Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 21
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Clin Immunol ; 210: 108309, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31751612

RESUMO

Mutations affecting the non-canonical pathway of NF-κB were recently identified to underlie a form of common variable immunodeficiency strongly associated with autoimmunity. Although intrinsic B-cell abnormalities explain most of the humoral defects of this disease, detailed data on the impact of NFKB2 on follicular helper (Tfh) and regulatory (Tregs) T cells are scarce. Here, we show that Tfh, CXCR5+, and CXCR5- Treg cell subsets were significantly reduced in patients heterozygous for a truncating mutation of NFKB2. Plasma CXCL13 levels were reduced, underlining an important role for NFKB2 in regulating the germinal center (GC) response. Proinflammatory IFNγ, IL-17 and IL-10 cytokine production by CD4 T cells was lower in the mutated patients, but the production of IL-4 and IL-21 was not altered. Taken together, our findings show that NFKB2 influences the quality and efficiency of human GC reaction, by affecting not only the B cells but also GC-relevant T cell subsets.

2.
Front Immunol ; 10: 1908, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456805

RESUMO

Severe combined immunodeficiencies (SCIDs) are a group of inborn errors of the immune system, usually associated with severe or life-threatening infections. Due to the variability of clinical phenotypes, the diagnostic complexity and the heterogeneity of the genetic basis, they are often difficult to recognize, leading to a significant diagnostic delay (DD). Aim of this study is to define presenting signs and natural history of SCID in a large cohort of patients, prior to hematopoietic stem cell or gene therapies. To this purpose, we conducted a 30-year retro-prospective multicenter study within the Italian Primary Immunodeficiency Network. One hundred eleven patients, diagnosed as typical or atypical SCID according to the European Society for Immune Deficiencies criteria, were included. Patients were subsequently classified based on the genetic alteration, pathogenic mechanism and immunological classification. A positive relationship between the age at onset and the DD was found. SCID patients with later onset were identified only in the last decade of observation. Syndromic SCIDs represented 28% of the cohort. Eight percent of the subjects were diagnosed in Intensive Care Units. Fifty-three percent had an atypical phenotype and most of them exhibited a discordant genotype-immunophenotype. Pre-treatment mortality was higher in atypical and syndromic patients. Our study broadens the knowledge of clinical and laboratory manifestations and genotype/phenotype correlation in patients with SCID and may facilitate the diagnosis of both typical and atypical forms of the disease in countries where newborn screening programs have not yet been implemented.

3.
J Allergy Clin Immunol Pract ; 7(7): 2369-2376, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30922987

RESUMO

BACKGROUND: Patients with 22q11.2 deletion syndrome (22q11.2DS) may develop severe thrombocytopenic purpura and hemolytic anemia. There are no reliable predictors for the development of hematologic autoimmunity (HA) in these patients. OBJECTIVE: To describe the peculiar B and T subpopulation defects in patients with 22q11DS who have developed HA and test if these defects precede the development of HA. METHODS: We performed a case-control multicenter study. Patients with HA were compared with a control population of 22q11.2DS without HA (non-HA). A complete immunological evaluation was performed at diagnosis and at the last follow-up including extensive T and B phenotypes. RESULTS: Immunophenotype at the last follow-up was available in 23 HA and 45 non-HA patients. HA patients had significantly decreased percentage of naïve CD4+ cells (26.8% vs 43.2%, P = .003) and recent thymic emigrants (48.6% vs 80.5%, P = .046); decreased class-switched B cells (2.0% vs 5.9%, P = .04) and increased naive B cells (83.5% vs 71.4%, P = .02); increased CD16+/56+ both in absolute number (312 vs 199, P = .009) and percentage (20.0% vs 13.0%, P = .03). Immunophenotype was performed in 36 patients (11 HA and 25 non-HA) at diagnosis. Odds ratio (OR) of immune cytopenia were estimated for both CD4 naïve ≤30% (OR 14.0, P = .002) and switched memory B cells ≤2% (OR 44.0, P = .01). The estimated survival curves reached statistical significance, respectively, P = .0001 and P = .002. CONCLUSIONS: Among patients with 22q11.2DS, those with HA have characteristic lymphocyte anomalies that appear considerably before HA onset. Systematic immunophenotyping of patients with 22q11.2DS at diagnosis is advisable for early identification of patients at risk for this severe complication.

