CRISTINA MIUKI ABE JACOB

(Fonte: Lattes)
Índice h a partir de 2011
12
Projetos de Pesquisa
Unidades Organizacionais
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder

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Agora exibindo 1 - 6 de 6
  • conferenceObject
    The Extended Clinical Phenotype of 36 Patients with Chronic Mucocutaneous Candidiasis Due to Gain-of-Function Mutations in STAT1
    (2014) FREDE, N.; DEPNER, M.; RAABE, J.; DOFFINGER, R.; GKRANIA-KLOTSAS, E.; KUMARARATNE, D.; ATKINSON, T. P.; SCHROEDER, H. W.; NIEHUES, T.; DUECKERS, G.; PUCK, J.; EISENSTEIN, E. M.; STRAY-PEDERSEN, A.; BAUMANN, U.; SCHMIDT, R. E.; FRANCO, J. L.; ORREGO, J. C.; BEN-SHOSHAN, M.; MCCUSKER, C.; JACOB, C. M.; CARNEIRO-SAMPAIO, M.; DEVLIN, L. A.; EDGAR, J. D.; HENDERSON, P.; DYRSO, T.; SENEVIRATNE, S. L.; WANDERS, J.; STAUSS, H.; MEYTS, I.; MOENS, L.; JESENAK, M.; GRIMBACHER, B.
  • article 105 Citação(ões) na Scopus
    The Extended Clinical Phenotype of 26 Patients with Chronic Mucocutaneous Candidiasis due to Gain-of-Function Mutations in STAT1
    (2016) DEPNER, Mark; FUCHS, Sebastian; RAABE, Jan; FREDE, Natalie; GLOCKER, Cristina; DOFFINGER, Rainer; GKRANIA-KLOTSAS, Effrossyni; KUMARARATNE, Dinakantha; ATKINSON, T. Prescott; SCHROEDER JR., Harry W.; NIEHUES, Tim; DUECKERS, Gregor; STRAY-PEDERSEN, Asbjorg; BAUMANN, Ulrich; SCHMIDT, Reinhold; FRANCO, Jose L.; ORREGO, Julio; BEN-SHOSHAN, Moshe; MCCUSKER, Christine; JACOB, Cristina Miuki Abe; CARNEIRO-SAMPAIO, Magda; DEVLIN, Lisa A.; EDGAR, J. David M.; HENDERSON, Paul; RUSSELL, Richard K.; SKYTTE, Anne-Bine; SENEVIRATNE, Suranjith L.; WANDERS, Jennifer; STAUSS, Hans; MEYTS, Isabelle; MOENS, Leen; JESENAK, Milos; KOBBE, Robin; BORTE, Stephan; BORTE, Michael; WRIGHT, Dowain A.; HAGIN, David; TORGERSON, Troy R.; GRIMBACHER, Bodo
    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)-alpha, IFN-gamma 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.
  • conferenceObject
    Profiling using protein x basophil array: current progress
    (2012) WANG, X.; WAN, D.; JACOB, C.; FALCONE, F.; ALCOCER, M.
    Background: Correlation between observed allergic clinical symptoms and specific IgE levels is poor in some cases. Current developments on basophil activation tests (BAT) are showing improved clinic relevance (compared to DBPCFC) than specific IgE alone. We are developing a two stages diagnostic device which combines the advantages of BAT with the numerical power of protein microarrays. Previously we have shown that a four immunoglobulin platform for simultaneous detection of IgM, A, G and E was feasible. We then demonstrated as proof-of-principle that human peripheral blood basophils and humanised basophil cell lines can bind to a protein array and that activation can be detected. Here we show an application of the basic platform (protein array) and discuss current stages of development of the basophil array system. Method: Microarrays containing proteins and extracts of food products, enterobacteria and inhaled allergens have been hybridised with sera from a retrospective longitudinal trial of children with clinically well-characterized cow’s milk allergy (n= 41) and control sera (n= 20) as previously described. The IgM, A, G and E levels have been determined and were analysed using chemometric multivariate routines. For the second stage (basophil cells), binding and incubation parameters to the array were experimentally optimised for three independent cell lines. Basophil cell activation markers involving Annexin V binding, Calcium influx and fluorescent inducible reporter systems have been compared to enzymatic degranulation tests. Result: The basic platform (protein array only) has shown that total IgG and IgA share similar specificity whilst IgM and IgE in particular are distantly related. The array has shown that four out of the 41 patients might have allergies other than milk origin. A good correlation (r2> 0.7) between dairy IgE and ImunoCAP, casein in particular, was observed. In the basophil system (2nd stage platform), measurement of Annexin V and calcium influx produced expected degranulation endpoints however, fluorescent reporter genes have shown higher sensitivity. The lack of stability of cells after successive passages is still a major issue. Conclusion: The basic platform (protein array) for the comprehensive profiling tools has produced qualitatively and quantitative reproducible results. The optimisation of the second component (basophil cells) of the profiling platform that is, reporter genes for key steps.
  • conferenceObject
    MUTATION SCREENING IN STAT1, CARD9 AND PKC-DELTA IN PATIENTS WITH CHRONIC MUCOCUTANEOUS CANDIDIASIS
    (2012) DEPNER, M.; VEERDONK, F. van de; WANDERS, J.; STAUSS, H.; RAABE, J.; ATKINSON, T. P.; SCHROEDER JR., H. W.; NIEHUES, T.; DUECKERS, G.; PUCK, J.; STRAY-PEDERSEN, A.; BAUMANN, U.; SCHMIDT, R.; FRANCO, J. L.; ORREGO, J.; BEN-SHOSHAN, M.; MCCUSKER, C.; JACOB, C. M. A.; CARNEIRO-SAMPAIO, M.; DEVLIN, L. A.; EDGAR, J. D.; GKRANIA-KLOTSAS, E.; KUMARARATNE, D.; DOFFINGER, R.; HENDERSON, P.; RUSSELL, R. K.; DYRSO, T.; SENEVIRATNE, S. L.; MATTHIJS, G.; ABINUN, M.; GENNERY, A.; JOHNSON, M.; MEER, J. W. M. van der; NETEA, M. G.; LILIC, D.; GRIMBACHER, B.
  • article 12 Citação(ões) na Scopus
    Prediction of tolerance in children with IgE mediated cow's milk allergy by microarray profiling and chemometric approach
    (2012) WULFERT, F.; SANYASI, G.; TONGEN, L.; WATANABE, L. A.; WANG, X.; RENAULT, N. K.; FALCONE, F. H.; JACOB, C. M. A.; ALCOCER, M. J. C.
    The sera of a retrospective cohort (n = 41) composed of children with well characterized cow's milk allergy collected from multiple visits were analyzed using a protein microarray system measuring four classes of immunoglobulins. The frequency of the visits, age and gender distribution reflected real situation faced by the clinicians at a pediatric reference center for food allergy in 530 Paulo, Brazil. The profiling array results have shown that total IgG and IgA share similar specificity whilst IgM and in particular IgE are distantly related. The correlation of specificity of IgE and IgA is variable amongst the patients and this relationship cannot be used to predict atopy or the onset of tolerance to milk. The array profiling technique has corroborated the clinical selection criteria for this cohort albeit it clearly suggested that 4 out of the 41 patients might have allergies other than milk origin. There was also a good correlation between the array data and ImmunoCAP results, casein in particular. By using qualitative and quantitative multivariate analysis routines it was possible to produce validated statistical models to predict with reasonable accuracy the onset of tolerance to milk proteins. If expanded to larger study groups, the array profiling in combination with the multivariate techniques show potential to improve the prognostic of milk allergic patients.
  • conferenceObject
    Gain-of-function mutations in STAT1: A new molecular cause for patients with chronic mucocutaneous candidiasis
    (2012) DEPNER, M.; WANDERS, J.; STAUSS, H.; JANSSON, A.; DUECKERS, G.; NIEHUES, T.; BAUMANN, U.; PEDERSEN, A. Stray; KILIC, S. S.; ATKINSON, T. P.; PUCK, J. M.; FRANCO, J. L.; DEVLIN, L.; JENSEN, T. D.; HENDERSON, P.; MATTHIJS, G.; SHOSHAN, M. Ben; MCCUSKER, C.; JACOB, C. M.; GRIMBACHER, B.
    Background: Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of skin, nails or mucosa with candida species. Most of the cases are sporadic; however, both autosomal dominant and autosomal recessive inheritance has been reported. Recent research suggests that autosomal dominant CMC may be due to heterozygous gain-of-function mutations in the signalling protein STAT1. Methods: We studied twelve unrelated families with autosomal dominant CMC and ten sporadic patients. We sequenced the genomic DNA of affected individuals, searching for heterozygous mutations in the 15 exons covering the coiled-coil and DNA-binding domain of STAT1. Results: After performing Sanger sequencing on all patients, we identified five different missense mutations in the coiled-coil domain of STAT1 in eight of the twelve CMC families. We then focused on sequencing the sporadic cases. In three of ten sporadic CMC patients we identified heterozygous missense mutation in the DNA-binding domain of STAT1. Conclusion: Missense mutations in the coiled-coil and DNA-binding domain of STAT1 may be the cause for sporadic and autosomal dominant CMC. Thus, STAT1 has to be taken into account when diagnosing this condition. The mutations we report are gain-of-function mutations. Interestingly, loss-of-function mutations in STAT1 lead to the susceptibility to mycobacterial and viral diseases.