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1.
Scand J Immunol ; 90(5): e12809, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31322747

RESUMO

We evaluated 18 DiGeorge syndrome (DGS) patients and aimed to investigate the immunological changes in this population. DGS patients with low naive CD4+ T and CD8+ T cells were defined as high-risk (HR) patients, whereas patients with normal numbers of naive CD4+ and CD8+ T cells were defined as standard risk (SR) patients. Level of serum IgM, CD3+ T cell counts and percentages of class-switched memory B cells were significantly low in HR group compared to SR ones. Severe infections and persistent hypoparathyroidism were detected significantly higher in HR group. Patients with reduced percentages of class-switched B cells had earlier onset of infection, lower blood IgM, lower CD4+ and CD8+ T counts than patients with normal class-switched memory B cells. Decreased levels of IgM were associated with low numbers of naive CD4+ and recent thymic emigrants T cells. Monitoring the immune changes of patients with DGS would be useful to predict the severe phenotype of disease.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Síndrome de DiGeorge/imunologia , Imunoglobulina M/sangue , Adolescente , Adulto , Criança , Pré-Escolar , Síndrome de DiGeorge/genética , Feminino , Humanos , Hipoparatireoidismo/diagnóstico , Switching de Imunoglobulina/imunologia , Memória Imunológica/imunologia , Lactente , Contagem de Linfócitos , Masculino
2.
J Allergy Clin Immunol Pract ; 7(8): 2790-2800.e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

3.
Int Arch Allergy Immunol ; : 1-9, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30404088

RESUMO

BACKGROUND AND OBJECTIVES: About 65-80% of children with IgE-mediated cow's milk allergy (CMA) can tolerate extensively heated milk. We have invested in the mass fabrication of a test product containing milk protein baked at 180°C for 30 min (SUTMEK-milk) and a milk-free placebo (SUTMEK-placebo) to carry out a standardised double-blind placebo-controlled food challenge (DBPCFC) test in patients with CMA. METHODS: We studied children with IgE-mediated CMA between 13 and 48 months of age. Specific IgEs (spIgE) to milk proteins were quantified. A DBPCFC with our bakery products was performed, and factors determining reactivity to extensively heated milk were evaluated. We also tested the applicability of SUTMEK products in baked-milk oral immunotherapy in a pilot assessment. RESULTS: We studied 15 children (8 girls, 7 boys) with a median age of 26 months (range: 13-48 months). Nine (60%) patients tolerated a challenge with extensively heated milk, while 6 (40%) were found reactive (anaphylaxis: 2, wheezing: 2, urticaria: 2). spIgE to milk, α-lactalbumin, and casein, and the wheal diameter on skin prick testing were higher in the reactive group than the tolerant groups (p = 0.001, p = 0.001, p = 0.002, and p = 0.048, respectively). Receiver-operating characteristic curve analyses yielded the following cut-off values for spIgEs that would predict a reactivity to extensively heated milk; milk: 25 kU/L (area under curve, AUC: 0.981), casein: 32 kU/L (AUC: 0.983), and α-lactalbumin: 17 kU/L (AUC: 0.981). Nine patients have tolerated well a continued daily consumption of SUTMEK-milk or -placebo for 6 months at the desired doses. CONCLUSIONS: Our bakery products were successfully used in DBPCFC studies and qualified as an acceptable tool for use in the research of interventional tolerance induction. Although spIgE appears useful in determining children at high risk of reacting to extensively heated milk, the predictive cut-off values are still far from being perfect.

4.
Int Arch Allergy Immunol ; 174(1): 52-56, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28950285

RESUMO

BACKGROUND: Sublingual immunotherapy (SLIT) has been successfully employed in IgE-mediated respiratory allergies. However, it is not known whether the modulation of immune responses in the sublingual area during SLIT has any deleterious effect on oral health. We sought to determine the oral health prospectively in children receiving SLIT for house dust mite allergy. MATERIAL AND METHODS: Eighteen children with allergic asthma and/or rhinitis and 31 age-matched healthy controls (HC) were included in an open-labeled trial. Oral health was evaluated by scoring the decayed, missing, and filled teeth for primary (dmft) and permanent (DMFT) dentition, and the plaque and gingival indices. Moreover, cariogenic food intake and teeth-brushing habits were also noted at baseline and at 19 months. RESULTS: The mean age of the SLIT participants was 9.5 ± 3.1 years and that of the HC was 9.2 ± 3.7 years. The mean duration of SLIT was 19.13 ± 3.81 months. At baseline, the total dmft and DMFT indices were similar in the SLIT and HC groups (p > 0.05), which demonstrated poor hygiene overall. In the within-group comparisons at the examination at 19 months, the SLIT group had a lower number of carious primary teeth and a higher number of filled primary teeth compared to the count at baseline (p = 0.027 and p = 0.058, respectively). CONCLUSION: Our study showed no detrimental effect of SLIT on oral health during a period of 19 months of follow-up. Parents should be motivated to use dental health services to prevent new caries formation since our cohort had overall poor oral hygiene at the baseline.