4.
Hum Mutat ; 40(6): 721-728, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30825388

RESUMO

The pathogenic variants in the neuroblastoma-amplified sequence (NBAS) are associated with a clinical spectrum involving the hepatic, skeletal, ocular, and immune systems. Here, we report on two unrelated subjects with a complex phenotype solved by whole-exome sequencing, who shared a synonymous change in NBAS that was documented to affect the transcript processing and co-occurring with a truncating change. Starting from these two cases, we systematically assessed the clinical information available for all subjects with biallelic NBAS pathogenic variants (73 cases in total). We revealed a recognizable facial profile (hypotelorism, thin lips, pointed chin, and "progeroid" appearance) determined by using DeepGestalt facial recognition technology, and we provide evidence for the occurrence of genotype-phenotype correlations. Notably, severe hepatic involvement was associated with variants affecting the NBAS-Nter and Sec39 domains, whereas milder liver involvement and immunodeficiency were generally associated with variants located at the N-terminus and C-terminus of the protein. Remarkably, no patient was reported to carry two nonsense variants, suggesting lethality of complete NBAS loss-of-function.

6.
Front Immunol ; 9: 1761, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30131802

RESUMO

Mutations in genes that control class switch recombination and somatic hypermutation during the germinal center (GC) response can cause diverse immune dysfunctions. In particular, mutations in CD40LG, CD40, AICDA, or UNG cause hyper-IgM (HIGM) syndrome, a heterogeneous group of primary immunodeficiencies. Follicular helper (Tfh) and follicular regulatory (Tfr) T cells play a key role in the formation and regulation of GCs, but their role in HIGM pathogenesis is still limited. Here, we found that compared to CD40 ligand (CD40L)- and activation-induced cytidine deaminase (AICDA)-deficient patients, circulating Tfh and Tfr cells were severely compromised in terms of frequency and activation phenotype in a child with CD40 deficiency. These findings offer useful insight for human Tfh biology, with potential implications for understanding the molecular basis of HIGM syndrome caused by mutations in CD40.


Assuntos
Antígenos CD40/deficiência , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Adulto , Antígenos CD40/genética , Ligante de CD40/genética , Pré-Escolar , Citidina Desaminase/deficiência , Citidina Desaminase/genética , Feminino , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/genética , Imunofenotipagem , Ativação Linfocitária , Masculino , Mutação , Adulto Jovem
7.
J Pediatr ; 198: 25-28.e1, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29605389

RESUMO

OBJECTIVES: To estimate the incidence of acute rheumatic fever (ARF) in a metropolitan area of Northern Italy and study how the introduction of the 2015 revised Jones criteria affects the epidemiology in a region with moderate to high incidence of ARF. STUDY DESIGN: The incidence of ARF in children 5-14 years old living in the Province of Turin was estimated using low-risk criteria in a 10-year period (group A patients). The proportion of patients fulfilling only high-risk (HR) criteria (group B patients) was also calculated both prospectively (from July 2015 through December 2016) and retrospectively (from January 2007 through June 2015). RESULTS: One hundred thirty-five group A patients were identified for an annual incidence of 3.2-9.6 out of 100 000 children. The use of HR criteria identified an additional 28 patients (group B), resulting in a 20.7% increase in the incidence of ARF. Age, sex annual incidence, and seasonal distribution pattern were comparable between group A and group B patients. CONCLUSIONS: HR criteria should be used for the diagnosis ARF in our region. The application of these criteria led to a 20% increase in patients with the diagnosis of ARF. The characteristics of patients fulfilling only HR criteria are similar to the remaining patients, suggesting that these criteria are sensitive and specific.


