Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 148
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
2.
Ann Neurol ; 85(6): 927-933, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30945334

RESUMO

c-Jun-amino-terminal kinase-interacting protein 3 (JIP3), encoded by MAPK8IP3, is an adaptor protein of the kinesin-1 complex and essential for axonal transport in neurons. However, an association between MAPK8IP3 variants and human disease has not been established. We identified 5 individuals from four families with recurrent de novo variants c.1732C>T (p.Arg578Cys) and c.3436C>T (p.Arg1146Cys) in MAPK8IP3. The core phenotype includes spastic diplegia, intellectual disability, cerebral atrophy, and corpus callosum hypoplasia. Zebrafish embryos overexpressing human mutant JIP3 showed axon varicosities of the posterior lateral line nerve, suggesting an adverse effect on the developing axons. Our results suggest that MAPK8IP3 variants cause a neurodevelopmental disease. ANN NEUROL 2019;85:927-933.

3.
Int J Hematol ; 109(5): 603-611, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30850927

RESUMO

X-Linked severe combined immunodeficiency (X-SCID) is a severe form of primary immunodeficiency characterized by absence of T cells and NK cells. X-SCID is caused by a loss-of-function mutation in the IL2RG gene that encodes common gamma chain (γc), which plays an essential role in lymphocyte development. We report the first case of hypomorphic X-SCID caused by a synonymous mutation in the IL2RG gene leading to a splice anomaly, in a family including two patients with diffuse cutaneous warts, recurrent molluscum contagiosum, and mild respiratory infections. The mutation caused aberrant splicing of IL2RG mRNA, subsequently resulted in reduced γc expression. The leaky production of normally spliced IL2RG mRNA produced undamaged protein; thus, T cells and NK cells were generated in the patients. Functional assays of the patients' T cells and NK cells revealed diminished cytokine response in the T cells and absent cytokine response in the NK cells. In addition, the TCR repertoire in these patients was limited. These data suggest that a fine balance between aberrant splicing and leaky production of normally spliced IL2RG mRNA resulted in late-onset combined immunodeficiency in these patients.


Assuntos
Subunidade gama Comum de Receptores de Interleucina , Mutação , Sítios de Splice de RNA , Processamento de RNA , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Adolescente , Feminino , Humanos , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/imunologia , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Masculino , Processamento de RNA/genética , Processamento de RNA/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/patologia
4.
PLoS One ; 14(1): e0211450, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30703135

RESUMO

Although mutations in several genes have been reported in pulmonary arterial hypertension (PAH), most of PAH cases do not carry these mutations. This study aimed to identify a novel cause of PAH. To determine the disease-causing variants, direct sequencing and multiplex ligation-dependent probe amplification were performed to analyze 18 families with multiple affected family members with PAH. In one of the 18 families with PAH, no disease-causing variants were found in any of BMPR2, ACVRL1, ENG, SMAD1/4/8, BMPR1B, NOTCH3, CAV1, or KCNK3. In this family, a female proband and her paternal aunt developed PAH in their childhood. Whole-exome next-generation sequencing was performed in the 2 PAH patients and the proband's healthy mother, and a BRCA1-associated protein (BRAP) gene variant, p.Arg554Leu, was identified in the 2 family members with PAH, but not in the proband's mother without PAH. Functional analyses were performed using human pulmonary arterial smooth muscle cells (hPASMCs). Knockdown of BRAP via small interfering RNA in hPASMCs induced p53 signaling pathway activation and decreased cell proliferation. Overexpression of either wild-type BRAP or p.Arg554Leu-BRAP cDNA constructs caused cell death confounding these studies, however we observed higher levels of p53 signaling inactivation and hPASMC proliferation in cells expressing p.Arg554Leu-BRAP compared to wild-type BRAP. In addition, p.Arg554Leu-BRAP induced decreased apoptosis of hPASMCs compared with wild-type BRAP. In conclusion, we have identified a novel variant of BRAP in a Japanese family with PAH and our results suggest it could have a gain-of-function. This study sheds light on new mechanism of PAH pathogenesis.


