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1.
J Biol Chem ; 293(39): 15208-15220, 2018 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-30115681

RESUMO

Interleukin-1 receptor (IL1R)-associated kinase 4 (IRAK4) is a central regulator of innate immune signaling, controlling IL1R and Toll-like receptor (TLR)-mediated responses and containing both scaffolding and kinase activities. Humans deficient in IRAK4 activity have autosomal recessive primary immune deficiency (PID). Here, we characterized the molecular mechanism of dysfunction of two IRAK4 PID variants, G298D and the compound variant R12C (R12C/R391H/T458I). Using these variants and the kinase-inactive D329A variant to delineate the contributions of IRAK4's scaffolding and kinase activities to IL1R signaling, we found that the G298D variant is kinase-inactive and expressed at extremely low levels, acting functionally as a null mutation. The R12C compound variant possessed WT kinase activity, but could not interact with myeloid differentiation primary response 88 (MyD88) and IRAK1, causing impairment of IL-1-induced signaling and cytokine production. Quantitation of IL-1 signaling in IRAK4-deficient cells complemented with either WT or the R12C or D329A variant indicated that the loss of MyD88 interaction had a greater impact on IL-1-induced signaling and cytokine expression than the loss of IRAK4 kinase activity. Importantly, kinase-inactive IRAK4 exhibited a greater association with MyD88 and a weaker association with IRAK1 in IRAK4-deficient cells expressing kinase-inactive IRAK4 and in primary cells treated with a selective IRAK4 inhibitor. Loss of IRAK4 kinase activity only partially inhibited IL-1-induced cytokine and NF-κB signaling. Therefore, the IRAK4-MyD88 scaffolding function is essential for IL-1 signaling, but IRAK4 kinase activity can control IL-1 signal strength by modulating the association of IRAK4, MyD88, and IRAK1.

2.
J Clin Immunol ; 38(4): 503-512, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29855752

RESUMO

PURPOSE: Subcutaneous immunoglobulin replacement therapy (IgRT) may be administered once a week with a pump or every other day with a syringe (rapid push). The objective of the study was to compare the impact of pump and rapid push infusions on patient's life quality index (LQI). METHODS: This study was a randomized, crossover, multicenter, non-inferiority trial conducted in adults with primary immunodeficiency (PID) accustomed to weekly infusions at home by pump. Patients used pump or rapid push for 3 months each according to the randomized sequence. Main criterion was PID-LQI factor I (treatment interference). Non-inferiority ratio was set at 90%. RESULTS: Thirty patients entered the study; 28 completed the two periods. IgRT exposure was similar during each period. At the end of each period, mean LQI factor 1 was 87.0 (IC95% [80.3; 94.3]) and 77.80 (IC95% [71.5; 84.7]) for pump and rapid push, respectively. There was a slightly larger effect of rapid push on treatment interference than with pump so that the primary endpoint could not be met. No difference was found on other LQI components, satisfaction (TSQM), or quality of life (SF36v2). Eight patients declared to prefer rapid push while 19 others preferred pump. Of rapid push infusions, 67.2% led to local reactions vs 71.8% of pump infusions (p = 0.11) illustrating its good tolerance. Rapid push and pump infusions achieved similar trough IgG levels with similar incidence of infections. Rapid push saved 70% of administration cost when compared to pump. CONCLUSIONS: Since IgRT is a lifelong treatment in PID patients, individualization of treatment is of paramount importance. Rapid push is a new administration method in the physician's armamentarium which is preferred by some patients and is cost-effective. CLINICALTRIALS. GOV IDENTIFIER: NCT02180763 CLINICAL IMPLICATIONS: Self-administration of small volumes of immunoglobulins at home, every other day, using a syringe (rapid push) is a cost-effective alternative to administration of larger volumes by pump once a week. This study compared subcutaneous infusions of immunoglobulins either weekly via a pump or every other day via a syringe (rapid push). Rapid push is preferred by some patients and is cost-effective, therefore completing a physician's armamentarium.