Assuntos
Febre Reumática/diagnóstico , Febre Reumática/epidemiologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Itália/epidemiologia , Masculino , Guias de Prática Clínica como Assunto , Estudos Retrospectivos , Estações do Ano , Distribuição por Sexo
9.
Cytometry B Clin Cytom ; 94(3): 423-427, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29059705

RESUMO

BACKGROUND: Oligoarticular juvenile idiopathic arthritis (oJIA) is the most frequent form of chronic arthritis in children; the clinical course is extremely variable. In this study we have characterized by flow cytometry synovial B and T cells subsets in patients with oJIA in order to identify any parameters that could predict a more aggressive course of disease. METHODS: B and T cells from synovial fluid (SF) of 39 patients with oJIA were characterized by flow cytometry. In 22 patients SF was analysed at the onset of the disease (GroupA), in 17 SF was analysed at articular relapse (Group B). All patients in Group A were followed up for at least for 2 years after SF analysis: 13 patients relapsed during the follow-up period. RESULTS: Comparison of SF from Group A and Group B demonstrated an activated phenotype in relapsed patients, with higher Switched Memory B cells (58.53 vs 36.07% of CD19+, P-value 0.004) and lower Naïve B cells (8.53 vs 25.9 of CD19+, P-value 0.002) in Group B. Furthermore, patients from Group A who did not relapse showed lower percentages of synovial DNT (2.38 vs 1.50% of CD3 + TCRalpha/beta+, P-value 0.025) and γδ T cells (19.1 vs 15.0% of CD3+ cells, P-value 0.004) at the onset, if compared with other Group A patients. CONCLUSIONS: In oJIA relapse SF present an activated B phenotype. Patients at disease onset with DNTs <1.8% and/or γδ T cells <16% of CD3+ in synovial fluid have longer free-disease survival. © 2017 International Clinical Cytometry Society.


Assuntos
Artrite Juvenil/imunologia , Artrite Juvenil/mortalidade , Líquido Sinovial/imunologia , Subpopulações de Linfócitos T/imunologia , Antígenos CD19/imunologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Citometria de Fluxo/métodos , Humanos , Masculino
10.
Int J Infect Dis ; 51: 22-24, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27569828

RESUMO

Two cases of neonatal group B streptococcal (GBS) infection occurring in a large consanguineous kindred are described. The observation suggests that susceptibility to isolated GBS disease in this family may have been the result of an inborn error of immunity inherited as a Mendelian autosomal recessive trait.


Assuntos
Consanguinidade , Infecções Estreptocócicas/genética , Streptococcus agalactiae , Antibioticoprofilaxia , Anticorpos Antibacterianos/genética , Anticorpos Antibacterianos/imunologia , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Recém-Nascido , Masculino , Infecções Estreptocócicas/tratamento farmacológico , Infecções Estreptocócicas/imunologia
11.
Mol Biotechnol ; 58(8-9): 540-50, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27246439

RESUMO

MicroRNAs (miRNAs) are short, single stranded, non-coding RNA molecules. They are produced by many different species and are key regulators of several physiological processes. miRNAs are also encoded by the genomes of multiple virus families, such as herpesvirus family. In particular, miRNAs from Epstein Barr virus were found at high concentrations in different associated pathologies, such as Burkitt's lymphoma, Hodgkin disease, and nasopharyngeal carcinoma. Thanks to their stability, these molecules could possibly serve as biomarkers for EBV-associated diseases. In this study, a stem-loop real-time PCR for miR-BART2-5p, miR-BART15, and miR-BART22 EBV miRNAs detection and quantification has been developed. Evaluation of these miRNAs in 31 serum samples (12 from patients affected by primary immunodeficiency, 9 from X-linked agammaglobulinemia and 10 from healthy subjects) has been carried out. The amplification performance showed a wide dynamic range (10(8)-10(2) copies/reaction) and sensibility equal to 10(2) copies/reaction for all the target tested. Serum samples analysis, on the other hand, showed a statistical significant higher level of miR-BART22 in primary immunodeficiency patients (P = 0.0001) compared to other groups and targets. The results confirmed the potential use of this assay as a tool for monitoring EBV-associated disease and for miRNAs expression profile analysis.


