RESUMO
A synthetic bioactive peptide composed of 17 amino acids (CKS-17) homologous to a highly conserved region of human and animal retroviral transmembrane envelope proteins induces not only significant immunoregulatory functions but also exhibits Th1-inhibiting properties, as described by its ability to suppress cell-mediated immunity and inhibit the production of interleukin (IL) 12, IL-2, gamma interferon, and tumor necrosis factor alpha, while enhancing IL-10. An important molecular mechanism responsible for the observed cytokine profiles by CKS-17 is provided by our findings demonstrating that this small peptide activates several intracellular signaling molecules, i.e., elevates intracellular cyclic adenosine monophosphate (cAMP) levels, and induces phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, mitogen-activated protein kinase/ERK kinase (MEK), protein kinase D, Raf1, and phospholipase C gamma1 (PLCgamma1). The activation of ERK1/2 is via the PLCgamma1-protein kinase C-Raf1-MEK signaling cascade. The activation of both ERK1/2 and cAMP appears to be via a mechanism sensitive to AG879, a receptor tyrosine kinase inhibitor, but not to AG825, AG1296, or AG1478. Furthermore, phosphoinositide-3 kinase appears to mediate the CKS-17-induced activation of ERK1/2, but not of cAMP. A specific amino acid sequence as well as the dimerization of this peptide is required to confer these biological activities. The results obtained are compelling and reproducible. This highly conserved molecule may enable us to understand a basic mechanism(s) of intracellular signaling pathways, regulation of Th1/Th2 cytokines, immunosuppression, and immunologic tolerance.
Assuntos
Peptídeos/imunologia , Transdução de Sinais/imunologia , Células Th1/imunologia , Células Th2/imunologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Tolerância Imunológica , Terapia de Imunossupressão , Peptídeos e Proteínas de Sinalização Intercelular , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/imunologia , Camundongos , Dados de Sequência Molecular , Peptídeos/genética , Peptídeos/farmacologia , Retroviridae , Proteínas Oncogênicas de Retroviridae/genética , Sistemas do Segundo Mensageiro/efeitos dos fármacos , Sistemas do Segundo Mensageiro/imunologia , Transdução de Sinais/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th2/efeitos dos fármacos , Proteínas do Envelope Viral/genéticaRESUMO
Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease that involves several vital organs including the cardiovascular system, joints, and kidneys. The pathology is characterized by accumulation of autoreactive lymphocytes that attack the patients' own tissues, secretion of autoantibodies and deposition of immune complexes in vital organs. Chronic widespread inflammation is the hallmark of SLE and the target of current therapy. According to recent theories, intonating immune circuits of inflammatory cytokines and immune cells constitute highly specialized targets for SLE therapy, which nonetheless consists for the most part of anti-inflammatory medications and cytotoxic drugs. For advanced autoimmune disorders, cell therapy aiming at introducing "healthy" stem cells has been promising, keeping in mind that in its current state, stem cell therapy is reserved for the most advanced diseases refractory to traditional therapy. Ongoing studies in our laboratories examined the role of the bone marrow microenvironment, in particular, mesenchymal stem cells (MSCs) in the etiopathogenesis of SLE. Specifically, we are testing the hypothesis that, in human SLE mouse model, marrow MSCs are defective structurally and functionally. Preliminary data indicate that structural and functional defects in MSC population from an autoimmune mouse model for human SLE may contribute to this pathology and consequently present a target for cell therapy.
Assuntos
Lúpus Eritematoso Sistêmico/etiologia , Células-Tronco Mesenquimais/imunologia , Células-Tronco Mesenquimais/patologia , Animais , Medula Óssea/imunologia , Comunicação Celular , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Ensaio de Unidades Formadoras de Colônias , Conexina 43/imunologia , Conexina 43/metabolismo , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Imuno-Histoquímica , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/imunologia , Osteoblastos/metabolismo , Osteoblastos/patologiaRESUMO
Through the analysis of a rare disorder called ataxia-telangiectasia (A-T), many important biological lessons have been gleaned. Today, it is clear that the underlying defect of A-T lies in the nucleus, as an inability to repair or process double strand breaks. More important, by the A-T phenotype now allows us to appreciate a much more general distinction between immunodeficiencies that are radiosensitive and those that are not.