3.
Patient Prefer Adherence ; 11: 1171-1180, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28744107

RESUMO

OBJECTIVE: To assess quality of life and satisfaction regarding immunoglobulin-replacement therapy (IgRT) treatment according to the route (intravenous Ig [IVIg] or subcutaneous Ig [SCIg]) and place of administration (home-based IgRT or hospital-based IgRT). SUBJECTS AND METHODS: Children 5-15 years old treated for primary immunodeficiency disease (PIDD) with IgRT for ≥3 months were included in a prospective, noninterventional cohort study and followed over 12 months. Quality of life was assessed with the Child Health Questionnaire - parent form (CHQ-PF)-50 questionnaire. Satisfaction with IgRT was measured with a three-dimensional scale (Life Quality Index [LQI] with three components: factor I [FI], treatment interference; FII, therapy-related problems; FIII, therapy settings). RESULTS: A total of 44 children (9.7±3.2 years old) receiving IgRT for a mean of 5.6±4.5 years (median 4.1 years) entered the study: 18 (40.9%) were receiving hospital-based IVIg, two (4.6%) were receiving home-based IVIg, and 24 (54.6%) were treated by home-based SCIg. LQI FIII was higher for home-based SCIg than for hospital-based IVIg (P=0.0003), but there was no difference for LQI FI or LQI FII. LQI FIII significantly improved in five patients who switched from IVIg to SCIg during the follow-up when compared to patients who pursued the same regimen (either IVIg or SCIg). No difference was found on CHQ-PF50 subscales, LQI FI, or LQI FII. CONCLUSION: Home-based SCIg gave higher satisfaction regarding therapy settings than hospital-based IVIg. No difference was found on other subscales of the LQI or CHQ-PF50 between hospital-based IVIG and home-based SCIG.

4.
Pediatr Res ; 74(2): 238-44, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23670282

RESUMO

Infant formulas have been shown to influence the development of the gut microbiota. Besides the probiotic- and prebiotic-containing formulas, fermented milk-based infant formulas offer an additional means for modulation of gut immunity and/or gut microbiota. These formulas are produced by the fermentation of cow's milk with specific lactic acid bacteria strains, followed by heat treatment; they do not contain viable bacteria or added prebiotic oligosaccharides but contain specific products resulting from the fermentation process. This review is focused on the effects of fermentation products, distinguishing them from those of living bacteria and prebiotic compounds on the immune system. Besides the possible modulation of gut microbiota composition, in vitro and in vivo studies suggest that specific fermentation products can actively participate in the establishment of immune balance and oral tolerance. Although further research is needed to confirm the clinical benefits observed in infants to better characterize the active fermentation compounds and to delineate the involved pathways, these fermented formulas appear to deserve interest.


Assuntos
Produtos Fermentados do Leite/imunologia , Fermentação , Fórmulas Infantis/métodos , Lactobacillaceae/metabolismo , Leite/microbiologia , Animais , Células Dendríticas/imunologia , Humanos , Lactente , Fórmulas Infantis/química , Microbiota/fisiologia
5.
Blood ; 120(25): 4992-5001, 2012 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-23002119

RESUMO

We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor-associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM(+)IgD(+)CD27(+) B cells were not affected in these patients. In contrast, the numbers of IgM(+)IgD(+)CD27(+) B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B-dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM(+)IgD(+)CD27(+) compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM(+)IgD(+)CD27(+) B cells in humans.


Assuntos
Linfócitos B/imunologia , Imunoglobulina D/imunologia , Imunoglobulina M/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Glicoproteínas de Membrana/genética , Proteínas de Membrana Transportadoras/genética , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Adolescente , Adulto , Linfócitos B/patologia , Criança , Pré-Escolar , Citocinas/imunologia , Humanos , Imunoglobulina D/análise , Imunoglobulina M/análise , Mutação , Receptor 10 Toll-Like/genética , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise , Adulto Jovem
6.
Medicine (Baltimore) ; 91(4): e1-19, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22751495