Assuntos
Herpesvirus Humano 4/genética , MicroRNAs/sangue , Reação em Cadeia da Polimerase em Tempo Real/métodos , Agamaglobulinemia/sangue , Agamaglobulinemia/virologia , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/virologia , Herpesvirus Humano 4/isolamento & purificação , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/virologia , Sequências Repetidas Invertidas , MicroRNAs/química , RNA Viral/sangue , RNA Viral/química , Reação em Cadeia da Polimerase em Tempo Real/economia , Sensibilidade e Especificidade
12.
J Clin Lab Anal ; 30(4): 277-83, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25853736

RESUMO

BACKGROUND: microRNAs play a critical role in many biological processes such as cell proliferation and maturation, apoptosis, regulation of chronic inflammation and development of cancer. METHODS: In this study is described a protocol for the isolation of RNA from serum and subsequent determination of miRNA expression levels using TaqMan-based MGB Real-Time PCR detection. RNA was extracted using two different isolation methods including available kits RNAzol and a modified RNAzol protocol. In all cases, RNA was eluted in RNase free H2 O, kept frozen until analysis and the presence of contaminants assessed by NanoDrop spectrophotometry. RESULTS: Higher RNA quantity was observed in RNAzol (378.8 ng/µl) vs RNAzol modified protocol (226.5 ng/µl) and a better performance in terms of RNA extraction yield and purity. Subsequently, measurements of endogenous miRNAs (RNU43), cellular miRNAs (mir155 and mir146a) and EBV miRNAs (mirBART2-5p, mirBART15 and mirBART22) were performed by RT-qPCR. CONCLUSION: In contrast to the findings in terms of purity and quantity, the amplifiable RNA was more abundant using RNAzol modified protocol compared to not modified protocol.


Assuntos
MicroRNAs/sangue , MicroRNAs/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/métodos , Humanos , MicroRNAs/química , Conformação de Ácido Nucleico , RNA/metabolismo
14.
J Allergy Clin Immunol ; 134(6): 1381-1387.e7, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24985396

RESUMO

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, heterogeneous, hyperinflammmatory disorder. Prompt identification of inherited forms resulting from mutation in genes involved in cellular cytotoxicity can be crucial. X-linked lymphoproliferative disease 1 (XLP1), due to mutations in SH2D1A (Xq25) encoding signaling lymphocyte activation molecule-associated protein (SAP), may present with HLH. Defective SAP induces paradoxical inhibitory function of the 2B4 coreceptor and impaired natural killer (NK) (and T) cell response against EBV-infected cells. OBJECTIVE: To characterize a cohort of patients with HLH and XLP1 for SAP expression and 2B4 function in lymphocytes, proposing a rapid diagnostic screening to direct mutation analysis. METHODS: We set up rapid assays for 2B4 function (degranulation or (51)Cr-release) to be combined with intracellular SAP expression in peripheral blood NK cells. We studied 12 patients with confirmed mutation in SH2D1A and some family members. RESULTS: The combined phenotypic/functional assays allowed efficient and complete diagnostic evaluation of all patients with XLP1, thus directing mutation analysis and treatment. Nine cases were SAP(-), 2 expressed SAP with mean relative fluorescence intensity values below the range of healthy controls (SAP(dull)), and 1, carrying the R55L mutation, was SAP(+). NK cells from all patients showed inhibitory 2B4 function and defective killing of B-EBV cells. Carriers with SH2D1A mutations abolishing SAP expression and low percentage of SAP(+) cells showed neutral 2B4 function at the polyclonal NK cell level. Three novel SH2D1A mutations have been identified. CONCLUSIONS: Study of SAP expression is specific but may have insufficient sensitivity for screening XLP1 as a single tool. Combination with 2B4 functional assay allows identification of all cases.