Assuntos
Exoma/genética , Hipertensão Pulmonar Primária Familiar/genética , Hipertensão Pulmonar Primária Familiar/patologia , Músculo Liso Vascular/patologia , Mutação , Artéria Pulmonar/patologia , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Apoptose , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Músculo Liso Vascular/metabolismo , Linhagem , Artéria Pulmonar/metabolismo , Transdução de Sinais , Sequenciamento Completo do Exoma , Adulto Jovem
5.
J Clin Immunol ; 2018 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-30353301

RESUMO

OBJECTIVE: Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive primary immunodeficiency. Hypogammaglobulinemia is a major manifestation of ICF syndrome, but immunoglobulin replacement therapy does not seem to be effective for some ICF patients. Therefore, we aimed to reassess the immunological characteristics of this syndrome. METHODS: Eleven Japanese patients with ICF syndrome were enrolled. We performed whole-exome sequencing in four cases and homozygosity mapping using SNP analysis in two. We evaluated their clinical manifestations and immunological status. RESULTS: We newly diagnosed six ICF patients who had tentatively been diagnosed with common variable immunodeficiency. We identified two novel mutations in the DNMT3B gene and one novel mutation in the ZBTB24 gene. All patients showed low serum IgG and/or IgG2 levels and were treated by periodic immunoglobulin replacement therapy. Three of the six patients showed worse results of the mitogen-induced lymphocyte proliferation test. Analyses of lymphocyte subpopulations revealed that CD19+CD27+ memory B cells were low in seven of nine patients, CD3+ T cells were low in three patients, CD4/8 ratio was inverted in five patients, CD31+ recent thymic emigrant cells were low in two patients, and CD19+ B cells were low in four patients compared with those in the normal controls. ICF2 patients showed lower proportions of CD19+ B cells and CD16+56+ NK cells and significantly higher proportions of CD3+ T cells than ICF1 patients. T cell receptor excision circles were undetectable in two patients. Despite being treated by immunoglobulin replacement therapy, three patients died of influenza virus, fatal viral infection with persistent Epstein-Barr virus infection, or JC virus infection. One of three dead patients showed normal intelligence with mild facial anomaly. Two patients presented with autoimmune or inflammatory manifestations. Infectious episodes decreased in three patients who were started on trimethoprim-sulfamethoxazole and/or antifungal drugs in addition to immunoglobulin replacement therapy. These patients might have suffered from T cell immunodeficiency. CONCLUSION: These results indicate that patients with ICF syndrome have a phenotype of combined immunodeficiency. Thus, to achieve a better prognosis, these patients should be treated as having combined immunodeficiency in addition to receiving immunoglobulin replacement therapy.

6.
Brain Dev ; 40(10): 891-896, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29960745

RESUMO

OBJECTIVE: To report detail of a patient with infantile spasms whose cytogenetic analysis revealed mosaic monocentric and duplicated supernumerary marker chromosome (SMC) 15. SUBJECT AND METHODS: The subject for this case was a 13-month-old girl with infantile spasms and delayed developmental milestones. Chromosomal analysis with G-band showed the presence of SMC in mosaic. Further investigations using in situ hybridization, methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), microsatellite marker, and single nucleotide polymorphism (SNP) array analysis were performed. RESULTS: Her karyotype was noted as mosaic 47,XX,+mar[26]/46,XX[4], ish der(15)(D15Z1+, SNRPN++, PML-) de novo. MS-MLPA analysis showed that the Prader-Willi syndrome/Angelman syndrome critical region is highly methylated, and microsatellite marker analysis proved that the 15q11.2 region of the patient comprises three kinds of alleles: one paternal and two maternal. SNP array analysis suggested an asymmetric structure of SMC(15) composed of 15q11-q13 recombination at breakpoint (BP) 4:BP5. CONCLUSIONS: This is the first report of SMC(15) with monocentric and duplicated proximal 15q. The clinical presentations are quite similar to those of isodicentric chromosome 15 syndrome. The results of microsatellite and SNP array analysis suggest two possibilities regarding the timing of the mosaic SMC(15) formation. One possibility is that it occurred during maternal meiosis, and the other possibility is formation during a very early stage of embryo development that was initially trisomic of chromosome 15.