RESUMO

Autosomal dominant deficiency of signal transducer and activator of transcription 3 (STAT3) is the main genetic etiology of hyper-immunoglobulin (Ig) E syndrome. We documented the molecular, cellular, and clinical features of 60 patients with heterozygous STAT3 mutations from 47 kindreds followed in France. We identified 11 known and 13 new mutations of STAT3. Low levels of interleukin (IL)-6-dependent phosphorylation and nuclear translocation (or accumulation) of STAT3 were observed in Epstein-Barr virus-transformed B lymphocytes (EBV-B cells) from all STAT3-deficient patients tested. The immunologic phenotype was characterized by high serum IgE levels (96% of the patients), memory B-cell lymphopenia (94.5%), and hypereosinophilia (80%). A low proportion of IL-17A-producing circulating T cells was found in 14 of the 15 patients tested. Mucocutaneous infections were the most frequent, typically caused by Staphylococcus aureus (all patients) and Candida albicans (85%). Up to 90% of the patients had pneumonia, mostly caused by Staph. aureus (31%) or Streptococcus pneumoniae (30%). Recurrent pneumonia was associated with secondary bronchiectasis and pneumatocele (67%), as well as secondary aspergillosis (22%). Up to 92% of the patients had dermatitis and connective tissue abnormalities, with facial dysmorphism (95%), retention of decidual teeth (65%), osteopenia (50%), and hyperextensibility (50%). Four patients developed non-Hodgkin lymphoma. The clinical outcome was favorable, with 56 patients, including 43 adults, still alive at the end of study (mean age, 21 yr; range, 1 mo to 46 yr). Only 4 patients died, 3 from severe bacterial infection (aged 1, 15, and 29 yr, respectively). Antibiotic prophylaxis (90% of patients), antifungal prophylaxis (50%), and IgG infusions (53%) improved patient health, as demonstrated by the large decrease in pneumonia recurrence. Overall, the prognosis of STAT3 deficiency may be considered good, provided that multiple prophylactic measures, including IgG infusions, are implemented.


Assuntos
Hospedeiro Imunocomprometido/genética , Síndrome de Job/epidemiologia , Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Pré-Escolar , Estudos Transversais , Análise Mutacional de DNA , Bases de Dados Factuais , Eczema/epidemiologia , Eczema/etiologia , Feminino , França/epidemiologia , Predisposição Genética para Doença/epidemiologia , Heterozigoto , Humanos , Incidência , Lactente , Recém-Nascido , Síndrome de Job/complicações , Síndrome de Job/imunologia , Masculino , Pessoa de Meia-Idade , Fosforilação , Pneumonia Bacteriana/epidemiologia , Pneumonia Bacteriana/etiologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/etiologia , Medição de Risco , Índice de Gravidade de Doença , Distribuição por Sexo , Transdução de Sinais , Dermatopatias Bacterianas/epidemiologia , Dermatopatias Bacterianas/etiologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/etiologia , Análise de Sobrevida , Adulto Jovem
7.
J Clin Immunol ; 32(1): 98-105, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22002594

RESUMO

The DEFI study has collected clinical data and biological specimens from kindreds with CVID. Patients with demonstrated parental consanguinity (cCVID group) were compared to patients without parental consanguinity (ncCVID). A total of 24 of the 436 patients with CVID had consanguineous parents. Age at first symptoms and age at diagnosis were comparable in the two groups. Some complications were more frequent in cCVID patients: splenomegaly (62.5% vs. 29%; p = 0.001), granulomatous disease (29% vs. 12%; p = 0.02), and bronchiectasis (58% vs. 29%; p = 0.003). A high incidence of opportunistic infections was also observed in this population (29% vs. 5%; p < 0.001). Distribution of B-cell subsets were similar in the two groups. Naïve CD4+ T cells were decreased in cCVID patients (15% vs. 28%; p < 0.001), while activated CD4 + CD95+ (88% vs. 74%; p = 0.002) and CD8 + HLA-DR + T cells (47% vs. 31%; p < 0.001) were increased in these patients when compared to ncCVID patients. Parental consanguinity is associated with an increased risk of developing severe clinical complications in patients with CVID. Most of these patients presented with severe T-cell abnormalities and should be considered with a diagnosis of late-onset combined immune deficiency (LOCID). Systematic investigation for parental consanguinity in patients with CVID provides useful information for specific clinical care and genetic screening.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/genética , Consanguinidade , Fenótipo , Adolescente , Adulto , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Criança , Imunodeficiência de Variável Comum/imunologia , Feminino , França , Estudos de Associação Genética , Testes Genéticos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
8.
Circ Cardiovasc Genet ; 5(1): 25-34, 2012 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22084479

