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BACKGROUND: Treatment of cystic fibrosis (CF) has been revolutionized by the use of cystic fibrosis transmembrane conductance regulator (CFTR) protein modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) triple therapy. Prior studies support a role for type 2 (T2) inflammation in many people with CF (PwCF) and CF-asthma overlap syndrome (CFAOS) is considered a separate clinical entity. It is unknown whether initiation of ETI therapy impacts T2 inflammation in PwCF. We hypothesized that ETI initiation decreases T2 inflammation in PwCF. METHODS: A single center retrospective chart review was conducted for adult PwCF. As markers of T2 inflammation, absolute eosinophil count (AEC) and total immunoglobulin E (IgE) data were collected longitudinally 12 months prior to ETI therapy initiation and 12 months following therapy initiation. Multivariable analyses adjusted for the age, gender, CFTR mutation, disease severity, inhaled steroid use, and microbiological colonization. RESULTS: There was a statistically significant reduction (20.10%, p < 0.001) in 12-month mean total IgE following ETI initiation; this change remained statistically significant in the multivariate model. The longitudinal analysis demonstrated no change in AEC following therapy initiation. CONCLUSION: This study demonstrates that there is a statistically significant percent reduction in mean total IgE but no change in AEC following ETI initiation. ETI may lead to decreased antigen and superantigen load in the airway as a result of improved mucociliary clearance and these changes may drive the decline in total IgE, without influencing the epigenetic drivers of eosinophilic inflammation. Further studies are warranted to determine the underlying mechanism of ETI impact on T2 inflammation and possible role for asthma immunomodulator therapy post ETI initiation in CFAOS.
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Ingestion of probiotics appears to have modest effects on the incidence of viral respiratory infection. The mechanism of these effects is not clear; however, there is evidence from animal models that the probiotic may have an effect on innate immune responses to pathogens. The purpose of this randomised, placebo-controlled study was to determine the effect of administration of Bifidobacterium animalis subspecies lactis Bl-04 on innate and adaptive host responses to experimental rhinovirus challenge. The effect on the response of chemokine (C-X-C motif) ligand 8 (CXCL8) to rhinovirus infection was defined as the primary endpoint for the study. 152 seronegative volunteers who had been supplemented for 28 days, 73 with probiotic and 79 with placebo, were challenged with RV-A39. Supplement or placebo administration was then continued for five days during collection of specimens for assessment of host response, infection, and symptoms. 58 probiotic and 57 placebo-supplemented volunteers met protocol-defined criteria for analysis. Probiotic resulted in higher nasal lavage CXCL8 on day 0 prior to virus challenge (90 vs 58 pg/ml, respectively, P=0.04, ANCOVA). The CXCL8 response to rhinovirus infection in nasal lavage was significantly reduced in the probiotic treated group (P=0.03, ANCOVA). Probiotic was also associated with a reduction in nasal lavage virus titre and the proportion of subjects shedding virus in nasal secretions (76% in the probiotic group, 91% in the placebo group, P=0.04, Fisher Exact test). The administration of probiotic did not influence lower respiratory inflammation (assessed by exhaled nitric oxide), subjective symptom scores, or infection rate. This study demonstrates that ingestion of Bl-04 may have an effect on the baseline state of innate immunity in the nose and on the subsequent response of the human host to rhinovirus infection. Clinicaltrials.gov registry number: NCT01669603.
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Bifidobacterium animalis , Resfriado Común/terapia , Inmunidad Innata/efectos de los fármacos , Probióticos/uso terapéutico , Rhinovirus/inmunología , Esparcimiento de Virus/efectos de los fármacos , Inmunidad Adaptativa/efectos de los fármacos , Adulto , Resfriado Común/virología , Suplementos Dietéticos/microbiología , Método Doble Ciego , Femenino , Humanos , Inflamación/tratamiento farmacológico , Interleucina-6/análisis , Interleucina-8/análisis , Masculino , Líquido del Lavado Nasal/química , Líquido del Lavado Nasal/virología , Placebos/administración & dosificaciónRESUMEN
Genetic studies have shown linkages for asthma to the chromosomal region 5q31-q33 in humans that includes the IL-9 gene. An A-to-G base substitution has been identified at bp -351 in the IL-9 promoter. The role of this polymorphism in IL-9 promoter function was assessed utilizing CD4+ T cells purified from individuals with one or two of the G alleles in comparison to those homozygous for the wild-type A. The presence of an A at -351 (A allele) increased mitogen-stimulated IL-9 transcription twofold in comparison to subjects with one or two G alleles at this position. Binding of nuclear extract proteins from IL-9-producing human cell lines to DNA sequences including this base exchange demonstrated specific binding of the transcription factor NF-kappaB. Binding of NF-kappaB to the IL-9 promoter was confirmed in vivo using the chromatin immunoprecipitation assay. Recombinant NF-kappaB bound to a promoter fragment with the A allele with fivefold higher affinity than it did to a promoter with the G allele. Individuals carrying the A allele of the IL-9 promoter display increased synthesis of IL-9, which may result in strong Th2 immune responses and a modulation of their susceptibility to infectious, neoplastic, parasitic or atopic disease.