7.
Clin Immunol ; 195: 59-66, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30053428

RESUMO

X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500 G > A, p.G167E and c.156 G > C, p.K52 N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.

8.
Hum Mutat ; 39(8): 1070-1075, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29768694

RESUMO

By whole exome sequencing, we identified three de novo RHOBTB2 variants in three patients with epileptic encephalopathies (EEs). Interestingly, all three patients showed acute encephalopathy (febrile status epilepticus), with magnetic resonance imaging revealing hemisphere swelling or reduced diffusion in various brain regions. RHOBTB2 encodes Rho-related BTB domain-containing protein 2, an atypical Rho GTPase that is a substrate-specific adaptor or itself is a substrate for the Cullin-3 (CUL3)-based ubiquitin ligase complex. Transient expression experiments in Neuro-2a cells revealed that mutant RHOBTB2 was more abundant than wild-type RHOBTB2. Coexpression of CUL3 with RHOBTB2 decreased the level of wild-type RHOBTB2 but not the level of any of the three mutants, indicating impaired CUL3 complex-dependent degradation of the three mutants. These data indicate that RHOBTB2 variants are a rare genetic cause of EEs, in which acute encephalopathy might be a characteristic feature, and that precise regulation of RHOBTB2 levels is essential for normal brain function.

9.
Clin Case Rep ; 6(5): 810-812, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29744062

RESUMO

Household is responsible for a large percentage of pertussis infection in young infants. Japanese vaccine recommendation committee does not recommend any boosters for teens and pregnant women. Because of its high vaccine effectiveness, introduction of vaccination for pregnant women is high priority to prevent pertussis infection in young infants.

10.
J Clin Immunol ; 38(3): 300-306, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29671114

RESUMO

OBJECTIVE: In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT). METHODS: We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases. RESULTS: The accuracy of the male/female chimerism analysis using ddPCR was confirmed by comparing the results with those of conventional methods (fluorescence in situ hybridization and short tandem repeat-PCR) and evaluating dilution assays. In particular, we found that this method was useful for analyzing small samples. Thus, this method could be used with patient samples, especially to sorted leukocyte subpopulations, during the early post-transplant period. Four mutation-specific ddPCR accurately detected post-transplant chimerism. CONCLUSION: ddPCR-based male/female chimerism analysis and mutation-specific ddPCR were useful for all HSCT, and these simple methods contribute to following the post-transplant chimerism, especially in disease-specific small leukocyte fractions.

11.
Front Immunol ; 9: 568, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29675019

RESUMO

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10- mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.

12.
Biochem Biophys Res Commun ; 497(2): 719-725, 2018 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-29462620

RESUMO

AK2 is an adenylate phosphotransferase that localizes at the intermembrane spaces of the mitochondria, and its mutations cause a severe combined immunodeficiency with neutrophil maturation arrest named reticular dysgenesis (RD). Although the dysfunction of hematopoietic stem cells (HSCs) has been implicated, earlier developmental events that affect the fate of HSCs and/or hematopoietic progenitors have not been reported. Here, we used RD-patient-derived induced pluripotent stem cells (iPSCs) as a model of AK2-deficient human cells. Hematopoietic differentiation from RD-iPSCs was profoundly impaired. RD-iPSC-derived hemoangiogenic progenitor cells (HAPCs) showed decreased ATP distribution in the nucleus and altered global transcriptional profiles. Thus, AK2 has a stage-specific role in maintaining the ATP supply to the nucleus during hematopoietic differentiation, which affects the transcriptional profiles necessary for controlling the fate of multipotential HAPCs. Our data suggest that maintaining the appropriate energy level of each organelle by the intracellular redistribution of ATP is important for controlling the fate of progenitor cells.