Assuntos
Antígenos CD/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Receptores Imunológicos/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/genética , Células Matadoras Naturais/imunologia , Leucócitos Mononucleares/imunologia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Masculino , Mutação , Proteína Associada à Molécula de Sinalização da Ativação Linfocitária , Família de Moléculas de Sinalização da Ativação Linfocitária , Adulto Jovem
15.
J Pediatr ; 164(6): 1475-80.e2, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24657119

RESUMO

OBJECTIVE: To investigate the clinical manifestations at diagnosis and during follow-up in patients with 22q11.2 deletion syndrome to better define the natural history of the disease. STUDY DESIGN: A retrospective and prospective multicenter study was conducted with 228 patients in the context of the Italian Network for Primary Immunodeficiencies. Clinical diagnosis was confirmed by cytogenetic or molecular analysis. RESULTS: The cohort consisted of 112 males and 116 females; median age at diagnosis was 4 months (range 0 to 36 years 10 months). The diagnosis was made before 2 years of age in 71% of patients, predominantly related to the presence of heart anomalies and neonatal hypocalcemia. In patients diagnosed after 2 years of age, clinical features such as speech and language impairment, developmental delay, minor cardiac defects, recurrent infections, and facial features were the main elements leading to diagnosis. During follow-up (available for 172 patients), the frequency of autoimmune manifestations (P = .015) and speech disorders (P = .002) increased. After a median follow-up of 43 months, the survival probability was 0.92 at 15 years from diagnosis. CONCLUSIONS: Our data show a delay in the diagnosis of 22q11.2 deletion syndrome with noncardiac symptoms. This study provides guidelines for pediatricians and specialists for early identification of cases that can be confirmed by genetic testing, which would permit the provision of appropriate clinical management.


Assuntos
Anormalidades Múltiplas/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Síndrome de DiGeorge/diagnóstico , Progressão da Doença , Monitorização Fisiológica/métodos , Anormalidades Múltiplas/epidemiologia , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Cromossomos Humanos Par 22/genética , Diagnóstico Tardio , Deficiências do Desenvolvimento/diagnóstico , Síndrome de DiGeorge/genética , Síndrome de DiGeorge/terapia , Diagnóstico Precoce , Feminino , Seguimentos , Testes Genéticos , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Adulto Jovem
16.
Clin Immunol ; 152(1-2): 164-70, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24674883

RESUMO

Hyper-IgE syndrome (HIES) is a genetic disorder characterized by elevated IgE serum levels, mostly due to mutations in STAT3 or DOCK8. Despite clinical heterogeneity between the two forms of the disease, clinical manifestations may not be conclusive for diagnosis and immunological differences are still unclear. Herein, we performed a detailed characterization of the T- and B-cell compartments by flow cytometry in seven HIES patients with homozygous DOCK8 mutations and six patients presenting heterozygous STAT3 mutations. We observed that DOCK8-deficient patients showed a marked reduction of naive and recent thymic emigrant (RTE) T lymphocytes together with a relative increase of activated T cells, most of which co-expressed the chemokine receptor CCR4, a marker of Th2 polarization. Moreover, an extreme reduction of memory B cells was detected, despite a normal/increased proportion of immunoglobulin-secreting cells. These observations indicate that DOCK8-deficient patients display a distinctive immunophenotype which is characteristic of this form of HIES.


Assuntos
Linfócitos B/imunologia , Fatores de Troca do Nucleotídeo Guanina/genética , Memória Imunológica/imunologia , Síndrome de Job/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fatores de Troca do Nucleotídeo Guanina/deficiência , Fatores de Troca do Nucleotídeo Guanina/imunologia , Humanos , Imunoglobulina E/sangue , Síndrome de Job/genética , Ativação Linfocitária/imunologia , Contagem de Linfócitos , Masculino , Receptores CCR4/imunologia , Fator de Transcrição STAT3/genética , Adulto Jovem
17.
J Allergy Clin Immunol ; 133(3): 799-806.e10, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24506932

RESUMO

BACKGROUND: Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. OBJECTIVE: We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. METHODS: Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. RESULTS: Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. CONCLUSIONS: ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.