Assuntos
Alérgenos/administração & dosagem , Antígenos de Dermatophagoides/administração & dosagem , Asma/imunologia , Saúde Bucal , Rinite Alérgica/imunologia , Imunoterapia Sublingual/efeitos adversos , Imunoterapia Sublingual/métodos , Administração Sublingual , Alérgenos/imunologia , Animais , Antígenos de Dermatophagoides/imunologia , Criança , Feminino , Humanos , Masculino , Pyroglyphidae/imunologia
5.
N Engl J Med ; 377(1): 52-61, 2017 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-28657829

RESUMO

BACKGROUND: Studies of monogenic gastrointestinal diseases have revealed molecular pathways critical to gut homeostasis and enabled the development of targeted therapies. METHODS: We studied 11 patients with abdominal pain and diarrhea caused by early-onset protein-losing enteropathy with primary intestinal lymphangiectasia, edema due to hypoproteinemia, malabsorption, and less frequently, bowel inflammation, recurrent infections, and angiopathic thromboembolic disease; the disorder followed an autosomal recessive pattern of inheritance. Whole-exome sequencing was performed to identify gene variants. We evaluated the function of CD55 in patients' cells, which we confirmed by means of exogenous induction of expression of CD55. RESULTS: We identified homozygous loss-of-function mutations in the gene encoding CD55 (decay-accelerating factor), which lead to loss of protein expression. Patients' T lymphocytes showed increased complement activation causing surface deposition of complement and the generation of soluble C5a. Costimulatory function and cytokine modulation by CD55 were defective. Genetic reconstitution of CD55 or treatment with a complement-inhibitory therapeutic antibody reversed abnormal complement activation. CONCLUSIONS: CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy (the CHAPLE syndrome) is caused by abnormal complement activation due to biallelic loss-of-function mutations in CD55. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Antígenos CD55/genética , Ativação do Complemento/genética , Proteínas do Sistema Complemento/metabolismo , Mutação , Enteropatias Perdedoras de Proteínas/genética , Trombose/genética , Antígenos CD55/sangue , Criança , Pré-Escolar , Ativação do Complemento/efeitos dos fármacos , Inativadores do Complemento/farmacologia , Feminino , Homozigoto , Humanos , Imunoglobulina A/sangue , Lactente , Intestino Delgado/patologia , Masculino , Linhagem , Enteropatias Perdedoras de Proteínas/complicações , Estatísticas não Paramétricas , Síndrome , Linfócitos T/metabolismo
6.
Int J Pediatr Otorhinolaryngol ; 97: 197-201, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28483235

RESUMO

OBJECTIVE: Flow cytometric quantification of in vitro basophil activation can be quite performant and reliable tool to measure IgE-dependent allergen-specific responses in allergic patients. Current study aimed to evaluate the clinical relevance of basophil activation test (BAT) for the diagnosis of pediatric grass pollen and house dust mite (HDM) allergies. METHODS: Forty-seven patients suffering from allergic rhinitis with HDM and grass pollen co-sensitization with clinical history of allergic rhinitis and/or asthma and 15 non-allergic healthy subjects were enrolled. BAT was determined by flow cytometry upon double staining with anti-IgE/anti-CD63 mAb. RESULTS: Regarding HDM with cut-off point greater than 12.5% for CD63+ basophils sensitivity and specificity of the BAT were 90% and 73%, with positive predictive value (PPV) and negative predictive value (NPV) as 0.70 and 0.91, respectively. The analysis of concordance of being either allergic or healthy in comparison to BAT results for HDM revealed a substantial concordance (κ index = 0.61, p < 0.001). Grass pollen with cut-off point greater than 11%, BAT attained a sensitivity, specificity, PPV, and NPV of 96%, 93%, 0.98, and 0.88, respectively. The analysis of concordance of being either allergic or healthy in comparison to BAT results for grass pollen revealed an almost perfect concordance (κ index = 0.87, p < 0.001). CONCLUSION: Our findings concluded that BAT is reliable technique in the diagnosis of sensitization to grass pollen and HDM. The sensitivity of BAT in pollen allergic children was found to be remarkably higher in our cohort compared to other studies.