Assuntos
Trifosfato de Adenosina/metabolismo , Adenilato Quinase/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/patologia , Células-Tronco Pluripotentes Induzidas/patologia , Leucopenia/patologia , Imunodeficiência Combinada Severa/patologia , Adenilato Quinase/genética , Células Cultivadas , Metabolismo Energético , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucopenia/genética , Leucopenia/metabolismo , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/metabolismo , Regulação para Cima
13.
Brain Dev ; 40(3): 233-237, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29289389

RESUMO

BACKGROUND: A heterozygous c.1228G > A p.E410K mutation in TUBB3 encoding neuronal-specific ß-tubulin isotype 3 causes TUBB3 E410K syndrome, which exhibits a wide range of neurological and endocrinological abnormalities. CASE DESCRIPTION: The patient is a 31-year-old Japanese woman who was diagnosed with atypical Moebius syndrome because of congenital facial weakness and extraocular ophthalmoplegia sparing abduction. She suffered a femoral neck fracture at 23 years of age, and radiological and endocrinological studies revealed osteoporosis because of hypogonadotropic hypogonadism. She also had borderline intellectual disability, cyclic vomiting, syncope with cough, and decreased sense of smell since childhood. Brain magnetic resonance imaging revealed abnormal morphology of the corpus callosum and pontine. Hypoplastic bilateral oculomotor and facial nerves were evident. Based on these symptoms, we analyzed the TUBB3 gene and identified a heterozygous c.1228G > A (p.E410K) mutation that confirmed the diagnosis of TUBB3 E410K syndrome. CONCLUSION: TUBB3 E410K syndrome may be diagnosed as atypical Moebius syndrome because of overlapping clinical symptoms. Genetic analysis of c.1228G > A in TUBB3 is useful to differentiate TUBB3 E410K syndrome from other disorders presenting congenital external ophthalmoplegia and facial nerve palsy.


Assuntos
Síndrome de Möbius/complicações , Mutação/genética , Osteoporose/genética , Síncope/genética , Tubulina (Proteína)/genética , Adulto , Corpo Caloso/diagnóstico por imagem , Movimentos Oculares/genética , Feminino , Ácido Glutâmico/genética , Humanos , Japão , Lisina/genética , Imagem por Ressonância Magnética , Síndrome de Möbius/diagnóstico por imagem , Osteoporose/complicações , Osteoporose/diagnóstico por imagem , Ponte/diagnóstico por imagem , Síncope/complicações , Síncope/diagnóstico por imagem
14.
J Pediatr Hematol Oncol ; 40(2): 137-140, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29324573

RESUMO

The clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT) was retrospectively analyzed in 6 patients with leukocyte adhesion deficiency. Of 3 patients transplanted with myeloablative conditioning, 2 patients had complete chimerism and 1 patient had mixed chimerism. By contrast, all 3 patients transplanted with reduced-intensity conditioning (RIC) had mixed chimerism, one of whom progressed to secondary graft failure. All patients with low-level mixed chimerism and secondary graft failure were rescued by donor lymphocyte infusion or a second HSCT. RIC-HSCT is feasible for leukocyte adhesion deficiency, although further refinement/modification of conditioning is required to achieve higher donor chimerism levels.