Assuntos
Ataxia Telangiectasia/genética , Quebras de DNA de Cadeia Dupla , Síndromes de Imunodeficiência/genética , Neoplasias/genética , Malformações do Sistema Nervoso/genética , Tolerância a Radiação/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 7/genética , Humanos , Síndrome , Translocação GenéticaAssuntos
Bolsa de Fabricius/imunologia , Galinhas/imunologia , Timo/imunologia , Animais , Animais Recém-Nascidos , Bolsa de Fabricius/citologia , Bolsa de Fabricius/efeitos da radiação , Bolsa de Fabricius/cirurgia , Galinhas/crescimento & desenvolvimento , Rejeição de Enxerto/história , Reação Enxerto-Hospedeiro/imunologia , História do Século XX , Hipersensibilidade Tardia/história , Hipersensibilidade Tardia/imunologia , Imunoglobulinas/história , Leucócitos/imunologia , Linfopenia/imunologia , Sistema Fagocitário Mononuclear/imunologia , Timectomia/história , Timo/citologia , Timo/efeitos da radiaçãoRESUMO
Dietary influences on Alzheimer disease (AD) are gaining recognition. Because many aging processes are attenuated in laboratory mammals by caloric restriction (CR), we examined the effects of short-term CR in two AD-transgenic mice, APP(swe/ind) (J20) and APP(swe) + PS1(M146L) (APP + PS1). CR substantially decreased the accumulation of Abeta-plaques in both lines: by 40% in APP(swe/ind) (CR, 6 weeks), and by 55% in APP + PS1 (CR, 14 weeks). CR also decreased astrocytic activation (GFAP immunoreactivity). These influences of CR on AD-transgenic mice are consistent with epidemiological reports that show that high caloric diets associate with the risk of AD, and suggest that dietary interventions in adult life might slow disease progression.
Assuntos
Doença de Alzheimer/dietoterapia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Restrição Calórica/métodos , Placa Amiloide/metabolismo , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/genética , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Imuno-Histoquímica/métodos , Proteínas de Membrana/genética , Camundongos , Camundongos Transgênicos , Emaranhados Neurofibrilares/metabolismo , Presenilina-1 , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodosRESUMO
BACKGROUND: Administration of influenza vaccine to human immunodeficiency virus (HIV)-infected children can lead to increased viral load. CCR5 and CXCR4 are known to play an important role in HIV cell entry and viral replication. OBJECTIVE: To determine the effects of influenza vaccine on chemokine receptors and on viral load in HIV-infected children. METHODS: Eight HIV-infected children receiving stable therapy and 11 healthy adults were enrolled. Chemokine expression and immune activation were determined before and 48 hours after influenza vaccination. CCR5 and beta-chemokine gene expression were analyzed using real-time polymerase chain reaction. Viral load was measured at baseline, 48 hours, and 6 to 12 weeks. RESULTS: Forty-eight hours after influenza vaccination, mean CCR5 expression was significantly decreased on the CD3 (21.1% vs 11.3% in HIV-infected children; P = .02; and 18.3% vs 10.7% in controls; P = .008) and CD4 (13.0% vs 3.6% in the HIV group; P = .04; and 13.6% vs 6.5% in controls; P = .02) lymphocytes. This was observed in conjunction with an increase in HLA-DR expression on T lymphocytes in HIV-infected children (P = .046). No significant changes were observed in HIV viral load, CD3 and CD8 lymphocyte counts, expression of interleukin 2 receptor and CXCR4, or gene expression of CCR5 and beta-chemokines 48 hours after vaccination. CONCLUSIONS: Influenza virus vaccine markedly decreased chemokine receptor CCR5 expression on CD4 T lymphocytes. However, this immunomodulatory effect does not seem to affect overall viral replication in HIV-infected children who received highly active antiretroviral therapy.
Assuntos
Linfócitos T CD4-Positivos/efeitos dos fármacos , Infecções por HIV/metabolismo , Vacinas contra Influenza/farmacologia , Receptores CCR5/biossíntese , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD4-Positivos/metabolismo , Criança , Pré-Escolar , Citocinas/biossíntese , Citocinas/genética , Depressão Química , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genes MHC da Classe II/efeitos dos fármacos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/fisiologia , Antígenos HLA-DR/biossíntese , Humanos , Interferon gama/biossíntese , Interferon gama/genética , Contagem de Linfócitos , Subpopulações de Linfócitos , Masculino , Receptores CCR5/genética , Carga Viral , Replicação Viral/efeitos dos fármacosRESUMO
Abstract We present our experience on treatment of three children with potentially fatal diseases using a unique protocol for non-myeloablative bone marrow transplantation. The protocol was designed to promote engraftment of bone marrow stromal/mesenchymal cells (SC/MSCs) based on the knowledge from preclinical models over the last three decades. Accordingly, our protocol is the first to test the use of bone fragments as an ideal vehicle to transplant such cells residing in the bone core. Because of the paucity of knowledge for optimum transplantation of SC/MSCs in humans, we used a multifaceted approach and implanted bone fragments both intraperitoneally and directly into bone on day 0 of BMT. We also infused cultured donor osteoblast-like cells intravenously post-BMT. We were able to achieve high levels of stroma cell engraftment as defined by molecular analyses of bone biopsy specimens.
Assuntos
Transplante de Medula Óssea/métodos , Transplante Ósseo , Células-Tronco Mesenquimais/citologia , Osteoblastos/transplante , Células Estromais/citologia , Células Cultivadas , Criança , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Masculino , Osteoblastos/citologia , Projetos Piloto , Regeneração , Transplante Homólogo , Resultado do TratamentoRESUMO
Male BXSB mice, a mouse model of systemic lupus erythematosus, were given bone marrow transplants (BMT) at 20 wk of age using MHC-matched donor cells and nonmyeloablative conditioning (550 cGy irradiation). Transplanted mice and irradiation controls were followed for a period of 20 wk. Mice transgenic for green fluorescent protein were used as donors to allow tracking of donor cells and a determination of chimerism. Radiation controls had reduced renal pathology at 10 wk posttransplant, but not at 20 wk compared with untreated mice, while nonmyeloablative BMT mice had significantly reduced pathology at both time intervals. The monocytosis characteristic of older BXSB mice was also reduced by BMT, but the treatment did not prevent production of Ab to dsDNA. A stable chimerism of 24-40% donor CD45-positive cells was achieved in spleen and bone marrow, and there was no evidence of clinical graft vs host disease. Donor cells were detected in most recipient organs, notably the thymus and renal glomeruli. The results suggest that complete depletion of mature lymphocytes or of progenitor stem cells is not required to control lupus nephritis in BXSB mice.
Assuntos
Transplante de Medula Óssea/imunologia , Teste de Histocompatibilidade , Proteínas Luminescentes/genética , Lúpus Eritematoso Sistêmico/imunologia , Condicionamento Pré-Transplante , Animais , Anticorpos Antinucleares/biossíntese , Transplante de Medula Óssea/métodos , Transplante de Medula Óssea/patologia , DNA/imunologia , Feminino , Proteínas de Fluorescência Verde , Teste de Histocompatibilidade/métodos , Rim/patologia , Leucocitose/genética , Leucocitose/imunologia , Leucocitose/patologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Camundongos Transgênicos , Monócitos/imunologia , Monócitos/patologia , Quimera por Radiação/imunologia , Timo/imunologia , Timo/patologia , Condicionamento Pré-Transplante/métodosRESUMO
BACKGROUND: Mannose-binding lectin (MBL), an acute-phase serum protein of hepatic origin, plays an essential protective role in host innate immunity in targeting microbial pathogens for destruction via opsonization, enhancement of phagocytosis and complement activation. MBL deficiency, characterized by low serum MBL, has been attributed to genetic mutations in both structural and promoter regions of the gene coding for the protein. Concomitant MBL deficiency in patients with chronic immunologic disease has been associated with increased susceptibility to complicating infections that may hasten disease progression. OBJECTIVE: Few cases of inherited MBL deficiency in adults and possible associations with recurrent infection have been reported. To address this issue, we investigated the MBL profile of four generations within a single adult family whose members have experienced a variety of persistent infections. METHODS: MBL serum levels and MBL genotypes of each participating family member were ascertained by enzyme-linked immunoadsorbent assay and reverse transcriptase-polymerase chain reaction, respectively. MBL complement activation, as measured by C4b deposition against mannan-coated wells, was assayed using an enzyme-linked immunoadsorbent assay. Routine immunologic and cellular tests were carried out to evaluate the immunologic status of each family member. RESULTS: Six of the 7 family members screened carried one or more of the variant MBL alleles in their genotype and had correspondingly low serum MBL and reduced ability to affect C4b opsonization. Medical histories of the participating family members revealed an array of mild to severe recurrent infections despite no apparent immunodeficiency. CONCLUSIONS: Our studies show that MBL deficiency is an inherited characteristic and may be a crucial factor in maintaining immunologic health.
Assuntos
Predisposição Genética para Doença , Infecções/genética , Infecções/imunologia , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/deficiência , Adulto , Ensaio de Imunoadsorção Enzimática , Família , Feminino , Humanos , Masculino , Lectina de Ligação a Manose/genética , Linhagem , Recidiva , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
T cells acquire immune functions during expansion and differentiation in the thymus. Mature T cells respond to peptide antigens (Ag) derived from foreign proteins when these peptide Ag are presented on the self major histocompatibility complex (MHC) molecules but not on allo-MHC. This is termed self-MHC restriction. On the other hand, T cells do not induce aggressive responses to self Ag (self-tolerance). Self-MHC restriction and self-tolerance are not genetically determined but acquired a posteriori by positive and negative selection in the thymus in harmony with the functional maturation. Allogeneic bone marrow (BM) chimera systems have been a useful strategy to elucidate mechanisms underlying positive and negative selection. In this communication, the contribution of BM chimera systems to the investigation of the world of T-ology is discussed.
Assuntos
Transplante de Medula Óssea/imunologia , Diferenciação Celular/imunologia , Linfócitos T/imunologia , Quimeras de Transplante/imunologia , Sequência de Aminoácidos , Animais , Células Apresentadoras de Antígenos/imunologia , Antígenos de Diferenciação de Linfócitos T/análise , Deleção Clonal/imunologia , Columbidae , Citocromos c/genética , Citocromos c/imunologia , Citometria de Fluxo , Reação Enxerto-Hospedeiro/imunologia , Tolerância Imunológica/imunologia , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Depleção Linfocítica , Complexo Principal de Histocompatibilidade/imunologia , Camundongos , Camundongos Endogâmicos AKR , Camundongos Endogâmicos C57BL , Modelos Imunológicos , Peptídeos/genética , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/química , Linfócitos T Citotóxicos/imunologia , Timo/citologia , Transplante HomólogoRESUMO
Interleukin-12 (IL-12), an important cytokine in host defense against microbial pathogens, regulates natural killer and T-cell function(s) including the induction of gamma-interferon production. The major cellular sources of IL-12 are monocytes/macrophages. Bacteria, bacterial products, and intracellular parasites are the most efficient inducers of IL-12 production. In the present study we show that a signal transduction pathway sensitive to rapamycin may have an important role in the regulation/suppression of Staphylococcus aureus-induced IL-12 production in vitro. Human peripheral blood mononuclear cells, monocytes, or a human monocytic cell line THP-1 were stimulated with S. aureus Cowan strain 1 (SAC) in the presence or absence of rapamycin and investigated for production of IL-12 protein by enzyme-linked immunosorbent assay and IL-12 p40 mRNA accumulation by RNase protection assay or real-time quantitative polymerase chain reaction. The results show that rapamycin significantly enhances SAC-induced IL-12 p70 protein production and IL-12 p40 mRNA accumulation. Further the results demonstrate that wortmannin enhances SAC-induced IL-12 p40 mRNA accumulation, whereas Ly294002 does not. These data indicate that a rapamycin-sensitive signaling pathway may act as a negative feedback cascade in the regulatory mechanisms of IL-12 production.
Assuntos
Regulação da Expressão Gênica , Interleucina-12/biossíntese , Transdução de Sinais , Sirolimo/farmacologia , Androstadienos/farmacologia , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Ensaio de Imunoadsorção Enzimática , Humanos , Leucócitos Mononucleares/metabolismo , Monócitos/metabolismo , Morfolinas/farmacologia , RNA Mensageiro/metabolismo , Ribonucleases/metabolismo , Staphylococcus aureus/metabolismo , WortmaninaRESUMO
CKS-17, a synthetic peptide representing a unique amino acid motif which is highly conserved in retroviral transmembrane proteins and other immunoregulatory proteins, induces selective immunomodulatory functions, both in vitro and in vivo, and activates intracellular signaling molecules such as cAMP and extracellular signal-regulated kinases. In the present study, using Jurkat T-cells, we report that CKS-17 phosphorylates protein kinase D (PKD)/protein kinase C (PKC) mu. Total cell extracts from CKS-17-stimulated Jurkat cells were immunoblotted with an anti-phospho-PKCmu antibody. The results show that CKS-17 significantly phosphorylates PKD/PKCmu in a dose- and time-dependent manner. Treatment of cells with the PKC inhibitors GF 109203X and Ro 31-8220, which do not act directly on PKD/PKCmu, attenuates CKS-17-induced phosphorylation of PKD/PKCmu. In contrast, the selective protein kinase A inhibitor H-89 does not reverse the action of CKS-17. Furthermore, a phospholipase C (PLC) selective inhibitor, U-73122, completely blocks the phosphorylation of PKD/PKCmu by CKS-17 while a negative control U-73343 does not. In addition, substitution of lysine for arginine residues in the CKS-17 sequence completely abrogates the ability of CKS-17 to phosphorylate PKD/PKCmu. These results clearly indicate that CKS-17 phosphorylates PKD/PKCmu through a PLC- and PKC-dependent mechanism and that arginine residues play an essential role in this activity of CKS-17, presenting a novel modality of the retroviral peptide CKS-17 and molecular interaction of this compound with target cells.
Assuntos
Peptídeos/farmacologia , Proteína Quinase C/metabolismo , Linfócitos T/enzimologia , Proteínas do Envelope Viral/farmacologia , Arginina/fisiologia , Linhagem Celular Tumoral , Diglicerídeos/análise , Relação Dose-Resposta a Droga , Vetores Genéticos , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Células Jurkat , Fosforilação , Retroviridae/genética , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo , Fatores de TempoRESUMO
beta-TrCP1 (also known as Fbw1a or FWD1) is the F-box protein component of an Skp1/Cul1/F-box (SCF)-type ubiquitin ligase complex. Although biochemical studies have suggested that beta-TrCP1 targets inhibitory subunit of NF-kappa B(I kappa B) proteins and beta-catenin for ubiquitylation, the physiological role of beta-TrCP1 in mammals has remained unclear. We have now generated mice deficient in beta-TrCP1 and shown that the degradation of I kappa B alpha and I kappa B beta is reproducibly, but not completely, impaired in the cells of these animals. The nuclear translocation and DNA-binding activity of NF-kappa B as well as the ability of this transcription factor to activate a luciferase reporter gene were also inhibited in beta-TrCP1-/- cells compared with those apparent in wild-type cells. The subcellular localization of beta-catenin was altered markedly in beta-TrCP1-/- cells. Furthermore, the rate of proliferation was reduced and both cell size and the percentage of polyploid cells were increased in embryonic fibroblasts derived from beta-TrCP1-/- mice compared with the corresponding wild-type cells. These results suggest that beta-TrCP1 contributes to, but is not absolutely required for, the degradation of I kappa B and beta-catenin and the consequent regulation of the NF-kappa B and Wnt signaling pathways, respectively. In addition, they implicate beta-TrCP1 in the maintenance of ploidy during cell-cycle progression.
Assuntos
Proteínas do Citoesqueleto/metabolismo , Proteínas de Ligação ao GTP/genética , Proteínas I-kappa B/metabolismo , NF-kappa B/metabolismo , Transativadores/metabolismo , Animais , Apoptose , Divisão Celular , Núcleo Celular/metabolismo , Células Cultivadas , Proteínas de Ligação ao GTP/deficiência , Proteínas de Ligação ao GTP/metabolismo , Marcação de Genes , Técnicas In Vitro , Camundongos , Camundongos Knockout , Inibidor de NF-kappaB alfa , NF-kappa B/antagonistas & inibidores , NF-kappa B/química , Poliploidia , Subunidades Proteicas , beta Catenina , Proteínas Contendo Repetições de beta-TransducinaAssuntos
Dor Abdominal/etiologia , Febre/etiologia , Doenças Pulmonares Intersticiais/etiologia , Sarcoidose Pulmonar/diagnóstico , Dor Abdominal/tratamento farmacológico , Dor Abdominal/imunologia , Adolescente , Diagnóstico Diferencial , Feminino , Febre/tratamento farmacológico , Febre/imunologia , Glucocorticoides/uso terapêutico , Humanos , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/imunologia , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/tratamento farmacológicoAssuntos
Alimentos Infantis/efeitos adversos , Hipersensibilidade a Leite/complicações , Vômito/etiologia , Animais , Aleitamento Materno , Bovinos , Pré-Escolar , Diagnóstico Diferencial , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/diagnóstico , Refluxo Gastroesofágico/diagnóstico , Liberação de Histamina , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Masculino , Carne/efeitos adversos , Hipersensibilidade a Leite/diagnóstico , Proteínas do Leite/efeitos adversos , Proteínas do Leite/química , Fragmentos de Peptídeos/efeitos adversos , Teste de Radioalergoadsorção , Testes Cutâneos , Proteínas de Soja/efeitos adversos , Triticum/efeitos adversos , Vômito/dietoterapiaRESUMO
Members of the Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R) superfamily share an intracytoplasmic Toll-IL-1 receptor (TIR) domain, which mediates recruitment of the interleukin-1 receptor-associated kinase (IRAK) complex via TIR-containing adapter molecules. We describe three unrelated children with inherited IRAK-4 deficiency. Their blood and fibroblast cells did not activate nuclear factor kappaB and mitogen-activated protein kinase (MAPK) and failed to induce downstream cytokines in response to any of the known ligands of TIR-bearing receptors. The otherwise healthy children developed infections caused by pyogenic bacteria. These findings suggest that, in humans, the TIR-IRAK signaling pathway is crucial for protective immunity against specific bacteria but is redundant against most other microorganisms.
Assuntos
Proteínas de Drosophila , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Infecções Pneumocócicas/imunologia , Infecções Estafilocócicas/imunologia , Alelos , Criança , Códon de Terminação , Citocinas/metabolismo , Feminino , Fibroblastos/imunologia , Humanos , Quinases Associadas a Receptores de Interleucina-1 , Interleucinas/imunologia , Interleucinas/metabolismo , Lipopolissacarídeos/imunologia , Masculino , Glicoproteínas de Membrana/química , Glicoproteínas de Membrana/imunologia , Glicoproteínas de Membrana/metabolismo , Monócitos/imunologia , Mutação , Neutrófilos/imunologia , Linhagem , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Infecções Pneumocócicas/metabolismo , Estrutura Terciária de Proteína , Receptores de Superfície Celular/química , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Receptores de Interleucina/imunologia , Receptores de Interleucina-1/química , Transdução de Sinais , Infecções Estafilocócicas/metabolismo , Receptores Toll-Like , Fator de Necrose Tumoral alfa/imunologiaAssuntos
Febre de Causa Desconhecida/etiologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunoglobulina M/sangue , Neutropenia/etiologia , Diagnóstico Diferencial , Febre de Causa Desconhecida/genética , Febre de Causa Desconhecida/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , Lactente , Masculino , Neutropenia/genética , Neutropenia/imunologia , Linhagem , SíndromeRESUMO
Scientific analyses fortified by interpretations of immunodeficiency diseases as 'experiments of nature' have revealed the specific immune systems to be comprised of T cells subserving cell-mediated immunities plus B cells and plasma cells which produce and secrete antibodies. These two separate cellular systems regularly interact with each other to produce a coordinated defense which permits mammals to live within a sea of microorganisms that threaten the integrity and the survival of individuals. We have shown that bone marrow transplantation (BMT) can be used as a form of cellular engineering to construct or reconstruct the immune systems and cure otherwise fatal severe combined immunodeficiency. When severe aplastic anemia complicated the first BMT which was performed to cure a fatal severe combined immunodeficiency, a second BMT cured for the first time a complicating severe aplastic anemia. Subsequently, BMT has been used effectively to treat some 75 otherwise fatal diseases such as resistant leukemias, lymphomas, inborn errors of metabolism, and genetic anomalies of the hematopoietic development such as sickle cell anemia, thalassemia, congenital neutropenias, and many other diseases. More recently, we have employed BMT in mice both to cure and cause autoimmunities, and, together, these experiments showed that autoimmunities actually reside in the hematopoietic stem cells. We have also found that mixed BMT or mixed hematopoietic stem cell transplantation (HSCT) can be used to prevent and cure the most complex autoimmunities such as those occurring in BXSB mice and in (NZW x BXSB)F1 W/BF1 mice. Untreated, the former develop fulminating lethal glomerulonephritis plus numerous humoral autoimmunities. Mice of the (W/B)F1 strain develop autoimmune thrombocytopenic purpura, coronary vascular disease with myocardial infarction, glomerulonephritis, and numerous autoantibodies. All of these abnormalities are prevented or cured by mixed syngeneic (autoimmune) plus allogeneic (normal healthy) BMT or mixed peripheral blood HSCT. Thus, the most complex autoimmune diseases can be prevented or cured in experimental animals by mixed syngeneic plus allogeneic BMT or HSCT which produce stable mixed chimerism as a form of cellular engineering.
Assuntos
Transplante de Medula Óssea , Lúpus Vulgar/veterinária , Doenças dos Roedores/prevenção & controle , Doenças dos Roedores/cirurgia , Transplante de Células-Tronco , Animais , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Quimeras de TransplanteRESUMO
Interleukin-10 (IL-10) plays an important immunopathogenic role in immunologic diseases, especially in HIV infection and atopic dermatitis. The control and regulatory mechanisms of IL-10 production have not been described in these diseases. Recently, we demonstrated that HIV-1 Nef induces IL-10 production in monocytes and that staphylococcal enterotoxin A (SEA) induces IL-10 production in T-lymphocytes. Here we show that Nef-induced IL-10 production and mRNA expression are strongly blocked by rapamycin, but are not blocked by cyclosporin (CsA) or FK506. Conversely, we show that CsA and FK506 completely inhibit SEA-induced IL-10 protein production and mRNA expression. The results of this study demonstrate that IL-10 production by Nef and SEA is controlled and regulated by different mechanisms.