe infections caused by varicella zoster virus and live vaccines. Retrospective TCR excision circle newborn screening was normal in both patients. One patient carried a novel non-sense mutation (p.A495fsX75); the other a previously described misense mutation (p.A507V). In contrast to CD4 T cells, the majority of the few CD8 T cells showed expression of the ZAP70-related tyrosine kinase SYK that correlated with residual TCR signaling including calcium flux and degranulation. Our findings highlight the differential requirements of ZAP70 and SYK during thymic development, peripheral homeostasis as well as effector functions of CD4 and CD8 T cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Proteínas Tirosina Quinases/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Imunodeficiência Combinada Severa/imunologia , Proteína-Tirosina Quinase ZAP-70/deficiência , Linfócitos T CD4-Positivos/imunologia , Pré-Escolar , Humanos , Síndromes de Imunodeficiência/imunologia , Lactente , Masculino , Mutação/imunologia , Estudos Retrospectivos , Transdução de Sinais/imunologia , Quinase Syk , Proteína-Tirosina Quinase ZAP-70/imunologia
17.
J Allergy Clin Immunol ; 136(3): 703-712.e10, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25843314

RESUMO

BACKGROUND: The clinical and immunologic features of CD27 deficiency remain obscure because only a few patients have been identified to date. OBJECTIVE: We sought to identify novel mutations in TNFRSF7/CD27 and to provide an overview of clinical, immunologic, and laboratory phenotypes in patients with CD27 deficiency. METHODS: Review of the medical records and molecular, genetic, and flow cytometric analyses of the patients and family members were performed. Treatment outcomes of previously described patients were followed up. RESULTS: In addition to the previously reported homozygous mutations c.G24A/p.W8X (n = 2) and c.G158A/p.C53Y (n = 8), 4 novel mutations were identified: homozygous missense c.G287A/p.C96Y (n = 4), homozygous missense c.C232T/p.R78W (n = 1), heterozygous nonsense c.C30A/p.C10X (n = 1), and compound heterozygous c.C319T/p.R107C-c.G24A/p.W8X (n = 1). EBV-associated lymphoproliferative disease/hemophagocytic lymphohistiocytosis, Hodgkin lymphoma, uveitis, and recurrent infections were the predominant clinical features. Expression of cell-surface and soluble CD27 was significantly reduced in patients and heterozygous family members. Immunoglobulin substitution therapy was administered in 5 of the newly diagnosed cases. CONCLUSION: CD27 deficiency is potentially fatal and should be excluded in all cases of severe EBV infections to minimize diagnostic delay. Flow cytometric immunophenotyping offers a reliable initial test for CD27 deficiency. Determining the precise role of CD27 in immunity against EBV might provide a framework for new therapeutic concepts.


Assuntos
Infecções por Vírus Epstein-Barr/genética , Doença de Hodgkin/genética , Linfo-Histiocitose Hemofagocítica/genética , Transtornos Linfoproliferativos/genética , Mutação , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Uveíte/genética , Adolescente , Pré-Escolar , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/patologia , Exoma , Feminino , Citometria de Fluxo , Heterozigoto , Doença de Hodgkin/diagnóstico , Doença de Hodgkin/imunologia , Doença de Hodgkin/patologia , Homozigoto , Humanos , Imunofenotipagem , Lactente , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Transtornos Linfoproliferativos/diagnóstico , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Masculino , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Uveíte/diagnóstico , Uveíte/imunologia , Uveíte/patologia , Adulto Jovem
20.
Clin Immunol ; 155(1): 74-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25217881

RESUMO

The lack or marked reduction of recently formed T and B cells provides a basis for neonatal screening for severe combined immunodeficiencies (SCID) and X-linked agammaglobulinemia (XLA). Newborns with other conditions are also identified if a severe T or B cell lymphopenia is present at birth. We retrospectively analyzed Guthrie card samples from 11 children with Wiskott-Aldrich syndrome (WAS), a rare disease that requires early diagnosis and treatment, to determine whether combined T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) screening could identify these patients. 4 of 11 patients showed markedly reduced TREC or KREC copy numbers in their DBS as compared to storage-time matched controls and prospectively screened Swedish and German newborns. No correlation was observed between the WAS gene mutations, the clinical severity/course and the result of the screening assay. A diagnosis of WAS should thus be considered in newborns with positive TREC or KREC screening results.


Assuntos
Linfócitos B/fisiologia , Linfopenia/diagnóstico , Linfócitos T/fisiologia , Síndrome de Wiskott-Aldrich/diagnóstico , Linfócitos B/citologia , DNA/genética , Predisposição Genética para Doença , Humanos , Recém-Nascido , Linfopenia/patologia , Estudos Retrospectivos , Linfócitos T/citologia , Síndrome de Wiskott-Aldrich/patologia
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