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Linfocitos T CD4-Positivos/inmunología , Regulación de la Expresión Génica , Interleucina-9/genética , FN-kappa B/metabolismo , Adolescente , Adulto , Alelos , Humanos , Interleucina-9/inmunología , Células Jurkat , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras Genéticas/fisiología , Proteínas Recombinantes/metabolismo , Adulto JovenRESUMEN
The aim of the present study was to assess the response of high-dose salmeterol/fluticasone combination (SFC) and low-dose SFC compared with regimens without inhaled corticosteroid (ICS) plus long-acting beta-agonist (LABA) in a large cohort with severe or difficult-to-treat asthma. Subjects were administered low-dose SFC (100/50 or 250/50 microg) or high-dose SFC (500/50 microg), and a control group received medications that could include ICS or LABA but not both. The present authors calculated unadjusted and propensity score-adjusted differences in outcomes consistent with components of asthma control, comparing high-dose and low-dose SFC cohorts with controls. The low-dose SFC cohort had higher asthma-related quality of life and fewer asthma control problems compared with controls. The high-dose SFC cohort had higher forced expiratory volume in one second but higher odds of having severe asthma compared with controls. The present results support the evidence that some asthmatics achieve better outcomes while receiving a low-dose salmeterol/fluticasone combination, but also suggest that those on a high-dose salmeterol/fluticasone combination fail to achieve significant improvement in many control-related health outcomes as compared with similar patients not receiving salmeterol/fluticasone combination. These findings suggest a limited value of high-dose salmeterol/fluticasone combination compared with the alternatives. While additional studies are needed, the present findings call for alternative therapeutic approaches in severe/difficult-to-treat asthma for those unable to attain asthma control with or without salmeterol/fluticasone combination.
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Albuterol/análogos & derivados , Androstadienos/administración & dosificación , Asma/tratamiento farmacológico , Quimioterapia Combinada , Corticoesteroides/metabolismo , Anciano , Albuterol/administración & dosificación , Estudios de Cohortes , Femenino , Fluticasona , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Calidad de Vida , Xinafoato de Salmeterol , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
BACKGROUND: Cysteinyl leukotrienes (CysLTs) are bioactive lipids that have been shown to contribute to allergic and inflammatory diseases. Eosinophils and mast cells have the capacity to produce large amounts of CysLTs after allergic or non-allergic stimulation. Molecular identification of both the synthetic and signalling proteins in the CysLT pathway allows the investigation of expression of the CysLT enzymes and receptors in active allergic rhinitis. OBJECTIVE: We examined the expression of the proteins involved in the synthesis of CysLTs and the cysteinyl leukotriene-1 (CysLT1) and cysteinyl leukotriene-2 (CysLT2) receptors in inflammatory cells from patients with active seasonal allergic rhinitis. METHODS: Nasal lavage samples were obtained from patients during active seasonal allergic rhinitis. Specific cellular immunocytochemical techniques were used to detect the cysteinyl leukotriene synthetic proteins, namely 5-lipoxygenase (5-LO), 5-lipoxygenase-activating protein (FLAP) and leukotriene C4 synthase (LTC4S). In situ hybridization and immunocytochemical techniques were used to identify the mRNA and proteins for the CysLT1 and CysLT2 receptors. RESULTS: 5-LO, FLAP and LTC4S, and the CysLT1 and CysLT2 receptors were expressed in the majority of eosinophils and in subsets of mast cells and mononuclear cells. 5-LO, FLAP and the CysLT1 receptor, but not LTC4S or the CysLT2 receptor, were expressed in a subset of nasal neutrophils. CONCLUSIONS: Our study demonstrates the presence of CysLT pathway proteins in key allergic and inflammatory cells from the upper airway of patients with active seasonal allergic rhinitis. Our expression data highlight the potential of CysLT-modifying agents to treat both upper and lower airway symptoms in patients suffering from allergic rhinitis and asthma.
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Cisteína/biosíntesis , Leucotrienos/biosíntesis , Rinitis Alérgica Estacional/metabolismo , Proteínas Activadoras de la 5-Lipooxigenasa , Adulto , Araquidonato 5-Lipooxigenasa/metabolismo , Proteínas Portadoras/metabolismo , Cisteína/genética , Expresión Génica , Glutatión Transferasa/metabolismo , Humanos , Hibridación in Situ , Leucotrienos/genética , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Líquido del Lavado Nasal/química , ARN Mensajero/genética , Receptores de Leucotrienos/biosíntesis , Receptores de Leucotrienos/genética , Transducción de SeñalRESUMEN
Diesel exhaust particles (DEP) are known to modulate the production of cytokines associated with acute and chronic respiratory symptoms and allergic respiratory disease. Tolerance is an important mechanism through which the immune system can maintain nonresponsiveness to common environmental antigens. We examined the effect of DEP on IL-10 and TGF-beta, cytokines produced by macrophages and repressor (Tr-like) lymphocytes which influence tolerance. Human PBMCs (n = 22) were incubated with 1-100 ng/ml of DEP, and suboptimally primed with LPS. IL-10 gene expression was assessed by the S1 nuclease protection assay, and production of IL-10, TGF-beta, TNF-alpha, IL-1 beta and IL-4 stimulated CD23 was evaluated by ELISA after 24 and 48 h. The effect of the order of exposure to DEP and LPS was evaluated on IL-10 protein and mRNA in cells (1) preincubated with LPS followed by DEP, or (2) exposed first to DEP followed by LPS. IL-10 was further evaluated using benzo[a]pyrene and [alpha]naphthoflavone as a surrogate for the polyaromatic hydrocarbons (PAHs) adsorbed to DEP. Control cells were incubated with carbon black, without PAHs. In PBMCs exposed to DEP with LPS, or preincubated with LPS before DEP, IL-10 production and mRNA fall significantly. TGF-beta is similarly suppressed, IL-1 beta secretion is significantly stimulated, and IL-4 stimulated CD23 release rises in the atopic subjects. In contrast, when DEP is added prior to LPS, IL-10 production rises, and IL-1 beta falls to zero. These effects on IL-10 are reproduced with benzo[a]pyrene and reversed by the coaddition of [alpha]naphthoflavone, its known antagonist. The carbon black fraction has no effect on IL-10 production. The effect of DEP on IL-10 can be inhibitory or stimulatory, depending on the order of exposure to DEP and LPS. Pro-inflammatory cytokines and factors rise when IL-10 is inhibited, and are suppressed when IL-10 is stimulated. These results are duplicated with benzo[a]pyrene, suggesting that the PAH portion of the DEP is the active agent.
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Interleucina-10/biosíntesis , Interleucina-1/biosíntesis , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/inmunología , Factor de Crecimiento Transformador beta/biosíntesis , Emisiones de Vehículos/efectos adversos , Adulto , Benzo(a)pireno/efectos adversos , Benzoflavonas/farmacología , Hiperreactividad Bronquial/etiología , Hiperreactividad Bronquial/inmunología , Carbono/farmacología , Expresión Génica/efectos de los fármacos , Humanos , Hipersensibilidad/etiología , Técnicas In Vitro , Interleucina-10/genética , Interleucina-4/farmacología , Lipopolisacáridos/farmacología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de IgE/biosíntesisRESUMEN
Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma is a complex genetic disorder that has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. We report the results of initial clinical trials, which demonstrate clinical efficacy of this naturally occurring IL-4 antagonist as a therapeutic agent in asthma.
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Asma/inmunología , Asma/terapia , Interleucina-4/inmunología , Receptores de Interleucina-4/antagonistas & inhibidores , Células Th2/inmunología , Animales , Humanos , Interleucina-4/genética , Receptores de Interleucina-4/genética , Receptores de Interleucina-4/uso terapéutico , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T(H)2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. OBJECTIVE: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. METHODS: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. RESULTS: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV(1) observed in the placebo group (-0.4 L and -13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -2% predicted; P =.05 over the 3-month treatment period). Daily patient-measured morning FEV(1) also demonstrated a significant decline in the placebo group (-0.5 L and -18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -4% predicted; P =.02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Delta 0.1) compared with that seen in the placebo group (Delta 1.4 over 1 month; P =.07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). CONCLUSION: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma.
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Asma/tratamiento farmacológico , Receptores de Interleucina-4/uso terapéutico , Adulto , Anciano , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Interleucina-4/antagonistas & inhibidores , Interleucina-4/metabolismo , Masculino , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Receptores de Interleucina-4/sangre , Receptores de Interleucina-4/genética , Proteínas Recombinantes/uso terapéutico , SolubilidadAsunto(s)
Hipersensibilidad a las Drogas/inmunología , Hipersensibilidad Inmediata/inducido químicamente , Hipersensibilidad Inmediata/inmunología , Interferón beta/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Urticaria/inducido químicamente , Urticaria/inmunología , Adulto , Antialérgicos/farmacología , Difenhidramina/farmacología , Hipersensibilidad a las Drogas/fisiopatología , Femenino , Humanos , Hipersensibilidad Inmediata/fisiopatología , Interferón beta-1a , Interferon beta-1b , Urticaria/fisiopatologíaRESUMEN
Cytokines play an important role in modulating inflammatory responses and, as a result, airway tone. IL-10 is a regulatory cytokine that has been suggested for treatment of asthma because of its immunosuppressive and anti-inflammatory properties. In contrast to these suggestions, we demonstrate in a model of allergic sensitization that mice deficient in IL-10 (IL-10-/-) develop a pulmonary inflammatory response but fail to exhibit airway hyperresponsiveness in both in vitro and in vivo assessments of lung function. Reconstitution of these deficient mice with the IL-10 gene fully restores development of airway hyperresponsiveness comparable to control mice. These results identify an important role of IL-10, downstream of the inflammatory cascade, in regulating the tone of the airways after allergic sensitization and challenge.
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Hiperreactividad Bronquial/fisiopatología , Interleucina-10/fisiología , Hipersensibilidad Respiratoria/fisiopatología , Ribonucleasas , Aerosoles , Animales , Proteínas Sanguíneas/análisis , Pruebas de Provocación Bronquial , Líquido del Lavado Bronquioalveolar/química , Citocinas/análisis , Estimulación Eléctrica , Proteínas en los Gránulos del Eosinófilo , Peroxidasa del Eosinófilo , Eosinofilia/etiología , Eosinofilia/fisiopatología , Femenino , Prueba de Complementación Genética , Terapia Genética , Inmunización , Inflamación/fisiopatología , Interleucina-10/deficiencia , Interleucina-10/genética , Leucotrienos/análisis , Pulmón/química , Pulmón/patología , Masculino , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso/fisiopatología , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Peroxidasas/análisis , Organismos Libres de Patógenos Específicos , Tráquea/fisiopatologíaRESUMEN
The present study extends prior work on the association between allergic rhinitis (AR) and common mental disorders by testing three related hypotheses: 1) that AR is associated with increased rates of depression and anxiety disorders in a large insured population, 2) comorbid AR, depression, and anxiety are associated with increased health and mental health expenditures, and 3) allergy treatment moderates the association between increased expenditures and comorbid AR, depression, and anxiety. Data are from MARKETSCAN, a large health care claims database of over 600,000 privately insured persons. Results indicate that AR is associated with higher rates of depression and anxiety disorder. Outpatient health care expenditures were increased by an average annual amount of $207 when AR and anxiety disorder were comorbid and $363 when AR and depression were comorbid. Finally, prescription treatment of AR moderated the increased expenditures associated with comorbidity.