Assuntos
Adenosina Desaminase/deficiência , Linfócitos B/fisiologia , Terapia de Reposição de Enzimas , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Adenosina Desaminase/genética , Adenosina Desaminase/uso terapêutico , Adolescente , Fator Ativador de Células B/fisiologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Humanos , Lactente
18.
Pediatr Gastroenterol Hepatol Nutr ; 17(4): 257-62, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25587526

RESUMO

Severe combined immunodeficiency (SCID) is a life-threatening syndrome of recurrent infections and gastrointestinal alterations due to severe compromise of T cells and B cells. Clinically, most patients present symptoms before the age of 3 months and without intervention SCID usually results in severe infections and death by the age of 2 years. Its association with intestinal anomalies as multiple intestinal atresias (MIA) is rare and worsens the prognosis, resulting lethal. We describe the case of a four year-old boy with SCID-MIA. He presented at birth with meconium peritonitis, multiple ileal atresias and underwent several intestinal resections. A targeted Sanger sequencing revealed a homozygous 4-bp deletion (c.313ΔTATC; p.Y105fs) in tetratricopeptide repeat domain 7A (TTC7A). He experienced surgical procedures including resection and stricturoplasty. Despite parenteral nutrition-associated liver disease, the patient is surviving at the time of writing the report. Precocious immune system assessment, scrutiny of TTC7A mutations and prompt surgical procedures are crucial in the management.

19.
J Allergy Clin Immunol ; 132(3): 656-664.e17, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23830146

RESUMO

BACKGROUND: Combined immunodeficiency with multiple intestinal atresias (CID-MIA) is a rare hereditary disease characterized by intestinal obstructions and profound immune defects. OBJECTIVE: We sought to determine the underlying genetic causes of CID-MIA by analyzing the exomic sequences of 5 patients and their healthy direct relatives from 5 unrelated families. METHODS: We performed whole-exome sequencing on 5 patients with CID-MIA and 10 healthy direct family members belonging to 5 unrelated families with CID-MIA. We also performed targeted Sanger sequencing for the candidate gene tetratricopeptide repeat domain 7A (TTC7A) on 3 additional patients with CID-MIA. RESULTS: Through analysis and comparison of the exomic sequence of the subjects from these 5 families, we identified biallelic damaging mutations in the TTC7A gene, for a total of 7 distinct mutations. Targeted TTC7A gene sequencing in 3 additional unrelated patients with CID-MIA revealed biallelic deleterious mutations in 2 of them, as well as an aberrant splice product in the third patient. Staining of normal thymus showed that the TTC7A protein is expressed in thymic epithelial cells, as well as in thymocytes. Moreover, severe lymphoid depletion was observed in the thymus and peripheral lymphoid tissues from 2 patients with CID-MIA. CONCLUSIONS: We identified deleterious mutations of the TTC7A gene in 8 unrelated patients with CID-MIA and demonstrated that the TTC7A protein is expressed in the thymus. Our results strongly suggest that TTC7A gene defects cause CID-MIA.


Assuntos
Síndromes de Imunodeficiência/genética , Atresia Intestinal/genética , Intestinos/anormalidades , Proteínas/genética , Animais , Pré-Escolar , Exoma/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/metabolismo , Timo/metabolismo , Análise Serial de Tecidos
20.
Autoimmun Rev ; 12(8): 796-801, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23219764

RESUMO

Common variable immunodeficiency is a collection of diseases characterized by primary hypogammaglobulinemia. The causes of CVID are extremely heterogeneous and may affect virtually every pathway linked to B cell development and function. Clinical manifestations of CVID mainly include recurrent bacterial infections, but autoimmune, gastrointestinal, lymphoproliferative, granulomatous, and malignant disorders have also been frequently reported as associated conditions. We aimed to focus on the state of the art of the relationship between infections, inflammation and autoimmunity in CVID.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/fisiopatologia , Agamaglobulinemia/imunologia , Animais , Autoimunidade/imunologia , Linfócitos B/imunologia , Infecções Bacterianas/imunologia , Imunodeficiência de Variável Comum/genética , Humanos , Inflamação/imunologia , Linfócitos T/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA