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1.
Blood ; 132(22): 2362-2374, 2018 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-30254128

RESUMO

ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.

2.
Clin Immunol ; 161(2): 373-83, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26307433

RESUMO

Intravenous IgG (IVIG) therapy can be used for immunomodulation. IL-2 is an immunoregulatory cytokine. We evaluated IVIG modulation of human blood lymphocyte response to IL-2 and other cytokines. Neither IVIG nor low concentrations of IL-2 (3-30U/ml) induced lymphocyte proliferation, but in combination they synergistically enhanced proliferation of NK cells. The CD56(bright) cells expanded more than CD56(dim) NK cells, with 90% of NK cells dividing up to 8 generations by day 6, while <8% of T cells divided. IVIG also potentiated NK cell proliferation with IL-12, IL-15 and IL-18. The IVIG+cytokine-expanded NK cells were less cytotoxic for K562 cells, than NK cells with cytokine alone. IVIG also enhanced interferon-γ production with IL-2, IL-12 and IL-18. In conclusion, IVIG selectively potentiates NK cell proliferation and interferon-γ secretion with IL-2, IL-12, IL-15 and IL-18 in vitro. These findings warrant evaluation in vivo in relation to NK cells and the immunoregulatory actions of IVIG.


Assuntos
Proliferação de Células/efeitos dos fármacos , Citocinas/farmacologia , Imunoglobulinas Intravenosas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Humanos , Fatores Imunológicos/farmacologia , Interferon gama/metabolismo , Interleucina-12/farmacologia , Interleucina-15/farmacologia , Interleucina-18/farmacologia , Interleucina-2/farmacologia , Células K562 , Células Matadoras Naturais/citologia , Células Matadoras Naturais/metabolismo
3.
Clin Immunol ; 160(2): 123-32, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25982320

RESUMO

IVIG modulates T cell activation in vitro and inflammatory-autoimmune conditions in vivo. Sialylation of IgG, Fc receptor interactions, modulation of monocyte/macrophage/B cell functions have been implicated in IVIG effects. Subcutaneous IgG (SCIG) therapy is increasingly used for IgG replacement but whether these preparations share the effects of IVIG on T cell modulation is not documented. We compared the potency of SCIG-Hizentra™ (20% IgG preparation) with IVIG-Privigen® (10% IgG) for T cell inhibition, and assessed the involvement of IgG sialylation, monocytes and B cells in this process. Human PBMCs or sorted cells were cultured 3-7 days, and T cells were stimulated with immobilized anti-CD3 mAb or Candida antigen. Thymidine incorporation into DNA was quantitated and cytokines assayed by ELISA/Luminex® assay. IVIG and SCIG both dose-dependently (1-20mg/ml) inhibited (up to >80%) T cell proliferation to anti-CD3 mAb. Response to Candida albicans was comparably inhibited by IVIG and SCIG by 50-80% at 10mg/ml with inhibition even at 3mg/ml (P<0.05). These effects were not affected by depletion of sialic acid containing IgG using neuraminidase treatment or lectin affinity chromatography. With anti-CD3 or Candida stimulation, IL-1ß, IL-2, IL-5, IL-6, IL-13, GMCSF, TNF-α, interferon-γ (with anti-CD3) and IL-17 (with Candida) levels were suppressed by IVIG or SCIG, with no effect on IL-4, IL-10, IL-12, IL-15 or TGFß. Monocytes or B cells were not required for IgG-induced suppression of proliferation, in fact depletion of monocytes potentiated the IgG-induced inhibition. Reconstitution with monocytes restored the original inhibitory effect. These data show that IVIG (Privigen®) and SCIG (Hizentra™) have comparable inhibitory effects on T cell activation, which do not require sialylation of IgG. Inhibition is independent of monocytes or B cells. There is a potent suppression of multiple effector cytokines. Like IVIG, SCIG therapy is expected to show immunomodulatory activity.


Assuntos
Linfócitos B/efeitos dos fármacos , Citocinas/efeitos dos fármacos , Imunoglobulinas Intravenosas/farmacologia , Fatores Imunológicos/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Antígenos de Fungos/imunologia , Linfócitos B/imunologia , Complexo CD3/imunologia , Candida albicans/imunologia , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Citocinas/metabolismo , Humanos , Imunoglobulina G/administração & dosagem , Imunoglobulina G/farmacologia , Imunoglobulinas Intravenosas/administração & dosagem , Fatores Imunológicos/administração & dosagem , Técnicas In Vitro , Infusões Subcutâneas , Ativação Linfocitária/imunologia , Ácido N-Acetilneuramínico , Linfócitos T/imunologia , Linfócitos T/metabolismo
4.
Pediatr Dermatol ; 32(1): 118-21, 2015 Jan-Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23534907

RESUMO

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis caused by mutations in extracellular matrix protein 1 (ECM1) that involves deposition of basement membrane-like material in the skin and other organs. Epidermodysplasia verruciformis (EV) is also a rare autosomal recessive genodermatosis involving susceptibility to human papillomavirus (HPV) infections and squamous cell carcinoma, caused in most cases by homozygous mutations in EVER1 or EVER2. We describe a case of EV in a patient with LP and discuss the pathophysiology. A 3-year-old Lebanese girl presented with hoarseness, beaded papules along the eyelid margins, waxy papules and plaques on her head and neck, and lichenoid verrucous papules on the forearms and hands. Histopathology of the waxy papules exhibited deposition of periodic acid Schiff-positive basement membrane-like material in the superficial dermis, characteristic of LP. The verruca plana-like lesions exhibited acanthosis and enlarged keratinocytes with pale blue-grey cytoplasm and a perinuclear halo, consistent with verrucae and EV. Polymerase chain reaction amplification and sequencing of ECM1, EVER1, and EVER2 demonstrated a homozygous point mutation, c.389C>T (p.Thr130Met), in exon 6 of ECM1 and a heterozygous point mutation, c.917 A>T (p.Asn306Ile), in exon 8 in EVER2, known to cause EV in homozygous patients. The homozygous point mutation c.389C>T in ECM1 may be a novel mutation causing LP. Verruca plana-like lesions seen in LP appear to represent a form of acquired EV. In this patient, a heterozygous mutation in EVER2 at c.917 A>T may also have conferred susceptibility to HPV infection.


Assuntos
Epidermodisplasia Verruciforme/fisiopatologia , Proteinose Lipoide de Urbach e Wiethe/fisiopatologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/fisiopatologia , Pré-Escolar , Epidermodisplasia Verruciforme/genética , Epidermodisplasia Verruciforme/virologia , Proteínas da Matriz Extracelular/genética , Feminino , Humanos , Proteinose Lipoide de Urbach e Wiethe/genética , Proteinose Lipoide de Urbach e Wiethe/virologia , Proteínas de Membrana/genética , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/virologia , Mutação Puntual , Reação em Cadeia da Polimerase
5.
J Immunol ; 193(10): 4934-44, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25274531

RESUMO

Regulatory T cells (Tregs) play critical roles in restricting T cell-mediated inflammation. In the skin, this is dependent on expression of selectin ligands required for leukocyte rolling in dermal microvessels. However, whether there are differences in the molecules used by Tregs and proinflammatory T cells to undergo rolling in the skin remains unclear. In this study, we used spinning disk confocal microscopy in Foxp3-GFP mice to visualize rolling of endogenous Tregs in dermal postcapillary venules. Tregs underwent consistent but low-frequency rolling interactions under resting and inflamed conditions. At the early stage of the response, Treg adhesion was minimal. However, at the peak of inflammation, Tregs made up 40% of the adherent CD4(+) T cell population. In a multiple challenge model of contact hypersensitivity, rolling of Tregs and conventional CD4(+) T cells was mostly dependent on overlapping contributions of P- and E-selectin. However, after a second challenge, rolling of Tregs but not conventional CD4(+) T cells became P-selectin independent, and Tregs showed reduced capacity to bind P-selectin. Moreover, inhibition of E-selectin at this time point resulted in exacerbation of inflammation. These findings demonstrate that in this multiple challenge model of inflammation, Treg selectin binding capacity and the molecular basis of Treg rolling can be regulated dynamically.


Assuntos
Dermatite de Contato/imunologia , Selectina E/imunologia , Selectina-P/imunologia , Pele/imunologia , Linfócitos T Reguladores/imunologia , Animais , Adesão Celular , Movimento Celular , Dermatite de Contato/etiologia , Dermatite de Contato/genética , Dermatite de Contato/patologia , Selectina E/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/imunologia , Regulação da Expressão Gênica , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/imunologia , Ligantes , Camundongos , Camundongos Transgênicos , Oxazóis/farmacologia , Selectina-P/genética , Ligação Proteica , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/imunologia , Transdução de Sinais , Pele/irrigação sanguínea , Pele/patologia , Linfócitos T Reguladores/patologia
6.
J Clin Immunol ; 34(3): 267-71, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24596024

RESUMO

UNLABELLED: IRAK-4 deficiency causes IL-1R and TLR signaling failure, resulting in minimal clinical features despite invasive bacterial infection. We report the course of a 7-year-old IRAK-4-deficient girl presenting in the first year with multiple occult Staphylococcus aureus lymphadenitis. She was managed with antibiotic prophylaxis (sulfa/trimethoprim/PenV, then - due to neutropenia - Cefprozil), pneumococcal vaccination (PCV-7, Pneumovax23, PCV-13) and vigilance. Pneumococcal-specific IgG levels were monitored. No bacterial infections occurred on prophylaxis for 6 years after initial presentation. IgG response to pneumococcal polysaccharide was satisfactory but short-lived, requiring frequent boosting. At age 7, patient developed a morning headache and vomited once. Cefprozil was administered and re-dosed. Over 12 h, she was fatigued without other symptoms. Low fever accompanied another emesis. A few hours later she was confused, and purpuric rash appeared. Emergency physicians diagnosed sepsis/meningitis and started vancomycin-ceftriaxone. Respiratory failure and cerebellar herniation occurred <24 h after first symptoms. Blood and CSF grew Streptococcus pneumoniae type 6C resistant to second-generation cephalosporins. The patient's latest PCV-13 vaccination was 6 weeks before death, which included serotype 6A. Immunoglobulins were normal except IgG4 was increased (3.4 g/L). IgG response to vaccine antigens was satisfactory. IgG to 6A is reported to cross-react with 6C, but this was not the case here. CONCLUSION: Despite antibiotic prophylaxis and repeated vaccination, even older IRAK-4-deficient patients are at high risk of rapidly fatal infection due to emergence of antibiotic resistance. These patients need early assessment at any age, bacterial culturing, alternative empiric antibiotic therapy and close observation when even vaguely unwell. Based on increasingly recognized immunological and/or clinical impairments in B cell function, and possibly other defects, long-term IgG prophylaxis in addition to antibiotics is recommended.


Assuntos
Antibioticoprofilaxia , Imunoglobulina G/imunologia , Síndromes de Imunodeficiência/imunologia , Meningite Pneumocócica/tratamento farmacológico , Meningite Pneumocócica/etiologia , Vacinas Pneumocócicas/imunologia , Streptococcus pneumoniae/imunologia , Criança , Evolução Fatal , Feminino , Humanos , Quinases Associadas a Receptores de Interleucina-1/imunologia
7.
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
8.
J Immunol ; 189(1): 337-46, 2012 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-22664869

RESUMO

CCR4 on T cells is suggested to mediate skin homing in mice. Our objective was to determine the interaction of CCR4, E-selectin ligand (ESL), and α(4)ß(1) on memory and activated T cells in recruitment to dermal inflammation. mAbs to rat CCR4 were developed. CCR4 was on 5-21% of memory CD4 cells, and 20% were also ESL(+). Anti-TCR-activated CD4 and CD8 cells were 40-55% CCR4(+), and ∼75% of both CCR4(+) and CCR4(-) cells were ESL(+). CCR4(+) memory CD4 cells migrated 4- to 7-fold more to dermal inflammation induced by IFN-γ, TNF, TLR agonists, and delayed-type hypersensitivity than CCR4(-) cells. CCR4(+) activated CD4 cells migrated only 5-50% more than CCR4(-) cells to these sites. E-selectin blockade inhibited ∼60% of CCR4(+) activated CD4 cell migration but was less effective on memory cells where α(4)ß(1) was more important. Anti-α(4)ß(1) also inhibited CCR4(-) activated CD4 cells more than CCR4(+) cells. Anti-E-selectin reduced activated CD8 more than CD4 cell migration. These findings modify our understanding of CCR4, ESL, α(4)ß(1), and dermal tropism. There is no strict relationship between CCR4 and ESL for skin homing of CD4 cells, because the activation state and inflammatory stimulus are critical determinants. Dermal homing memory CD4 cells express CCR4 and depend more on α(4)ß(1) than ESL. Activated CD4 cells do not require CCR4, but CCR4(+) cells are more dependent on ESL than on α(4)ß(1), and CCR4(-) cells preferentially use α(4)ß(1). The differentiation from activated to memory CD4 cells increases the dependence on CCR4 for skin homing and decreases the requirement for ESL.


Assuntos
Movimento Celular/imunologia , Selectina E/fisiologia , Memória Imunológica , Integrina alfa4beta1/fisiologia , Ativação Linfocitária/imunologia , Receptores CCR4/fisiologia , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Animais , Células CHO , Inibição de Migração Celular/imunologia , Cricetinae , Cricetulus , Modelos Animais de Doenças , Selectina E/biossíntese , Selectina E/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Integrina alfa4beta1/antagonistas & inibidores , Masculino , Glicoproteínas de Membrana/biossíntese , Glicoproteínas de Membrana/fisiologia , Ratos , Ratos Endogâmicos Lew , Receptores CCR4/biossíntese , Receptores CCR4/deficiência , Receptores de Fatores de Crescimento de Fibroblastos/biossíntese , Sialoglicoproteínas/biossíntese , Pele/patologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia
9.
Blood ; 119(17): 4009-12, 2012 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-22427204

RESUMO

EBV-associated smooth muscle tumors are found in immunocompromised patients, most commonly HIV/AIDS. We present a 12-year-old girl with the first documented case of EBV-related smooth muscle tumors in the presence of a rare classic NK cell deficiency. This sheds light on the role of NK cells in controlling EBV-related smooth muscle tumors.


Assuntos
Glândulas Suprarrenais/patologia , Herpesvirus Humano 4/patogenicidade , Células Matadoras Naturais/patologia , Tumor de Músculo Liso/patologia , Glândulas Suprarrenais/virologia , Criança , Infecções por Vírus Epstein-Barr/imunologia , Infecções por Vírus Epstein-Barr/virologia , Feminino , Humanos , Hospedeiro Imunocomprometido , Tumor de Músculo Liso/virologia
10.
Clin Immunol ; 141(2): 187-96, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21917526

RESUMO

High-dose intravenous immunoglobulin (IVIG) has anti-inflammatory effects via incompletely understood mechanisms. By investigating whether IVIG might modulate neutrophil (PMN) recruitment, we observed that IVIG dose-dependently inhibited (by 30-50%) PMN transendothelial migration (TEM) across human umbilical vein endothelial cells (EC) stimulated with IL-1α, IL-1ß, TNF-α or IL-1ß+TNF-α. Inhibition required the presence of IVIG with the responding PMNs, was attributable to the F(ab)(2) portion and was unrelated to putative contaminants in IVIG. IVIG did not inhibit IL-1ß- or TNF-α-induced increase of PMN adhesion to EC, nor did it affect C5a- or IL-8-induced PMN TEM across unstimulated EC. Effects of IVIG and F(ab)(2) fragments were not associated with PMN activation, assessed by CD62L shedding, CD11b upregulation or PMN shape. Thus, IVIG selectively inhibits PMN TEM across inflammatory-cytokine-stimulated - but not unstimulated - EC, perhaps contributing to therapeutic benefit in chronic inflammation with minimal impact on chemotactic-factor-induced PMN recruitment during acute infection.


Assuntos
Fatores Quimiotáticos/farmacologia , Fragmentos Fab das Imunoglobulinas/farmacologia , Imunoglobulinas Intravenosas/farmacologia , Interleucina-1alfa/antagonistas & inibidores , Interleucina-1beta/antagonistas & inibidores , Neutrófilos/efeitos dos fármacos , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Antígeno CD11b/biossíntese , Adesão Celular/efeitos dos fármacos , Células Cultivadas/citologia , Células Cultivadas/efeitos dos fármacos , Complemento C5a/imunologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Humanos , Técnicas In Vitro , Infecção/imunologia , Inflamação/imunologia , Interleucina-1alfa/farmacologia , Interleucina-1beta/farmacologia , Interleucina-8/imunologia , Selectina L/biossíntese , Neutrófilos/citologia , Fator de Necrose Tumoral alfa/fisiologia , Veias Umbilicais
11.
Arthritis Rheum ; 63(11): 3467-76, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21739422

RESUMO

OBJECTIVE: To investigate P- and E-selectin ligand coexpression with chemokine receptors (CKRs) on T cells in the synovial fluid (SF) and blood of children with juvenile idiopathic arthritis (JIA). METHODS: Sixteen patients with polyarticular or persistent oligoarticular JIA (ages 5.3-15.1 years) were studied. SF and venous blood were collected, and immunostaining for the expression of CCR4, CCR5, CXCR3, and P- or E-selectin ligands was performed. RESULTS: Compared to blood, SF was greatly enriched for CD4+ T cells bearing CCR5, CCR4, CXCR3, and both P- and E-selectin ligand. Twenty-five percent of the CD4+ T cells in SF expressed both CCR5 and CCR4, some also coexpressing CXCR3. Such cells were rare in blood. Half of the few CCR5+ T cells in blood coexpressed P- or E-selectin ligand, a phenotype that was enriched up to 50-fold in SF. A minority of CCR4+ and CXCR3+ cells in blood (∼25%) coexpressed selectin ligand; these were enriched 4-8-fold in SF. Most CCR4-expressing CD4+ T cells expressed both E-selectin ligand and cutaneous lymphocyte antigen. CONCLUSION: CCR4-, CCR5-, CXCR3-, and selectin ligand-expressing CD4+ T cells preferentially accumulate in the joints of children with JIA. The marked enrichment of CCR5+ T cells coexpressing P-selectin and/or E-selectin ligand in CD4+ SF T cells suggests that the few such cells in blood selectively migrate to inflamed joints via endothelial P- and E-selectin- and CCR5-activating chemokines. The predominance of CCR4-expressing CD4+ T cells coexpressing E-selectin ligand suggests that such cells migrate not only to areas of cutaneous inflammation, as previously reported, but also to the joints in JIA. Combined targeting of CCR5- and E-selectin-dependent mechanisms may be a relevant treatment strategy.


Assuntos
Artrite Juvenil/imunologia , Selectina E/metabolismo , Selectina-P/metabolismo , Receptores CCR4/metabolismo , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Linfócitos T/imunologia , Adolescente , Artrite Juvenil/genética , Criança , Pré-Escolar , Selectina E/genética , Feminino , Humanos , Ligantes , Masculino , Selectina-P/genética , Receptores CCR4/genética , Receptores CCR5/genética , Receptores CXCR3/genética
12.
Blood ; 118(10): 2688-94, 2011 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-21725047

RESUMO

Genetic deficiency of adenosine deaminase (ADA) can cause profound lymphopenia and result in the clinical presentation of severe combined immune deficiency (SCID). However, because of the ubiquitous expression of ADA, ADA-deficient patients often present also with nonimmunologic clinical problems, affecting the skeletal, central nervous, endocrine, and gastrointestinal systems. We now report that myeloid dysplasia features and bone marrow hypocellularity are often found in patients with ADA-SCID. As a clinical correlate to this finding, we have observed vulnerability to antibiotic-induced myelotoxicity and prolonged neutropenia after nonmyeloablative chemotherapy. We have also noted that, in the absence of enzyme replacement therapy, absolute neutrophil counts of patients with ADA deficiency vary inversely with the accumulation of deoxynucleotides. These data have significant implications for the application of standard and investigational therapies to patients with ADA-SCID and support further studies to investigate the possibility that ADA deficiency is associated with a stem cell defect. These trials were registered at www.clinicaltrials.gov as #NCT00018018 and #NCT00006319.


Assuntos
Adenosina Desaminase/deficiência , Agamaglobulinemia/complicações , Medula Óssea/patologia , Síndromes Mielodisplásicas/etiologia , Imunodeficiência Combinada Severa/complicações , Adenosina Desaminase/genética , Adolescente , Adulto , Agamaglobulinemia/terapia , Transplante de Medula Óssea , Criança , Pré-Escolar , Feminino , Terapia Genética , Humanos , Lactente , Masculino , Síndromes Mielodisplásicas/terapia , Imunodeficiência Combinada Severa/terapia , Adulto Jovem
13.
J Virol ; 85(2): 1145-50, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21068256

RESUMO

Vascular perturbation is a hallmark of severe forms of dengue disease. We show here that antibody-enhanced dengue virus infection of primary human cord blood-derived mast cells (CBMCs) and the human mast cell-like line HMC-1 results in the release of factor(s) which activate human endothelial cells, as evidenced by increased expression of the adhesion molecules ICAM-1 and VCAM-1. Endothelial cell activation was prevented by pretreatment of mast cell-derived supernatants with a tumor necrosis factor (TNF)-specific blocking antibody, thus identifying TNF as the endothelial cell-activating factor. Our findings suggest that mast cells may represent an important source of TNF, promoting vascular endothelial perturbation following antibody-enhanced dengue virus infection.


Assuntos
Vírus da Dengue/patogenicidade , Células Endoteliais/imunologia , Mastócitos/virologia , Anticorpos Bloqueadores/imunologia , Células Cultivadas , Vírus da Dengue/imunologia , Expressão Gênica , Humanos , Molécula 1 de Adesão Intercelular/biossíntese , Mastócitos/imunologia , Fator de Necrose Tumoral alfa/imunologia , Molécula 1 de Adesão de Célula Vascular/biossíntese
14.
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
15.
PLoS One ; 5(10): e13406, 2010 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-20975993

RESUMO

PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G(0/1) into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development.


Assuntos
Transformação Celular Neoplásica , Proteínas/fisiologia , Animais , Proteínas Argonauta , Sequência de Bases , Linhagem Celular Tumoral , Primers do DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Metástase Neoplásica , Neoplasias/metabolismo , Neoplasias/patologia , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Proteínas/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Interferência de RNA , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Células-Tronco/metabolismo , Transplante Heterólogo , Regulação para Cima/fisiologia
16.
J Immunol ; 185(6): 3718-27, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20709957

RESUMO

Angiotensin II (Ang-II) displays inflammatory activity and is implicated in several cardiovascular disorders. This study evaluates the effect of cis- and trans (t)-resveratrol (RESV) in two in vivo models of vascular inflammation and identifies the cardioprotective mechanisms that underlie them. In vivo, Ang-II-induced arteriolar leukocyte adhesion was inhibited by 71% by t-RESV (2.1 mg/kg, i.v.), but was not affected by cis-RESV. Because estrogens influence the rennin-angiotensin system, chronic treatment with t-RESV (15 mg/kg/day, orally) inhibited ovariectomy-induced arteriolar leukocyte adhesion by 81%, partly through a reduction of cell adhesion molecule (CAM) expression and circulating levels of cytokine-induced neutrophil chemoattractant, MCP-1, and MIP-1alpha. In an in vitro flow chamber system, t-RESV (1-10 microM) undermined the adhesion of human leukocytes under physiological flow to Ang-II-activated human endothelial cells. These effects were accompanied by reductions in monocyte and endothelial CAM expression, chemokine release, phosphorylation of p38 MAPK, and phosphorylation of the p65 subunit of NF-kappaB. Interestingly, t-RESV increased the expression of peroxisome proliferator-activated receptor-gamma in human endothelial and mononuclear cells. These results demonstrate for the first time that the in vivo anti-inflammatory activity of RESV is produced by its t-RESV, which possibly interferes with signaling pathways that cause the upregulation of CAMs and chemokine release. Upregulation of proliferator-activated receptor-gamma also appears to be involved in the cardioprotective effects of t-RESV. In this way, chronic administration of t-RESV may reduce the systemic inflammatory response associated with the activation of the rennin-angiotensin system, thereby decreasing the risk of further cardiovascular disease.


Assuntos
Angiotensina II/antagonistas & inibidores , Endotélio Vascular/patologia , Mediadores da Inflamação/farmacologia , NF-kappa B/antagonistas & inibidores , PPAR gama/biossíntese , Estilbenos/farmacologia , Regulação para Cima/imunologia , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Angiotensina II/fisiologia , Animais , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Comunicação Celular/efeitos dos fármacos , Comunicação Celular/imunologia , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Feminino , Humanos , Mediadores da Inflamação/administração & dosagem , Mediadores da Inflamação/química , Masculino , NF-kappa B/metabolismo , Ovariectomia , Ratos , Ratos Sprague-Dawley , Resveratrol , Estereoisomerismo , Estilbenos/administração & dosagem , Estilbenos/química , Regulação para Cima/efeitos dos fármacos
17.
Nat Immunol ; 11(9): 836-45, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20676093

RESUMO

BAFF and APRIL are innate immune mediators that trigger immunoglobulin G (IgG) and IgA class-switch recombination (CSR) in B cells by engaging the receptor TACI. The mechanism that underlies CSR signaling by TACI remains unknown. Here we found that the cytoplasmic domain of TACI encompasses a conserved motif that bound MyD88, an adaptor that activates transcription factor NF-kappaB signaling pathways via a Toll-interleukin 1 (IL-1) receptor (TIR) domain. TACI lacks a TIR domain, yet triggered CSR via the DNA-editing enzyme AID by activating NF-kappaB through a Toll-like receptor (TLR)-like MyD88-IRAK1-IRAK4-TRAF6-TAK1 pathway. TACI-induced CSR was impaired in mice and humans lacking MyD88 or the kinase IRAK4, which indicates that MyD88 controls a B cell-intrinsic, TIR-independent, TACI-dependent pathway for immunoglobulin diversification.


Assuntos
Linfócitos B/imunologia , Switching de Imunoglobulina/imunologia , Fator 88 de Diferenciação Mieloide/imunologia , Proteína Transmembrana Ativadora e Interagente do CAML/imunologia , Animais , Células Cultivadas , Humanos , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Transdução de Sinais
18.
J Allergy Clin Immunol ; 126(2): 332-7, 337.e1-2, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20621347

RESUMO

BACKGROUND: IL-1 receptor-associated kinase 4 (IRAK-4) is an effector of the Toll-like receptor and IL-1 receptor pathways that plays a critical role in innate immune responses. The role of IRAK-4 in adaptive immune functions in human subjects is incompletely understood. OBJECTIVE: We sought to evaluate T-cell function in IRAK-4 deficient patients. METHODS: We compared upregulation of CD25 and CD69 on T cells and production of IL-2, IL-6, and IFN-gamma after stimulation of PBMCs from 4 IRAK-4-deficient patients and healthy control subjects with anti-CD3 and anti-CD28. RESULTS: Upregulation of CD25 and CD69 on T cells and production of IL-6 and IFN-gamma, but not IL-2, was significantly reduced in IRAK-4-deficient patients. CONCLUSIONS: IRAK-4-deficient patients have defects in T-cell activation.


Assuntos
Doenças Genéticas Inatas , Síndromes de Imunodeficiência , Quinases Associadas a Receptores de Interleucina-1 , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T , Imunidade Adaptativa/genética , Imunidade Adaptativa/imunologia , Antígenos CD/biossíntese , Antígenos CD/genética , Antígenos CD/imunologia , Antígenos de Diferenciação de Linfócitos T/biossíntese , Antígenos de Diferenciação de Linfócitos T/genética , Antígenos de Diferenciação de Linfócitos T/imunologia , Estudos de Casos e Controles , Citocinas/biossíntese , Citocinas/genética , Citocinas/imunologia , Feminino , Doenças Genéticas Inatas/enzimologia , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/imunologia , Humanos , Síndromes de Imunodeficiência/enzimologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Quinases Associadas a Receptores de Interleucina-1/genética , Quinases Associadas a Receptores de Interleucina-1/imunologia , Quinases Associadas a Receptores de Interleucina-1/metabolismo , Subunidade alfa de Receptor de Interleucina-2/biossíntese , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lectinas Tipo C/biossíntese , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/enzimologia , Linfócitos T/imunologia , Regulação para Cima/genética , Regulação para Cima/imunologia
19.
Autoimmunity ; 43(8): 619-27, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20380586