15.
J Clin Immunol ; 38(1): 144-148, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29255996

RESUMO

PURPOSE: A 42-year-old man with hyper-IgM syndrome type 2 caused by activation-induced cytidine deaminase (AID) deficiency developed a severe anaphylactic reaction to intravenous immunoglobulin. The purpose of this study was to clarify the cause of the anaphylactic reaction of the patient. METHODS: We measured IgM-class anti-human IgG and anti-human IgA antibodies in his serum by sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The sandwich ELISA assay revealed that serum from the patient, but not the controls, reacted to three different IgG products and purified human IgA. This indicated that the patient had IgM-class anti-human IgG and IgA antibodies in his serum, which associated with the anaphylactic reactions after the administration of IgG products. The anti-IgG antibody was likely to be the main cause of the reactions because an IgA-depleted IgG product also induced a severe reaction in this case and showed high absorbance in the ELISA system, similar to other IgG products containing more IgA. CONCLUSIONS: This is the first report of IgM-class anti-human IgG associated with an anaphylactic reaction to an IgG infusion. The anaphylactic reactions were very severe in this case, probably because IgM-class antibodies are potent activators of the complement pathway.

17.
Front Immunol ; 8: 685, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28952612

RESUMO

Immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) have been isolated from primary immunodeficiency (PID) patients exposed to oral poliovirus vaccine (OPV). Patients may excrete poliovirus strains for months or years; the excreted viruses are frequently highly divergent from the parental OPV and have been shown to be as neurovirulent as wild virus. Thus, these patients represent a potential reservoir for transmission of neurovirulent polioviruses in the post-eradication era. In support of WHO recommendations to better estimate the prevalence of poliovirus excreters among PIDs and characterize genetic evolution of these strains, 635 patients including 570 with primary antibody deficiencies and 65 combined immunodeficiencies were studied from 13 OPV-using countries. Two stool samples were collected over 4 days, tested for enterovirus, and the poliovirus positive samples were sequenced. Thirteen patients (2%) excreted polioviruses, most for less than 2 months following identification of infection. Five (0.8%) were classified as iVDPVs (only in combined immunodeficiencies and mostly poliovirus serotype 2). Non-polio enteroviruses were detected in 30 patients (4.7%). Patients with combined immunodeficiencies had increased risk of delayed poliovirus clearance compared to primary antibody deficiencies. Usually, iVDPV was detected in subjects with combined immunodeficiencies in a short period of time after OPV exposure, most for less than 6 months. Surveillance for poliovirus excretion among PID patients should be reinforced until polio eradication is certified and the use of OPV is stopped. Survival rates among PID patients are improving in lower and middle income countries, and iVDPV excreters are identified more frequently. Antivirals or enhanced immunotherapies presently in development represent the only potential means to manage the treatment of prolonged excreters and the risk they present to the polio endgame.

18.
J Microbiol Methods ; 141: 108-114, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28807759

RESUMO

Rapid and easy detection of sequence polymorphisms, including nucleotide point mutations of bacterial pathogens responsible for amino acid substitutions linked to drug resistance, is essential for the proper use of antimicrobial agents. Here, a detection method using loop-mediated amplification (LAMP) combined with amplification refractory mutation system (ARMS) to accurately distinguish a different single nucleotide in the target sequence was established, named ARMS-SNP LAMP. This procedure is capable of species-specific detection of a nucleotide (1578T) in the ftsI gene on Haemophilus influenzae without amplifying the sequence carrying the point mutations (T1578G/A) in ß-lactamase-negative ampicillin resistant (BLNAR) strains. Reactions were performed at 61°C for 45min. Successful target gene amplifications were detected by measuring real-time turbidity using a turbidimeter and visual detection. The assay had a detection limit of 10.0pg of genomic DNA per reaction and showed specificity against 52 types of pathogens, whereas amplifications were completely blocked in even 100.0ng/µL of genomic DNA with point mutations at T1578G and T1578A. The expected ARMS-SNP LAMP products were confirmed through identical melting curves in real-time LAMP procedures. This novel procedure was also used to analyze 57 clinical isolates of H. influenzae. All 25 clinical isolates with the naïve sequence of 1578T gave positive results. In addition, concordant negative results were obtained for 31 of the BLNAR strains with the T1578G mutation and one strain with the T1578A mutation. The ARMS-SNP LAMP method is a simple and rapid method for SNP-genotyping of a clinical isolate as point-of-care testing (POCT) technology. It is suitable for use in both resource-limited situations and well-equipped clinical settings because of its simplicity and convenience.


Assuntos
Resistência a Ampicilina/genética , Haemophilus influenzae/genética , Técnicas de Amplificação de Ácido Nucleico/métodos , Proteínas de Ligação às Penicilinas/genética , Mutação Puntual , beta-Lactamases/metabolismo , Ampicilina/farmacologia , Antibacterianos/farmacologia , DNA Bacteriano/genética , Genótipo , Infecções por Haemophilus/microbiologia , Haemophilus influenzae/efeitos dos fármacos , Haemophilus influenzae/enzimologia , Humanos , Limite de Detecção , Testes de Sensibilidade Microbiana , Nefelometria e Turbidimetria , Testes Imediatos , Polimorfismo Genético , Sensibilidade e Especificidade , Temperatura Ambiente , beta-Lactamases/genética
19.
J Clin Immunol ; 37(5): 434-444, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28493158

RESUMO

Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4+ T cells were skewed toward CD45RO+ memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.


Assuntos
Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Proteínas de Grupos de Complementação da Anemia de Fanconi/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Mutação , Adolescente , Adulto , Biomarcadores , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/terapia , Análise Mutacional de DNA , Diagnóstico Diferencial , Anemia de Fanconi/diagnóstico , Anemia de Fanconi/genética , Anemia de Fanconi/imunologia , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Feminino , Citometria de Fluxo , Humanos , Lactente , Masculino , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Linfócitos T/metabolismo , Sequenciamento Completo do Exoma , Adulto Jovem
20.
PLoS One ; 12(5): e0176957, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28542183

RESUMO

BACKGROUND: We recently reported that the combination of the neutrophil-to-lymphocyte ratio (NLR) and the platelet-to-lymphocyte ratio (PLR) is a novel and useful predictor of intravenous immunoglobulin (IVIG)-resistance in Kawasaki disease (KD). In the present study, to evaluate the effectiveness of the new risk score, we compared its predictive validity to that of previously reported risk scores. MATERIALS AND METHODS: The laboratory records of 437 patients with KD before IVIG therapy were retrospectively analyzed, and the IVIG-responsive (n = 344) and IVIG-resistant (n = 93) patients were compared. The validity of the new score (the combination of NLR≥3.83 and PLR≥150) for predicting IVIG resistance in KD was compared to that of the Kobayashi, Egami and Sano risk scores. RESULTS: The new score and the Kobayashi score displayed high sensitivity (0.72 and 0.70 respectively) and specificity (0.67 and 0.68 respectively), while the Egami and Sano scores showed high specificity (0.71 and 0.81 respectively) but relatively low sensitivity (0.56 and 0.45 respectively). The odds ratios (ORs) for the new score, the Kobayashi score, the Egami score and the Sano score were 5.34 (95% confidence interval [CI] 3.22-8.85), 4.87 (95% CI 2.96-8.01), 3.14 (95% CI 1.96-5.03) and 3.53 (95% CI 2.17-5.77) respectively. CONCLUSIONS: The predictive validity of the combination of NLR≥3.83 and PLR≥150, which is a simple and convenient indicator, was equal to or higher than that of the other risk scores. This suggests that the new score could be a widely available marker for predicting IVIG resistance in KD.


Assuntos
Contagem de Células Sanguíneas , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Contagem de Células Sanguíneas/métodos , Plaquetas , Resistência a Medicamentos , Feminino , Humanos , Lactente , Linfócitos , Masculino , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Neutrófilos , Razão de Chances , Prognóstico , Estudos Retrospectivos , Medição de Risco , Sensibilidade e Especificidade , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA