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1.
Epigenetics ; : 1-9, 2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32657253

RESUMO

Air pollution is associated with early declines in lung function and increased levels of asthma-related cysteinyl leukotrienes (CysLT) but a biological pathway linking this rapid response has not been delineated. In this randomized controlled diesel exhaust (DE) challenge study of 16 adult asthmatics, increased exposure-attributable urinary leukotriene E4 (uLTE4, a biomarker of cysteinyl leukotriene production) was correlated (p = 0.04) with declines in forced expiratory volume in 1-second (FEV1) within 6 hours of exposure. Exposure-attributable uLTE4 increases were correlated (p = 0.02) with increased CysLT receptor 1 (CysLTR1) methylation in peripheral blood mononuclear cells which, in turn, was marginally correlated (p = 0.06) with decreased CysLTR1 expression. Decreased CysLTR1 expression was, in turn, correlated (p = 0.0007) with FEV1 declines. During the same time period, increased methylation of GPR17 (a negative regulator of CysLTR1) was observed after DE exposure (p = 0.02); this methylation increase was correlated (p = 0.001) with decreased CysLTR1 methylation which, in turn, was marginally correlated (p = 0.06) with increased CysLTR1 expression; increased CysLTR1 expression was correlated (p = 0.0007) with FEV1 increases. Collectively, these data delineate a potential mechanistic pathway linking increased DE exposure-attributable CysLT levels to lung function declines through changes in CysLTR1-related methylation and gene expression.

2.
PLoS One ; 15(6): e0233563, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497050

RESUMO

Activation of the steroidogenic enzyme CYP11A1 was shown to be necessary for the development of peanut-induced intestinal anaphylaxis and IL-13 production in allergic mice. We determined if levels of CYP11A1 in peripheral blood T cells from peanut-allergic (PA) children compared to non-allergic controls were increased and if levels correlated to IL-13 production and oral challenge outcomes to peanut. CYP11A1 mRNA and protein levels were significantly increased in activated CD4+ T cells from PA patients. In parallel, IL-13 production was significantly increased; IFNγ levels were not different between groups. There were significant correlations between expression levels of CYP11A1 mRNA and levels of IL13 mRNA and protein, levels of serum IgE anti-Ara h 2 and to outcomes of peanut challenge. The importance of CYP11A1 on cytokine production was tested using a CYP11A1 CRISPR/Cas9 KO plasmid or an inhibitor of enzymatic CYP11A1 activity. Inhibition of CYP11A1 activation in patient cells treated with the inhibitor, aminoglutethimide, or CD4+ T cell line transfected with the CYP11A1 KO plasmid resulted in reduced IL-13 production. These data suggest that the CYP11A1-CD4+Tcell-IL-13 axis in activated CD4+ T cells from PA children is associated with development of PA reactions. CYP11A1 may represent a novel target for therapeutic intervention in PA children.


Assuntos
Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Enzima de Clivagem da Cadeia Lateral do Colesterol/metabolismo , Interleucina-13/biossíntese , Hipersensibilidade a Amendoim/imunologia , Células Th2/imunologia , Adolescente , Aminoglutetimida/farmacologia , Linhagem Celular , Criança , Pré-Escolar , Enzima de Clivagem da Cadeia Lateral do Colesterol/antagonistas & inibidores , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Ativação Linfocitária , Masculino , Hipersensibilidade a Amendoim/sangue , RNA Mensageiro/genética , Transfecção , Adulto Jovem
4.
J Allergy Clin Immunol ; 145(3): 933-946.e4, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31626843

RESUMO

BACKGROUND: Inducible CD4+CD25+ regulatory T (iTreg) cells can become pathogenic effector cells, enhancing lung allergic responses. OBJECTIVE: We aimed to define the underlying cellular and molecular pathways activated by TGF-ß, which determine the suppressor or enhancing activities of iTreg cells. METHODS: Sensitized wild-type and CD8-deficient (CD8-/-) mice were challenged with allergen. Isolated CD4+CD25- T cells were activated by using anti-CD3/anti-CD28. To generate suppressor iTreg cells, cells were then differentiated in the presence of TGF-ß, whereas IL-17-producing effector T cells were additionally exposed to IL-6. After TGF-ß, Smad3 and TGF-ß-activated kinase 1 (TAK1) kinase levels were monitored. The consequences of inhibiting either kinase were determined in vitro and after transfer into CD8-/- recipients. Quantitative PCR and chromatin immunoprecipitation were used to monitor gene expression and histone modifications at the retinoic acid-related orphan receptor γt (Rorγt) locus. RESULTS: In wild-type mice, iTreg cells suppressed lung allergic responses linked to Smad3-dependent forkhead box P3 (Foxp3) expression and IL-10 production. In the presence of IL-6, iTreg cells converted to TH17 cells, mediating a neutrophil-dependent enhancement of lung allergic responses in CD8-/- mice. Conversion was regulated by TAK1. Inhibition or silencing of TAK1 prevented expression of Rorγt and TH17 differentiation through histone modifications of Rorγt; Foxp3 expression and iTreg cell-mediated suppression remained intact. In the same cell, TGF-ß induced coexpression of Smad3 and TAK1 proteins; in the presence of IL-6, expression of Smad3 and Foxp3 but not TAK1 decreased. CONCLUSION: TGF-ß regulates iTreg cell outcomes through 2 distinct signal transduction pathways: one Smad3 dependent and the other TAK1 dependent. The balance of these pathways has important implications in TH17-mediated autoimmune diseases and neutrophil-dependent asthma.


Assuntos
MAP Quinase Quinase Quinases/imunologia , Hipersensibilidade Respiratória/imunologia , Proteína Smad3/imunologia , Linfócitos T Reguladores/imunologia , Fator de Crescimento Transformador beta/imunologia , Animais , Diferenciação Celular/imunologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologia
5.
Cell Mol Immunol ; 17(5): 519-532, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31853001

RESUMO

Allergic asthma, a chronic inflammatory airway disease associated with type 2 cytokines, often originates in early life. Immune responses at an early age exhibit a Th2 cell bias, but the precise mechanisms remain elusive. Plasmacytoid dendritic cells (pDCs), which play a regulatory role in allergic asthma, were shown to be deficient in neonatal mice. We report here that this pDC deficiency renders neonatal mice more susceptible to severe allergic airway inflammation than adult mice in an OVA-induced experimental asthma model. Adoptive transfer of pDCs or administration of IFN-α to neonatal mice prevented the development of allergic inflammation in wild type but not in IFNAR1-/- mice. Similarly, adult mice developed more severe allergic inflammation when pDCs were depleted. The protective effects of pDCs were mediated by the pDC-/IFN-α-mediated negative regulation of the secretion of epithelial cell-derived CCL20, GM-CSF, and IL-33, which in turn impaired the recruitment of cDC2 and ILC2 cells to the airway. In asthmatic patients, the percentage of pDCs and the level of IFN-α were lower in children than in adults. These results indicate that impairment of pDC-epithelial cell crosstalk in neonates is a susceptibility factor for the development of allergen-induced allergic airway inflammation.

6.
Sci Transl Med ; 11(519)2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748230

RESUMO

Patients with rheumatoid arthritis (RA) may display atypical CD21-/lo B cells in their blood, but the implication of this observation remains unclear. We report here that the group of patients with RA and elevated frequencies of CD21-/lo B cells shows decreased ataxia telangiectasia-mutated (ATM) expression and activation in B cells compared with other patients with RA and healthy donor controls. In agreement with ATM involvement in the regulation of V(D)J recombination, patients with RA who show defective ATM function displayed a skewed B cell receptor (BCR) Igκ repertoire, which resembled that of patients with ataxia telangiectasia (AT). This repertoire was characterized by increased Jκ1 and decreased upstream Vκ gene segment usage, suggesting improper secondary recombination processes and selection. In addition, altered ATM function in B cells was associated with decreased osteoprotegerin and increased receptor activator of nuclear factor κB ligand (RANKL) production. These changes favor bone loss and correlated with a higher prevalence of erosive disease in patients with RA who show impaired ATM function. Using a humanized mouse model, we also show that ATM inhibition in vivo induces an altered Igκ repertoire and RANKL production by immature B cells in the bone marrow, leading to decreased bone density. We conclude that dysregulated ATM function in B cells promotes bone erosion and the emergence of circulating CD21-/lo B cells, thereby contributing to RA pathophysiology.


Assuntos
Artrite Reumatoide/imunologia , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Linfócitos B/metabolismo , Reabsorção Óssea/imunologia , Animais , Artrite Reumatoide/fisiopatologia , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Densidade Óssea , Reabsorção Óssea/fisiopatologia , Sobrevivência Celular/imunologia , Humanos , Imunoglobulinas/imunologia , Articulações/patologia , Contagem de Linfócitos , Camundongos , Pessoa de Meia-Idade , Osteogênese , Osteoprotegerina/metabolismo , Fenótipo , Ligante RANK/metabolismo , Receptores de Complemento 3d/metabolismo , Recombinação Genética/genética
7.
Eur Respir Rev ; 28(154)2019 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-31748421

RESUMO

The complexity of asthma is underscored by the number of cell types and mediators implicated in the pathogenesis of this heterogeneous syndrome. Type 2 CD4+ T-cells (Th2) and more recently, type 2 innate lymphoid cells dominate current descriptions of asthma pathogenesis. However, another important source of these type 2 cytokines, especially interleukin (IL)-5 and IL-13, are CD8+ T-cells, which are increasingly proposed to play an important role in asthma pathogenesis, because they are abundant and are comparatively insensitive to corticosteroids. Many common triggers of asthma exacerbations are mediated via corticosteroid-resistant pathways involving neutrophils and CD8+ T-cells. Extensive murine data reveal the plasticity of CD8+ T-cells and their capacity to enhance airway inflammation and airway dysfunction. In humans, Tc2 cells are predominant in fatal asthma, while in stable state, severe eosinophilic asthma is associated with greater numbers of Tc2 than Th2 cells in blood, bronchoalveolar lavage fluid and bronchial biopsies. Tc2 cells strongly express CRTH2, the receptor for prostaglandin D2, the cysteinyl leukotriene receptor 1 and the leukotriene B4 receptor. When activated, these elicit Tc2 cell chemotaxis and production of chemokines and type 2 and other cytokines, resulting directly or indirectly in eosinophil recruitment and survival. These factors position CD8+ Tc2 cells as important and underappreciated effector cells contributing to asthma pathogenesis. Here, we review recent advances and new insights in understanding the pro-asthmatic functions of CD8+ T-cells in eosinophilic asthma, especially corticosteroid-resistant asthma, and the molecular mechanisms underlying their pathologic effector function.


Assuntos
Asma/etiologia , Asma/patologia , Linfócitos T CD8-Positivos/fisiologia , Linfócitos T Citotóxicos/fisiologia , Asma/terapia , Humanos
8.
Front Pediatr ; 7: 390, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709200

RESUMO

A subset of patients with Ataxia-Telangiectasia (A-T) have dramatically reduced levels of IgG, IgA, and IgE with retained or elevated IgM levels. Several reports suggest that these A-T patients with a "hyper-IgM phenotype" (HIgM) suffer more clinical immunologic consequences than other A-T patients. The immunopathologic mechanism driving this phenomenon is unknown, making it difficult to predict response to immunomodulatory therapy. We describe an A-T patient with HIgM who underwent tumor necrosis factor (TNF) receptor blockade for cutaneous granuloma and after several months of successful therapy developed non-malignant lymphoproliferation, cytopenia, and increased serum immunoglobulin levels. This process was subsequently followed by an immune-complex-mediated intrarenal small vessel vasculitis that led to renal failure. The vasculitis was successfully treated with rituximab and corticosteroids. This case underscores the importance of HIgM as an unfavorable prognostic indicator in A-T and highlights the complexity of immunomodulatory treatment in this population, and the potential for a successful approach tailored to the immune defect.

9.
Am J Hum Genet ; 105(3): 549-561, 2019 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-31447097

RESUMO

FOXN1 is the master regulatory gene of thymic epithelium development. FOXN1 deficiency leads to thymic aplasia, alopecia, and nail dystrophy, accounting for the nude/severe combined immunodeficiency (nu/SCID) phenotype in humans and mice. We identified several newborns with low levels of T cell receptor excision circles (TRECs) and T cell lymphopenia at birth, who carried heterozygous loss-of-function FOXN1 variants. Longitudinal analysis showed persistent T cell lymphopenia during infancy, often associated with nail dystrophy. Adult individuals with heterozygous FOXN1 variants had in most cases normal CD4+ but lower than normal CD8+ cell counts. We hypothesized a FOXN1 gene dosage effect on the function of thymic epithelial cells (TECs) and thymopoiesis and postulated that these effects would be more prominent early in life. To test this hypothesis, we analyzed TEC subset frequency and phenotype, early thymic progenitor (ETP) cell count, and expression of FOXN1 target genes (Ccl25, Cxcl12, Dll4, Scf, Psmb11, Prss16, and Cd83) in Foxn1nu/+ (nu/+) mice and age-matched wild-type (+/+) littermate controls. Both the frequency and the absolute count of ETP were significantly reduced in nu/+ mice up to 3 weeks of age. Analysis of the TEC compartment showed reduced expression of FOXN1 target genes and delayed maturation of the medullary TEC compartment in nu/+ mice. These observations establish a FOXN1 gene dosage effect on thymic function and identify FOXN1 haploinsufficiency as an important genetic determinant of T cell lymphopenia at birth.


Assuntos
Fatores de Transcrição Forkhead/genética , Heterozigoto , Linfopenia/genética , Linfócitos T/metabolismo , Timo/citologia , Adulto , Idoso , Animais , Pré-Escolar , Feminino , Fatores de Transcrição Forkhead/fisiologia , Humanos , Lactente , Recém-Nascido , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Adulto Jovem
11.
J Allergy Clin Immunol Pract ; 7(6): 1970-1985.e4, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30877075

RESUMO

BACKGROUND: Although autoimmunity and hyperinflammation secondary to recombination activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. OBJECTIVE: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. METHODS: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. RESULTS: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. Most patients (55.6%) presented with more than 1 autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median, 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in most cases (64.7%, 73.7%, and 71.4% for autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. CONCLUSIONS: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multilineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.


Assuntos
Proteínas de Homeodomínio , Síndromes de Imunodeficiência , Adolescente , Adulto , Autoimunidade , Criança , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Imunossupressores/uso terapêutico , Lactente , Inflamação , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
12.
J Allergy Clin Immunol ; 143(6): 2026-2037.e7, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30660639

RESUMO

BACKGROUND: CD8+ type 2 cytotoxic T (TC2) cells undergo transcriptional reprogramming to IL-13 production in the presence of IL-4 to become potent, steroid-insensitive, pathogenic effector cells in asthmatic patients and in mice in a model of experimental asthma. However, no studies have described the effects of hypoxia exposure on TC2 cell differentiation. OBJECTIVE: We determined the effects of hypoxia exposure on IL-13-producing CD8+ TC2 cells. METHODS: CD8+ transgenic OT-1 cells differentiated with IL-2 and IL-4 (TC2 cells) were exposed to normoxia (21% oxygen) or hypoxia (3% oxygen), and IL-13 production in vitro was monitored. After differentiation under these conditions, cells were adoptively transferred into CD8-deficient mice, and lung allergic responses, including airway hyperresponsiveness to inhaled methacholine, were assessed. The effects of pharmacologic inhibitors of hypoxia-inducible factor (HIF) 1α and HIF-2α were determined, as were responses in HIF-1α-deficient OT-1 cells. RESULTS: Under hypoxic conditioning, CD8+ TC2 cell differentiation was significantly enhanced, with increased numbers of IL-13+ T cells and increased production of IL-13 in vitro. Adoptive transfer of TC2 cells differentiated under hypoxic conditioning restored lung allergic responses in sensitized and challenged CD8-deficient recipients to a greater degree than seen in recipients of TC2 cells differentiated under normoxic conditioning. Pharmacologic inhibition of HIF-1α or genetic manipulation to reduce HIF-1α expression reduced the hypoxia-enhanced differentiation of TC2 cells, IL-13 production, and the capacity of transferred cells to restore lung allergic responses in vivo. IL-4-dependent, hypoxia-mediated increases in HIF-1α and TC2 cell differentiation were shown to be mediated through activation of Janus kinase 1/3 and GATA-3. CONCLUSIONS: Hypoxia enhances CD8+ TC2 cell-dependent airway hyperresponsiveness and inflammation through HIF-1α activation. These findings coupled with the known insensitivity of CD8+ T cells to corticosteroids suggests that activation of the IL-4-HIF-1α-IL-13 axis might play a role in the development of steroid-refractory asthma.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/imunologia , Hipóxia/imunologia , Inflamação/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/antagonistas & inibidores , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Broncoconstritores , Células Cultivadas , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Pulmão/imunologia , Pulmão/fisiopatologia , Cloreto de Metacolina , Camundongos Transgênicos , Hipersensibilidade Respiratória/fisiopatologia
13.
Clin Immunol ; 200: 55-63, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30639167

RESUMO

Ataxia-Telangiectasia (AT) is an immunodeficiency most often associated with T cell abnormalities. We describe a patient with a hyper-IgM phenotype and immune cell abnormalities that suggest a distinct clinical phenotype. Significant B cell abnormalities with increased unswitched memory B cells, decreased naive transitional B cells, and an elevated frequency of CD19+CD38loCD27-CD10-CD21-/low B cells expressing high levels of T-bet and Fas were demonstrated. The B cells were hyporesponsive to in vitro stimulation through the B cell receptor, Toll like receptors (TLR) 7 and 9, and CD40. T cell homeostasis was also disturbed with a significant increase in γδ T cells, circulating T follicular helper cells (Tfh), and decreased numbers of T regulatory cells. The ATM mutations in this patient are posited to have resulted in the perturbations in the frequencies and distributions of B and T cell subsets, resulting in the phenotype in this patient. KEY MESSAGES: A novel mutation creating a premature stop codon and a nonsense mutation in the ATM gene are postulated to have resulted in the unique clinical picture characterized by abnormal B and T cell populations, lymphocyte subset dysfunction, granuloma formation, and a hyper-IgM phenotype. CAPSULE SUMMARY: A patient presented with ataxia-telangiectasia, cutaneous granulomas, and a hyper-IgM phenotype; a novel combination of mutations in the ATM gene was associated with abnormal distributions, frequencies, and function of T and B lymphocyte subsets.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Ataxia Telangiectasia/genética , Subpopulações de Linfócitos B/imunologia , Granuloma/genética , Síndrome de Imunodeficiência com Hiper-IgM/genética , Dermatopatias/genética , Subpopulações de Linfócitos T/imunologia , Ataxia Telangiectasia/imunologia , Linfócitos B/imunologia , Pré-Escolar , Códon sem Sentido , Feminino , Granuloma/imunologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Memória Imunológica , Análise de Sequência de DNA , Dermatopatias/imunologia , Linfócitos T/imunologia
14.
J Clin Invest ; 128(12): 5489-5504, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30395541

RESUMO

We report the molecular, cellular, and clinical features of 5 patients from 3 kindreds with biallelic mutations in the autosomal LIG1 gene encoding DNA ligase 1. The patients exhibited hypogammaglobulinemia, lymphopenia, increased proportions of circulating γδT cells, and erythrocyte macrocytosis. Clinical severity ranged from a mild antibody deficiency to a combined immunodeficiency requiring hematopoietic stem cell transplantation. Using engineered LIG1-deficient cell lines, we demonstrated chemical and radiation defects associated with the mutant alleles, which variably impaired the DNA repair pathway. We further showed that these LIG1 mutant alleles are amorphic or hypomorphic, and exhibited variably decreased enzymatic activities, which lead to premature release of unligated adenylated DNA. The variability of the LIG1 genotypes in the patients was consistent with that of their immunological and clinical phenotypes. These data suggest that different forms of autosomal recessive, partial DNA ligase 1 deficiency underlie an immunodeficiency of variable severity.


Assuntos
Alelos , DNA Ligase Dependente de ATP , Síndromes de Imunodeficiência , Mutação , DNA Ligase Dependente de ATP/genética , DNA Ligase Dependente de ATP/imunologia , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia
17.
Immunol Allergy Clin North Am ; 38(4): 655-665, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30342586

RESUMO

Diagnosis and management of asthma is commonly implemented based on clinical assessment. Although these nonmolecular biomarkers have been useful, limited resolution of the heterogeneity among asthmatic patients and little information regarding the underlying pathobiology of disease in individuals have been provided. Molecular endotying using global transcriptome expression profiling associated with clinical features of asthma has improved our understanding of disease mechanisms, risk assessment of asthma exacerbations, and treatment responses, especially in patients with type 2 inflammation. Further advances in establishing pathobiological subgroups, bioactive pathways, and true disease endotypes hold potential for a more personalized medical approach in asthmatic patients.


Assuntos
Asma/genética , Asma/imunologia , Fenótipo , Transcriptoma/genética , Transcriptoma/imunologia , Humanos , Escarro/imunologia
18.
J Thorac Imaging ; 33(6): 377-383, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30067570

RESUMO

Common variable immunodeficiency (CVID) is associated with significant chronic lung disease. The purpose of this paper was to describe the clinical, radiologic, and pathologic findings of CVID-associated lung diseases. These include airways' disease, interstitial lung disease, lymphoma, and mucosa-associated lymphoid tissue lymphoma. In addition, a genetic syndrome termed Kabuki syndrome results in CVID-like immune abnormalities. These patients may also present with CVID-associated lung disease. Awareness and precise identification of CVID-associated lung disease may allow for better assessment of prognosis and direction of therapy.


Assuntos
Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/diagnóstico por imagem , Pneumopatias/complicações , Pneumopatias/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Doença Crônica , Imunodeficiência de Variável Comum/imunologia , Humanos , Pulmão/diagnóstico por imagem , Pulmão/imunologia , Pneumopatias/imunologia
19.
Stem Cells Transl Med ; 7(7): 551-558, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29730892

RESUMO

All-trans retinoic acid (ATRA) or mesenchymal stem cells (MSCs) have been shown to promote lung tissue regeneration in animal models of emphysema. However, the reparative effects of the combination of the two and the role of p70S6 kinase-1 (p70S6k1) activation in the repair process have not been defined. Twenty-one days after intratracheal instillation of porcine pancreatic elastase (PPE), MSC and/or 10 days of ATRA treatment was initiated. Thirty-two days later, static lung compliance (Cst), mean linear intercepts (MLIs), and alveolar surface area (S) were measured. After PPE, mice demonstrated increased values of Cst and MLI, and decreased S values. Both ATRA and MSC transfer were individually effective in improving these outcomes while the combination of ATRA and MSCs was even more effective. The combination of p70S6k1-/- MSCs transfer followed by ATRA demonstrated only modest effects, and rapamycin treatment of recipients with wild-type (WT) MSCs and ATRA failed to show any effect. However, transfer of p70S6k1 over-expressing-MSCs together with ATRA resulted in further improvements over those seen following WT MSCs together with ATRA. ATRA activated p70S6k1 in MSCs in vitro, which was completely inhibited by rapamycin. Tracking of transferred MSCs following ATRA revealed enhanced accumulation and extended survival of MSCs in recipient lungs following PPE but not vehicle instillation. These data suggest that in MSCs, p70S6k1 activation plays a critical role in ATRA-enhanced lung tissue repair, mediated in part by prolonged survival of transferred MSCs. p70S6k1-activated MSCs may represent a novel therapeutic approach to reverse the lung damage seen in emphysema. Stem Cells Translational Medicine 2018;7:551-558.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Enfisema Pulmonar/terapia , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Animais , Células da Medula Óssea/citologia , Modelos Animais de Doenças , Feminino , Pulmão/fisiologia , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Elastase Pancreática/toxicidade , Fosforilação , Enfisema Pulmonar/etiologia , Regeneração , Proteínas Quinases S6 Ribossômicas 70-kDa/genética , Engenharia Tecidual , Tretinoína/farmacologia , Tretinoína/uso terapêutico
20.
J Immunol ; 200(4): 1261-1269, 2018 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-29352000

RESUMO

Mesenchymal stem cells (MSC) exert immune modulatory properties and previous studies demonstrated suppressive effects of MSC treatment in animal models of allergic airway inflammation. However, the underlying mechanisms have not been fully elucidated. We studied the role of MSC in immune activation and subsequent recruitment of monocytes in suppressing airway hyperresponsiveness and airway inflammation using a mouse model of allergic airway inflammation. MSC administration prior to or after allergen challenge inhibited the development of airway inflammation in allergen-sensitized mice. This was accompanied by an influx of CCR2-positive monocytes, which were localized around injected MSC in the lungs. Notably, IL-10-producing monocytes and/or macrophages were also increased in the lungs. Systemic administration of liposomal clodronate or a CCR2 antagonist significantly prevented the suppressive effects of MSC. Activation of MSC by IFN-γ leading to the upregulation of CCL2 expression was essential for the suppressive effects, as administration of wild-type MSC into IFN-γ-deficient recipients, or IFN-γ receptor-deficient or CCL2-deficient MSC into wild-type mice failed to suppress airway inflammation. These results suggest that MSC activation by IFN-γ, followed by increased expression of CCL2 and recruitment of monocytes to the lungs, is essential for suppression by MSC in allergen-induced airway hyperresponsiveness and airway inflammation.


Assuntos
Células-Tronco Mesenquimais/imunologia , Monócitos/imunologia , Receptores CCR2/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Movimento Celular/imunologia , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR2/biossíntese , Hipersensibilidade Respiratória/metabolismo
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