RESUMO

OBJECTIVES: Intravenous immunoglobulin (IVIG) G at high doses has therapeutic benefits in a variety of autoimmune and inflammatory disorders. The mechanism by which IVIG modulates inflammation is incompletely understood. We tested the hypothesis that IVIG modulates inflammation by inhibiting interactions between neutrophils and vascular endothelium, required for leukocyte recruitment to inflamed tissues. METHODS: The adhesion of human blood neutrophils to resting or cytokine-activated human umbilical vein endothelial cells (HUVECs) was measured, and the effect of IVIG or normal donor sera added at various stages was determined. RESULTS: IVIG completely inhibited neutrophil adhesion to endothelium stimulated with interleukin-1 (IL-1α), when it was present during the endothelial stimulation phase. IVIG had no effect on adhesion when IL-1ß or TNF-α was the activating cytokine. The plasma of some (one of five) healthy donors also selectively blocked the IL-1α activation of the endothelium for supporting adhesion, and this was due to the presence of neutralizing IgG at high levels in the blood of the donor. CONCLUSIONS: Thus, IgG antibodies to IL-1α are present in IVIG at a biologically significant level, which can prevent endothelial activation. However, IVIG does not directly affect activation of endothelium or neutrophil adhesion mechanisms. The anti-inflammatory properties of IVIG may in part be related to blocking IL-1α-dependent leukocyte recruitment. Potentially, such antibodies may also have immunoregulatory effects by binding and neutralizing membrane-bound IL-1α during cell-cell interactions.


Assuntos
Adesão Celular/imunologia , Endotélio Vascular/imunologia , Imunoglobulinas Intravenosas/farmacologia , Inflamação/imunologia , Interleucina-1alfa/imunologia , Neutrófilos/imunologia , Endotélio Vascular/citologia , Humanos , Imunoglobulina G/sangue , Inflamação/tratamento farmacológico , Neutrófilos/citologia
20.
FASEB J ; 23(10): 3361-7, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19535683

RESUMO

Recent attempts at rebuilding the myocardium using stem cells have yielded disappointing results. The lack of a supporting vasculature may, in part, explain these disappointing findings. However, concerns over possible side effects have hampered attempts at revascularizing the infarcted myocardium using systemic delivery of proangiogenic compounds. In this study, we develop the technology to enhance the morphology and function of postinfarct neovasculature. Previously, we have shown that the up-regulated expression of endothelial cell adhesion molecules in the myocardial infarction (MI) region provides a potential avenue for selectively targeting drugs to infarcted tissue. After treatment with anti-P-selectin-conjugated liposomes containing vascular endothelial growth factor (VEGF), changes in cardiac function and vasculature post-MI were quantified in a rat MI model. Targeted delivery of VEGF to post-MI tissue resulted in significant increase in fractional shortening and improved systolic function. These functional improvements were accompanied by a 21% increase in the number of anatomical vessels and a 74% increase in the number of perfused vessels in the MI region of treated animals. No significant improvements in cardiac function were observed in untreated, systemic VEGF-treated, nontargeted liposome-treated, or blank immunoliposome-treated animals. Targeted delivery of low doses of proangiogenic compounds to post-MI tissue results in significant improvements in cardiac function and vascular structure.


Assuntos
Sistemas de Liberação de Medicamentos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/fisiopatologia , Miocárdio , Neovascularização Fisiológica/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Animais , Coração/efeitos dos fármacos , Coração/fisiopatologia , Lipossomos , Masculino , Selectina-P/imunologia , Ratos , Ratos Sprague-Dawley
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