Assuntos
Basófilos/imunologia , Citometria de Fluxo/métodos , Rinite Alérgica/diagnóstico , Adolescente , Alérgenos , Animais , Anticorpos Anti-Idiotípicos , Criança , Pré-Escolar , Feminino , Humanos , Imunoglobulina E , Masculino , Pólen/imunologia , Valor Preditivo dos Testes , Pyroglyphidae/imunologia , Sensibilidade e Especificidade
7.
Iran J Allergy Asthma Immunol ; 15(4): 264-274, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27921406

RESUMO

Atopic dermatitis (AD) is a heterogeneous disease with regard to clinical phenotype and natural history. We investigated T cell subtypes and cytokine responses in peripheral blood and skin lesions of AD patients with various sensitivities. Immunological studies were performed in 27 subjects: 9 house dust mite (HDM)-sensitized; 6 subjects with sensitizations other than HDM; 7 non-allergic AD patients and 5 healthy controls. Among those, skin biopsy samples of 13 subjects were evaluated for immunohistochemical analyses, as well. The mean age was 8.93±5.17 years. HDM-allergic AD emerged as a distinct immunologic phenotype, with higher production of interleukin (IL)-4, -5, -2 both at rest and when stimulated by Der p1 or SEB along with higher Th17. As for TH17 cell percentage, it was increased in all AD groups compared to healthy controls, while HDM-allergic group was distinguished with a significantly lower production of IL-17. Patients with sensitizations other than HDM were mostly similar to non-allergic AD, with increased Th17 and CD4+CD69+interferon-gamma (IFN-γ)+ T cells percentage. The biopsy of lesional skin showed that HDM-allergic AD had lower IFN-γ and IFN-γ co-expressing CD8+ T cells compared to patients with other sensitizations (p=0.03 and p=0.04, respectively). Among the HDM allergic patients, pairwise comparison of lesional versus non-lesional skin revealed higher CD4+ T cells numbers, expression of forkhead box P3 (Foxp3) and T-cell-specific transcription factor (T-bet) (p=0.018, p=0.018, p=0.018, respectively). HDM-allergic AD is a distinct subtype with a predominant skewing in Th2 and higher Th17 cell percentage along with a blunted Th1 response in the skin, all of which may have therapeutic implications.


Assuntos
Antígenos de Dermatophagoides/administração & dosagem , Proteínas de Artrópodes/administração & dosagem , Cisteína Endopeptidases/administração & dosagem , Dermatite Atópica/imunologia , Pyroglyphidae/imunologia , Células Th17/imunologia , Células Th2/imunologia , Adolescente , Animais , Criança , Pré-Escolar , Citocinas/imunologia , Dermatite Atópica/diagnóstico , Dermatite Atópica/patologia , Feminino , Humanos , Lactente , Masculino , Testes Cutâneos , Células Th17/patologia , Células Th2/patologia
8.
J Clin Immunol ; 36(7): 641-8, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27379765

RESUMO

PURPOSE: Loss and gain-of-function (GOF) mutations in human signal transducer and activator of transcription 1 (STAT1) lead to distinct phenotypes. Although recurrent infections are common to both types of STAT1 mutations, GOF mutations are distinguished by chronic mucocutaneous candidiasis and autoimmunity. However, the clinical spectra of STAT1 GOF mutations continue to expand. We here describe two patients with STAT1 GOF mutations presenting early in life with combined immunodeficiency (CID). METHODS: Clinical data and laboratory findings including immunophenotyping, level of interferon (IFN)-γ/IL-17(+) T cells, interferon-induced STAT1 phosphorylation, and JAK inhibitor assays were evaluated. Sequencing of STAT1 gene was performed by Sanger sequencer. RESULTS: Patient 1 (P1) had persistent oral candidiasis and cytomegalovirus (CMV) infection since 2 months of age and later developed cavitary lung lesions due to Mycobacterium tuberculosis. Patient 2 (P2) presented with oral candidiasis and recurrent pneumonia at 4 months of age and subsequently developed CMV pneumonitis. Both patients suffered heterozygous missense mutations in STAT1, leading to deleterious amino acid substitutions in the DNA binding domain (P1: c.1154C > T; p.T385M; P2. c.971G > T; p.C324F). Circulating CD4(+) T cells of both patients exhibited increased interferon-γ and decreased IL-17 expression as compared to controls. They also exhibited increased IFN-ß and -γ-induced STAT1 phosphorylation that was reversed upon treatment with the JAK kinase inhibitor ruxolitinib. CONCLUSION: STAT1 GOF mutations may present early in life with CID, consistent with the clinical heterogeneity of the disease. JAK kinase inhibitors may potentially be useful in some patients as adjunct therapy pending definitive treatment with bone marrow transplantation.


Assuntos
Mutação com Ganho de Função , Heterozigoto , Fator de Transcrição STAT1/genética , Imunodeficiência Combinada Severa/genética , Imunodeficiência Combinada Severa/imunologia , Idade de Início , Autoimunidade/genética , Biomarcadores , Citocinas/genética , Citocinas/metabolismo , Análise Mutacional de DNA , Feminino , Expressão Gênica , Genes Dominantes , Humanos , Isotipos de Imunoglobulinas/sangue , Isotipos de Imunoglobulinas/imunologia , Imunofenotipagem , Lactente , Infecção/diagnóstico , Infecção/etiologia , Interferon beta/metabolismo , Interferon beta/farmacologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Linhagem , Fosforilação , Pirazóis/farmacologia , Fator de Transcrição STAT1/metabolismo , Imunodeficiência Combinada Severa/complicações , Imunodeficiência Combinada Severa/diagnóstico , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Tomografia Computadorizada por Raios X , Turquia
9.
Eur J Pediatr ; 175(5): 685-93, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26833050

RESUMO

UNLABELLED: The severity and duration of immunosuppression caused by corticosteroids (CSs) usage have not been extensively studied. We aimed to investigate the effects of CSs on the various compartments of immune system in relation to timing of initiation and persistence of therapy. Pediatric patients with idiopathic nephrotic syndrome (NS) treated with 2 mg/kg/day prednisolone and healthy control (HC) were enrolled. Blood samples were drawn for immunologic analyses at baseline and at the first and second weeks and first, second, and third months of CS therapy in addition to first and second weeks and first, second, and third months of discontinuation. Fourteen patients (M/F, 7/7) between 1 and 8 years old were evaluated. Untreated NS exhibited high absolute lymphocyte count (ALC)(p = 0.010), absolute CD3(+) T cells (p = 0.020) and absolute CD8(+) T cells (p = 0.006) compared to HC. Suppression in ALC was observed and nadir value was noted at first month of therapy compared to baseline (p = 0.002). The CD4(+) (p = 0.036) and CD8(+) T cell (p = 0.013) counts decreased significantly at the first week of treatment compared to baseline. While baseline B cell counts was indifferent from HC, gradually increased in 2 weeks of CS initiation and decreased during the treatment with a statistical significance compared to HC (p = 0.010). However, after cessation of CS, B cell counts continued to decline and found to be significantly different than baseline at first week (p = 0.008) and at third month (p = 0.040). CONCLUSION: Apart from baseline lymphocyte subset changing observed in untreated NS patients, our data implies that T cells were suppressed very early in the CS treatment. Interestingly, depressed B cell counts were detected later but persisted even after CS cessation. Due to early decrease in T cells, it would be beneficial to assume the patients as immunosuppressed at the very beginning of CS treatment to avoid infections. WHAT IS KNOWN: • Corticosteroids (CSs) are widely used for a variety of diseases including nephrotic syndrome, which is related with complex immune disturbance including T and B cells dysfunctions. • CSs induce neutrophilic leukocytosis concomitant with lymphopenia and eosinopenia leading to immunosupression. What is New: • T cell subsets and proliferation are susceptible to CSs more than B cells; however, the reversibility is faster with dose reduction in CS. • The change of B cells and B cell subtypes (CD27 (+) memory) shows prolonged effect of CSs on B cells which may alter antibody production even after 3 months of CSs cessation.


Assuntos
Imunidade Adaptativa/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Imunossupressão/métodos , Síndrome Nefrótica/imunologia , Prednisolona/administração & dosagem , Biópsia , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Feminino , Glucocorticoides/administração & dosagem , Humanos , Lactente , Masculino , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/tratamento farmacológico , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Resultado do Tratamento
10.
Minerva Pediatr ; 2016 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-26763692

RESUMO

AIM: The immunomodulatory effects of vitamin B12 deficiency in children have not yet been established in the literature. In the current study, the effects of vitamin B12 on the immune system in asymptomatic and otherwise healthy infants have been studied. METHODS: The study was conducted at Marmara University, "well-child" outpatient clinic. Vitamin B12 level was measured in a cohort of 611 healthy term infants, followed regularly for at least 6 months. Immunoglobulin measurements, lymphocyte subset analysis, cytokine production analysis, lymphocyte proliferation assays and evaluation of lymphocyte apoptosis were performed in a subset of 60 infants. RESULTS: In this cohort, one out of three babies displayed vitamin B12 deficiency. The percentage of CD4+CD25+ regulatory T cells (Tregs) was lower in vitamin B12 deficient babies than in controls. Although the percentage of Tregs increased after treatment, the change was not significant. There was no difference of cytokine levels between vitamin B12 deficient and control groups. However, proinflammatory cytokines were reduced after treatment. No significant difference was observed for immunoglobulins, early apoptosis and lymphocyte proliferation. CONCLUSION: Vitamin B12 deficiency is an underestimated health problem among the developing countries. The clinical consequences of the decreased percentage of Tregs associated with vitamin B12 deficiency, and reduction of proinflammatory cytokines after vitamin supplementation needs to be further studied, especially in terms of emerging allergies, autoimmune disorders and anti-inflammatory effects.

11.
J Pediatr Hematol Oncol ; 37(8): 616-22, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26479985

RESUMO

Glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency was recently defined as a new severe congenital neutropenia subgroup remarkable with congenital heart defects, urogenital malformations, endocrine abnormalities, and prominent superficial veins. Here, we report 3 patients with G6PC3 deficiency presenting with recurrent diarrhea, failure to thrive, and sinopulmonary infections leading to bronchiectasis. In patient I and II, a combined immune deficiency was suspected due to early-onset disease with lymphopenia, neutropenia, and thrombocytopenia, along with variable reductions in lymphocyte subpopulations and favorable response to intravenous γ-globulin therapy. Apart from neutropenia, all 3 patients had intermittent thrombocytopenia, anemia, and lymphopenia. All patients had failure to thrive and some of the classic syndromic features of G6PC3 deficiency, including cardiac abnormalities and visibility of superficial veins in all, endocrinologic problems in PI and PIII, and urogenital abnormalities in PII. Our experience suggests that a diagnosis of congenital neutropenia due to G6PC3 may not be as straightforward in such patients with combined lymphopenia and thrombocytopenia. A high index of suspicion and the other syndromic features of G6PC3 were clues to diagnosis. Screening of all combined immune deficiencies with neutropenia may help to uncover the whole spectra of G6PC3 deficiency.


Assuntos
Anormalidades Múltiplas/genética , Glucose-6-Fosfatase/genética , Doença de Depósito de Glicogênio Tipo I/genética , Síndromes de Imunodeficiência/genética , Subpopulações de Linfócitos/patologia , Neutropenia/genética , Anormalidades Múltiplas/enzimologia , Adolescente , Bronquiectasia/etiologia , Domínio Catalítico , Linhagem da Célula , Criança , Códon sem Sentido , Colite/enzimologia , Colite/genética , Consanguinidade , Diarreia/enzimologia , Diarreia/genética , Éxons/genética , Insuficiência de Crescimento/enzimologia , Insuficiência de Crescimento/genética , Feminino , Mutação da Fase de Leitura , Doença de Depósito de Glicogênio Tipo I/imunologia , Humanos , Síndromes de Imunodeficiência/enzimologia , Linfopenia/congênito , Linfopenia/enzimologia , Linfopenia/genética , Masculino , Mutagênese Insercional , Neutropenia/enzimologia , Linhagem , Fenótipo , Sítios de Splice de RNA/genética , Infecções Respiratórias/complicações , Trombocitopenia/congênito , Trombocitopenia/enzimologia , Trombocitopenia/genética , Turquia
12.
J Clin Immunol ; 35(6): 523-6, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26233237

RESUMO

Protein kinase C delta (PRKCD) has essential functions in controlling B-cell proliferation and apoptosis, development of B-cell tolerance and NK-cell cytolitic activity. Human PRKCD deficiency was recently identified to be causative for an autoimmune lymphoproliferative syndrome like disorder with significant B-cell proliferation particularly of immature B cells. Here we report a child with a novel mutation in PRKCD gene who presented with CMV infection and an early onset SLE-like disorder which was successfully treated with hydroxychloroquine.


Assuntos
Antirreumáticos/administração & dosagem , Síndrome Linfoproliferativa Autoimune/imunologia , Linfócitos B/imunologia , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Hidroxicloroquina/administração & dosagem , Células Matadoras Naturais/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteína Quinase C-delta/genética , Síndrome Linfoproliferativa Autoimune/tratamento farmacológico , Síndrome Linfoproliferativa Autoimune/genética , Pré-Escolar , Infecções por Citomegalovirus/tratamento farmacológico , Humanos , Lactente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Masculino , Mutação/genética
13.
N Biotechnol ; 32(6): 612-9, 2015 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-25644640

RESUMO

Bacillus subtilis has the capacity to produce more than two dozen bioactive compounds with an amazing variety of chemical structures. Among them, bacilysin is a non-ribosomally synthesized dipeptide antibiotic consisting of l-alanine residue at the N terminus and a non-proteinogenic amino acid, l-anticapsin, at the C terminus. In spite of its simple structure, it is active against a wide range of bacteria and fungi. As a potent antimicrobial agent, we briefly review the biochemistry and genetics as well as the regulation of bacilysin biosynthesis within the frame of peptide pheromones-based control of secondary activities. Biological functions of bacilysin in the producer B. subtilis beyond its antimicrobial activity as well as potential biotechnological use of the biosynthetic enzyme l-amino acid ligase (Lal) are also discussed.


Assuntos
Antibacterianos/biossíntese , Antibacterianos/química , Bacillus subtilis/fisiologia , Regulação Bacteriana da Expressão Gênica/fisiologia , Antibacterianos/isolamento & purificação , Dipeptídeos/biossíntese , Dipeptídeos/genética , Modelos Biológicos
14.
Int Immunopharmacol ; 22(1): 31-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24957687

RESUMO

New strategies are needed to suppress airway inflammation and prevent or reverse airway remodeling in asthma. Reprogramming induced pluripotent stem cells (iPSCs) have the potential of embryonic stem cells (ESCs) and provide a resource for stem cell-based utility. The aim of this study was to evaluate the histopathological and immunomodulatory effects of ESCs and iPSCs for potential allogenic application in a murine model of acute asthma. BALB/c mice were sensitized with alum-absorbed ovalbumin (OVA) and then challenged with 1% aerosolized OVA. 5×10(5) ESCs and iPSCs were administrated intranasally on the last day of nebulization. Mice were sacrificed after 24 h, and serum allergen specific antibody level, airway remodeling, cytokine levels in lung supernatants, and eosinophilic infiltration in BAL fluid were examined. As a result, more ESCs and iPSCs integrated into the lungs of mice in OVA groups than those of the controls. Epithelial, smooth muscle and basal membrane thicknesses as well as goblet cell hyperplasia occurring in airway remodeling were significantly suppressed by pluripotent stem cells in both distal and proximal airways. Percentage of eosinophils decreased significantly in BAL fluid as well as serum allergen-specific IgE and IL-4 levels in lung supernatants. On the contrary, regulatory cytokine - IL-10 level - was enhanced. Application of especially ESCs significantly increased the percentage of Treg subsets. Our comparative results showed that i.n. delivery of miRNA-based reprogrammed iPSCs is beneficial in attenuating airway inflammation in a murine model of acute asthma, and that cells also have similar immunomodulatory effects in mice.


Assuntos
Asma/terapia , Células-Tronco Embrionárias/fisiologia , Células Caliciformes/patologia , Pulmão/imunologia , Células-Tronco Pluripotentes/fisiologia , Transplante de Células-Tronco , Linfócitos T Reguladores/imunologia , Células Th2/imunologia , Doença Aguda , Remodelação das Vias Aéreas , Animais , Asma/imunologia , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Células-Tronco Embrionárias/transplante , Eosinófilos/imunologia , Humanos , Hiperplasia , Imunoglobulina E/sangue , Imunossupressão , Pulmão/patologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos BALB C , MicroRNAs/genética , Células-Tronco Pluripotentes/transplante , Pneumonia , Transplante Homólogo
15.
Int Immunopharmacol ; 20(1): 101-9, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24613203

RESUMO

New therapeutic strategies are needed in the treatment of asthma besides vaccines and pharmacotherapies. For the development of novel therapies, the use of mesenchymal stem cells (MSCs) is a promising approach in regenerative medicine. Delivery of compact bone (CB) derived MSCs to the injured lungs is an alternative treatment strategy for chronic asthma. In this study, we aimed to isolate highly enriched population of MSCs from mouse CB with regenerative capacity, and to investigate the impact of these cells in airway remodeling and inflammation in experimental ovalbumin-induced mouse model of chronic asthma. mCB-MSCs were isolated, characterized, labeled with GFP and then transferred into mice with chronic asthma developed by ovalbumin (OVA) provocation. Histopathological changes including basement membrane, epithelium, subepithelial smooth thickness and goblet cell hyperplasia, and MSCs migration to lung tissues were evaluated. These histopathological alterations were increased in ovalbumin-treated mice compared to PBS group (P<0.001). Intravenous administration of mCB-MSC significantly reduced these histopathological changes in both distal and proximal airways (P<0.001). We showed that GFP-labeled MSCs were located in the lungs of OVA group 2weeks after intravenous induction. mCB-MSCs also significantly promoted Treg response in ovalbumin-treated mice (OVA+MSC group) (P<0.037). Our studies revealed that mCB-MSCs migrated to lung tissue and suppressed histopathological changes in murine model of asthma. The results reported here provided evidence that mCB-MSCs may be an alternative strategy for the treatment of remodeling and inflammation associated with chronic asthma.


Assuntos
Remodelação das Vias Aéreas/imunologia , Asma , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Alérgenos , Animais , Asma/imunologia , Asma/patologia , Asma/terapia , Diferenciação Celular , Modelos Animais de Doenças , Fêmur/citologia , Pulmão/imunologia , Pulmão/patologia , Linfócitos/imunologia , Camundongos Endogâmicos BALB C , Ovalbumina , Pneumonia/imunologia , Pneumonia/patologia , Pneumonia/terapia , Linfócitos T Reguladores/imunologia , Tíbia/citologia
16.
J Mol Microbiol Biotechnol ; 20(3): 144-55, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21709425

RESUMO

In Bacillus subtilis, bacilysin is a nonribosomally synthesized dipeptide antibiotic composed of L-alanine and L-anticapsin. The biosynthesis of bacilysin depends on the bacABCDEywfG operon (bac operon)and the adjacent ywfH gene. To elucidate the effects of global regulatory genes on the expression of bac operon, we used the combination of lacZ fusion analysis and the gel mobility shift assays. The cell density-dependent transition state induction of the bac operon was clearly shown. The basal expression level of the bac operon as well as transition state induction of bac is directly ComA dependent. Three Phr peptides, PhrC, PhrF and PhrK, are required for full-level expression of ComA-dependent bac operon expression, but the most important role seemed to be played by PhrC in stimulating bac expression through a RapC-independent manner. Spo0A is another positive regulator which participates in the transition state induction of bac both directly by interacting with the bac promoter and indirectly by repressing abrB expression. AbrB and CodY proteins do not only directly repress the bac promoter, but they also mutually stimulate the transition state induction of bac indirectly, most likely by antagonizing their repressive effects without preventing each other's binding since both proteins can bind to the bac promoter simultaneously.


Assuntos
Bacillus subtilis/genética , Bacillus subtilis/metabolismo , Regulação Bacteriana da Expressão Gênica , Alanina/análogos & derivados , Antibacterianos/biossíntese , Proteínas de Bactérias/biossíntese , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Bacteriocinas/biossíntese , DNA Bacteriano/genética , DNA Bacteriano/metabolismo , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Dipeptídeos/biossíntese , Ensaio de Desvio de Mobilidade Eletroforética , Genes Bacterianos , Óperon Lac/genética , Mutação , Regiões Promotoras Genéticas , Percepção de Quorum , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/biossíntese , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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