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) deficiency is responsible for autosomal dominant hyperimmunoglobulin E syndrome, characterized by recurrent bacterial and fungal infections, connective tissue abnormalities, hyperimmunoglobulin E, and Th17 lymphopenia. Although vascular abnormalities have been reported in some patients, the prevalence, characteristics, and etiology of these features have yet to be described. METHODS AND RESULTS: We prospectively screened 21 adult STAT3-deficient patients [corrected] (median age, 26 years; range, 17-44 years) [corrected] for vascular abnormalities. We explored the entire arterial vasculature with whole-body magnetic resonance imaging angiography, coronary multislice computed tomography, and echo-tracking-based imaging specifically for the [corrected] carotid arteries. We also assayed for serum biomarkers of inflammation and endothelial dysfunction. Finally, we studied murine models of aortic aneurysm in the presence and absence of inhibitors of STAT3-dependent signaling. Ninety-five percent of patients showed brain abnormalities (white matter hyperintensities, lacunar lesions suggestive of ischemic infarcts, and atrophy). We reported peripheral and brain artery abnormalities in 84% of the patients and detected coronary artery abnormalities in 50% of the patients. The most frequent vascular abnormalities were ectasia and aneurysm. The carotid intima-media thickness was markedly decreased, with a substantial increase in circumferential wall stress, indicating the occurrence of hypotrophic arterial remodeling in this STAT3-deficient population. Systemic inflammatory biomarker levels correlated poorly with the vascular phenotype. In vivo inhibition of STAT3 signaling or blockade of IL-17A resulted in a marked increase in aneurysm severity and fatal rupture in mouse models. CONCLUSIONS: Vascular abnormalities are highly prevalent in patients with STAT3 deficiency. This feature is consistent with the greater susceptibility to vascular aneurysm observed after inhibition of STAT3-dependent signaling in mouse models.


Assuntos
Síndrome de Job/genética , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Transdução de Sinais , Anormalidades Múltiplas/genética , Adolescente , Adulto , Animais , Aneurisma Aórtico/patologia , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Modelos Animais de Doenças , Heterozigoto , Humanos , Interleucina-17/metabolismo , Síndrome de Job/patologia , Angiografia por Ressonância Magnética , Imagem por Ressonância Magnética , Camundongos , Mutação , Estudos Prospectivos , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/metabolismo , Tomografia Computadorizada por Raios X , Ultrassonografia , Imagem Corporal Total , Adulto Jovem
9.
MAbs ; 3(5): 461-6, 2011 Sep-Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21822056

RESUMO

Monoclonal antibodies (mAbs), especially those that interact with immune or hematologic leukocyte membrane targets, have changed the outcome of numerous diseases. However, mAbs can block or reduce immune cells and cytokines, and can lead to increased risk of infection. Some of these risks are predictable and can be explained by their mechanisms of action. Others have been observed only after the mAbs were licensed and used extensively in patients. In this review, we focus on infectious complications that occur upon treatment with mAbs or Fc-containing fusion proteins targeting leukocyte membrane proteins, including CD52, CD20, tumor necrosis factor, VLA4, CD11a and CTLA4. We report their known infectious risks and the recommendations for their use. Although most of these drugs are clinically safe when the indications are respected, we emphasize the need for regular updating of pharmacovigilance data.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Fragmentos Fc das Imunoglobulinas/efeitos adversos , Imunoterapia/efeitos adversos , Infecção/etiologia , Proteínas Recombinantes de Fusão/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Antígenos de Superfície/imunologia , Humanos , Sistema Imunitário/efeitos dos fármacos , Fragmentos Fc das Imunoglobulinas/genética , Fragmentos Fc das Imunoglobulinas/imunologia , Fragmentos Fc das Imunoglobulinas/uso terapêutico , Imunoterapia/métodos , Infecção/imunologia , Farmacovigilância , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Proteínas Recombinantes de Fusão/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
10.
Medicine (Baltimore) ; 89(6): 403-25, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21057262

RESUMO

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/deficiência , Fator 88 de Diferenciação Mieloide/deficiência , Adolescente , Antibacterianos/uso terapêutico , Infecções Bacterianas/epidemiologia , Infecções Bacterianas/prevenção & controle , Criança , Pré-Escolar , Suscetibilidade a Doenças , Feminino , Humanos , Imunidade , Lactente , Quinases Associadas a Receptores de Interleucina-1/genética , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/genética , Receptores de Interleucina-1/metabolismo , Receptores Toll-Like/metabolismo
11.
Med Sci (Paris) ; 25(12): 1135-40, 2009 Dec.
Artigo em Francês | MEDLINE | ID: mdl-20035693

RESUMO

The large experience accumulated with the therapeutic use of monoclonal antibodies has revealed undesirable effects, among which opportunistic infections when prescribed in inflammatory or hematological diseases. This deleterious effect is a direct consequence of the immunosuppression induced by these antibodies through the blockade of several key pathways involved in both innate and adaptative immune responses, including migration of effector cells, depletion of B or T lymphocytes, inhibition of key cell-cell interactions. Four antibodies are concerned, targeting CD52, CD20, TNF-a and VLA-4, and major risks include activation of latent tuberculosis, or of normally silent viruses. Precise evaluation of these risks and understanding of their mechanisms have now led to the improvement of clinical safety, based on the detection of patients at risk, weighting of the benefit/risk ratio, and a very rigorous detection of latent infections before the onset of treatment by monoclonal antibodies know to induce immunosuppression.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Infecções Oportunistas/etiologia , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais Murinos , Anticorpos Antineoplásicos/efeitos adversos , Anticorpos Antineoplásicos/uso terapêutico , Antígenos CD/imunologia , Antígenos CD20/imunologia , Antígenos de Neoplasias/imunologia , Antígeno CD52 , Estudos de Coortes , Glicoproteínas/imunologia , Humanos , Imunossupressão/efeitos adversos , Integrina alfa4beta1/imunologia , Metanálise como Assunto , Infecções Oportunistas/epidemiologia , Recidiva , Estudos Retrospectivos , Rituximab , Tuberculose/etiologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Ativação Viral
12.
J Exp Med ; 205(7): 1543-50, 2008 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-18591412

RESUMO

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.


Assuntos
Diferenciação Celular/imunologia , Doenças Genéticas Inatas/imunologia , Interleucina-17/imunologia , Receptores de Interleucina-12/imunologia , Fator de Transcrição STAT3/imunologia , Transdução de Sinais/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Diferenciação Celular/genética , Citocinas/genética , Citocinas/imunologia , Feminino , Doenças Genéticas Inatas/genética , Humanos , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Interleucina-17/genética , Masculino , Mutação , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/imunologia , Locos de Características Quantitativas/imunologia , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Interleucina-12/genética , Receptores de Fatores de Crescimento Transformadores beta/genética , Receptores de Fatores de Crescimento Transformadores beta/imunologia , Fator de Transcrição STAT3/genética , Transdução de Sinais/genética
13.
PLoS One ; 3(7): e2753, 2008 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-18648505

RESUMO

BACKGROUND: Probiotic bacteria have been shown to modulate immune responses and could have therapeutic effects in allergic and inflammatory disorders. However, the signaling pathways engaged by probiotics are poorly understood. We have previously reported that a fermentation product from Bifidobacterium breve C50 (BbC50sn) could induce maturation, high IL-10 production and prolonged survival of DCs via a TLR2 pathway. We therefore studied the roles of mitogen-activated protein kinases (MAPK), glycogen synthase kinase-3 (GSK3) and phosphatidylinositol 3-kinase (PI3K) pathways on biological functions of human monocyte-derived DCs treated with BbC50sn. METHODOLOGY/PRINCIPAL FINDINGS: DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50sn, lipopolysaccharide (LPS) or Zymosan, with or without specific inhibitors of p38MAPK (SB203580), ERK (PD98059), PI3K (LY294002) and GSK3 (SB216763). We found that 1) the PI3K pathway was positively involved in the prolonged DC survival induced by BbC50sn, LPS and Zymosan in contrast to p38MAPK and GSK3 which negatively regulated DC survival; 2) p38MAPK and PI3K were positively involved in DC maturation, in contrast to ERK and GSK3 which negatively regulated DC maturation; 3) ERK and PI3K were positively involved in DC-IL-10 production, in contrast to GSK3 that was positively involved in DC-IL-12 production whereas p38MAPK was positively involved in both; 4) BbC50sn induced a PI3K/Akt phosphorylation similar to Zymosan and a p38MAPK phosphorylation similar to LPS. CONCLUSION/SIGNIFICANCE: We report for the first time that a fermentation product of a bifidobacteria can differentially activate MAPK, GSK3 and PI3K in order to modulate DC biological functions. These results give new insights on the fine-tuned balance between the maintenance of normal mucosal homeostasis to commensal and probiotic bacteria and the specific inflammatory immune responses to pathogen bacteria.


Assuntos
Bifidobacterium/metabolismo , Células Dendríticas/citologia , Bifidobacterium/genética , Células Dendríticas/microbiologia , Fermentação , Quinase 3 da Glicogênio Sintase/metabolismo , Humanos , Hipersensibilidade , Sistema Imunitário , Inflamação , Interleucina-10/metabolismo , Sistema de Sinalização das MAP Quinases , Modelos Biológicos , Monócitos/citologia , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Receptor 2 Toll-Like/metabolismo
14.
J Immunol ; 179(7): 4754-65, 2007 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-17878374

RESUMO

Polymorphonuclear neutrophils (PMN) play a key role in innate immunity. Their activation and survival are tightly regulated by microbial products via pattern recognition receptors such as TLRs, which mediate recruitment of the IL-1R-associated kinase (IRAK) complex. We describe a new inherited IRAK-4 deficiency in a child with recurrent pyogenic bacterial infections. Analysis of the IRAK4 gene showed compound heterozygosity with two mutations: a missense mutation in the death domain of the protein (pArg12Cys) associated in cis-with a predicted benign variant (pArg391His); and a splice site mutation in intron 7 that led to the skipping of exon 7. A nontruncated IRAK-4 protein was detected by Western blotting. The patient's functional deficiency of IRAK-4 protein was confirmed by the absence of IRAK-1 phosphorylation after stimulation with all TLR agonists tested. The patient's PMNs showed strongly impaired responses (L-selectin and CD11b expression, oxidative burst, cytokine production, cell survival) to TLR agonists which engage TLR1/2, TLR2/6, TLR4, and TLR7/8; in contrast, the patient's PMN responses to CpG-DNA (TLR9) were normal, except for cytokine production. The surprisingly normal effect of CpG-DNA on PMN functions and apoptosis disappeared after pretreatment with PI3K inhibitors. Together, these results suggest the existence of an IRAK-4-independent TLR9-induced transduction pathway leading to PI3K activation. This alternative pathway may play a key role in PMN control of infections by microorganisms other than pyogenic bacteria in inherited IRAK-4 deficiency.


Assuntos
Quinases Associadas a Receptores de Interleucina-1/deficiência , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Receptor Toll-Like 9/metabolismo , Adolescente , Sequência de Bases , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Humanos , Interleucina-1/farmacologia , Quinases Associadas a Receptores de Interleucina-1/química , Quinases Associadas a Receptores de Interleucina-1/genética , Interleucina-18/farmacologia , Masculino , Modelos Moleculares , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Mutação/genética , Neutrófilos/citologia , Neutrófilos/efeitos dos fármacos , Estrutura Terciária de Proteína , Espécies Reativas de Oxigênio/metabolismo , Receptor Toll-Like 9/agonistas
15.
J Allergy Clin Immunol ; 117(3): 696-702, 2006 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-16522473

RESUMO

BACKGROUND: Commensal gut bacteria are essential for the development and maintenance of the gut's immune system. Some bacteria strains, such as Lactobacillus and Bifidobacterium species, have been reported to provide protection from allergic and inflammatory bowel diseases. However, the interactions between these commensal bacteria and the immune system are largely unknown. OBJECTIVE: We studied the effects of a supernatant from the culture of B breve C50 (BbC50) on the maturation, activation, and survival of human dendritic cells (DCs). METHODS: DCs were differentiated from human monocytes with IL-4 and GM-CSF for 5 days and cultured with BbC50 supernatant (BbC50SN) or LPS for 2 days. RESULTS: BbC50SN induced DC maturation, with increase in CD83, CD86, and HLA-DR expression. We also showed, for the first time, that BbC50SN prolonged DC survival, with high IL-10 and low IL-12 production compared with that seen in LPS-DCs. Moreover, BbC50SN inhibited the effects of LPS on DCs, both in terms of IL-12 production and in terms of survival. The prolonged DC survival was independent of IL-10 production and nuclear factor kappaB pathway but was associated with an upregulation of Bcl-xL and Phospho-Bad. Finally, BbC50SN induced activation of Toll-like receptor 2 (TLR2)-transfected cells in contrast to TLR4-, TLR7-, and TLR9-transfected cells. CONCLUSION: The supernatant of B breve C50 can induce DC maturation and prolonged DC survival through TLR2, with high IL-10 production. These properties might correspond to a regulatory DC profile, which could limit the excessive TH1 response and control the excessive TH2 polarization observed in atopic newborns.


Assuntos
Bifidobacterium/imunologia , Células Dendríticas/imunologia , Receptor 2 Toll-Like/imunologia , Linhagem Celular , Proliferação de Células , Sobrevivência Celular/imunologia , Humanos , Imunidade Celular/imunologia , Interleucina-10/imunologia , Transdução de Sinais/imunologia
16.
Eur J Haematol ; 75(1): 54-9, 2005 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-15946311

RESUMO

The Wiskott-Aldrich syndrome is a rare genetic disorder due to mutations in the WAS gene situated on chromosome X. It is comprised of microthrombocytopenia, eczema and immunodeficiency. However, the phenotypical presentation may vary as to the number and intensity of its manifestations. A milder form of Wiskott-Aldrich syndrome is known as the X-linked thrombocytopenia. We independently found eight individual or familial cases with the V75M substitution (9.76%). This high incidence was partly accounted for by the fact that three cases turned out to be related. The V75M mutation is recurrent, however, due to a CpG island. A genuine homozygous female patient was found. She showed microthrombocytopenia and infections to the same degree as her hemizygous father and brother. The WAS protein was decreased in a comparable fashion in the hemizygotes and the homozygote as well. Its amount was about 10% and 15% of normal in platelets and mononucleated white cells, respectively. In all patients was the picture consistent with XLT.


Assuntos
Substituição de Aminoácidos/genética , Homozigoto , Mutação Puntual , Proteínas/genética , Síndrome de Wiskott-Aldrich/genética , Adulto , Criança , Pré-Escolar , Cromossomos Humanos X , Ilhas de CpG/genética , Eczema/etiologia , Feminino , Humanos , Lactente , Síndrome de Wiskott-Aldrich/complicações , Proteína da Síndrome de Wiskott-Aldrich
17.
Int Immunol ; 17(4): 351-63, 2005 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-15710908

RESUMO

Immature dendritic cells (DCs) can induce T-cell hyporesponsiveness, thus interfering with the process of DC maturation in a pro-inflammatory context, may therefore provide a novel approach to inducing allograft tolerance. We have studied the effects of mycophenolic acid (MPA), an immunosuppressive agent currently used in transplantation, using an in vitro model of a mixed human DC/alloreactive CD4(+) T lymphocyte culture. DCs differentiated from monocytes were exposed to MPA during maturation. MPA treatment affected the maturation of DCs, and this was reflected both in the impairment of the up-regulation of co-stimulatory molecule expression and the maintained endocytic capacity. However, MPA-DCs exhibited a distinctive microscopic morphology and secreted IL-10 and so could no longer be regarded as immature DC. Moreover, MPA-DCs had a mature phenotype for chemokine receptor expression, exhibiting down-regulation of CCR5 and up-regulation of CCR7. Interestingly, the abilities of the MPA-DCs to induce CD4(+) T-cell proliferation in response to alloantigens was impaired not only via direct but also via indirect pathways. The maintenance of endocytosis and the inhibition of syngeneic T-cell activation suggest that these cells could have a potential role to avoid chronic rejection. All these characteristics suggest that MPA-DCs may be used in cell therapy to induce allograft tolerance.


Assuntos
Movimento Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , IMP Desidrogenase/antagonistas & inibidores , Ácido Micofenólico/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Humanos , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia
18.
Transpl Immunol ; 10(4): 293-302, 2002 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-12507401

RESUMO

Graft endothelium has a key role in organ transplantation because it regulates graft infiltration by allogeneic activated T cells. Overexpression of death molecules that could induce apoptosis of alloreactive T cells might be an alternative to the immunosuppressive treatment currently used in graft transplantation. Several studies have shown that immune-privileged sites express Fas ligand (FasL) and induce apoptosis of activated T-cells. We propose that endothelial cells engineered to express FasL could inhibit alloreactive T cell-proliferation by inducing apoptosis. An expression vector was constructed with human FasL cDNA and used to transfect an endothelial cell line (ECV304 cells). We demonstrated that FasL-transfected ECV304 cells were effective in inducing apoptosis of Jurkat T cell lymphoma as an agonist anti-Fas antibody. Using a mixed lymphocyte-endothelial cell culture model we observed that FasL-transfected ECV304 cells which conserved their two principal costimulatory pathways inhibited alloreactive T cell-proliferation by inducing activated T-cell apoptosis. These results suggest that endothelial cells could be interesting candidates to convey a death signal and induce hyporesponsiveness of alloreactive T cells during organ transplantation.


Assuntos
Endotélio Vascular/citologia , Ativação Linfocitária , Glicoproteínas de Membrana/fisiologia , Linfócitos T/imunologia , Apoptose , Linhagem Celular , Citotoxicidade Imunológica , Endotélio Vascular/fisiologia , Proteína Ligante Fas , Humanos , Transfecção
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