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Trastornos de Ansiedad/economía , Trastorno Depresivo/economía , Rinitis Alérgica Perenne/economía , Rinitis Alérgica Estacional/economía , Adolescente , Adulto , Anciano , Trastornos de Ansiedad/tratamiento farmacológico , Trastornos de Ansiedad/epidemiología , Niño , Preescolar , Comorbilidad , Trastorno Depresivo/tratamiento farmacológico , Trastorno Depresivo/epidemiología , Costos de los Medicamentos/estadística & datos numéricos , Femenino , Gastos en Salud/estadística & datos numéricos , Humanos , Lactante , Revisión de Utilización de Seguros/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Rinitis Alérgica Perenne/tratamiento farmacológico , Rinitis Alérgica Perenne/epidemiología , Rinitis Alérgica Estacional/tratamiento farmacológico , Rinitis Alérgica Estacional/epidemiología , Estados Unidos/epidemiologíaRESUMEN
UNLABELLED: Interleukin-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, expression of VCAM-1 on endothelium, mucin production, 15-lipoxygenase activity, and Th2 lymphocyte stimulation leading to the secondary synthesis of IL-4, IL-5, and IL-13. Soluble recombinant human IL-4 receptor (IL-4R; Nuvance; altrakincept) inactivates naturally occurring IL-4 without mediating cellular activation. Nebulized IL-4R has a serum half-life of approximately 1 wk. In this double-blind, placebo-controlled trial, 25 patients with moderate asthma requiring inhaled corticosteroids were randomly assigned to receive a single nebulized dose of IL-4R 1,500 microg, IL-4R 500 microg, or placebo after stopping inhaled corticosteroids. No drug-related toxicity was observed. Treatment with IL-4R produced significant improvement in FEV(1) on Day 4 (1,500 microg versus placebo; p < 0.05) and in FEF(25-75) on Days 2 and 4 (1,500 microg versus placebo; p < 0.05). Asthma symptom scores stabilized among patients treated with IL-4R 1, 500 microg, despite abrupt withdrawal of corticosteroids, but not in the IL-4R 500 microg group or the placebo group (p < 0.05). Patients in the IL-4R 1,500 microg group also required significantly less beta(2)-agonist rescue use (p < 0.05). Anti-inflammatory effects were further demonstrated by significantly reduced exhaled nitric oxide (p < 0.05). CONCLUSIONS: A single dose of IL-4R appears safe and effective in moderate asthma. The 1,500 microg dose appears as safe but significantly more effective than the 500 microg dose.
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Asma/tratamiento farmacológico , Hipersensibilidad Inmediata/complicaciones , Receptores de Interleucina-4/administración & dosificación , Administración por Inhalación , Adulto , Anciano , Asma/inmunología , Asma/fisiopatología , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Inmunoglobulina E/sangre , Molécula 1 de Adhesión Intercelular/sangre , Masculino , Flujo Espiratorio Medio Máximo , Persona de Mediana Edad , Nebulizadores y Vaporizadores , Ápice del Flujo Espiratorio , Calidad de Vida , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/efectos adversos , Molécula 1 de Adhesión Celular Vascular/sangreAsunto(s)
Antagonistas de Leucotrieno/uso terapéutico , Urticaria/tratamiento farmacológico , Acetatos/administración & dosificación , Acetatos/uso terapéutico , Adolescente , Adulto , Niño , Enfermedad Crónica , Ciclopropanos , Evaluación de Medicamentos , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Estudios de Seguimiento , Antagonistas de los Receptores Histamínicos H1/administración & dosificación , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Indoles , Antagonistas de Leucotrieno/administración & dosificación , Masculino , Persona de Mediana Edad , Fenilcarbamatos , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Sulfuros , Sulfonamidas , Compuestos de Tosilo/administración & dosificación , Compuestos de Tosilo/uso terapéutico , Resultado del Tratamiento , Urticaria/epidemiologíaRESUMEN
Recent family-based studies have revealed evidence for linkage of human chromosome 5q31 to the diagnosis of asthma, elevated serum IgE levels, and bronchial hyperresponsiveness. Among the candidate genes in this region is the gene encoding for human interleukin-4 (IL-4). We reasoned that this gene could also serve as a candidate gene with respect to asthma severity as indicated by the FEV(1) measured when bronchodilator treatment was withheld. To test this hypothesis, we examined a large population of patients with asthma (ascertained without respect to genetic characteristics), for associations between a genetic variant in the IL-4 promoter region (C-589T) and asthma severity, as indicated by FEV(1). We used amplification by the polymerase chain reaction followed by BsmF1 restriction digestion to assign genotypes at the IL-4 promoter C-589T locus. We compared genotypes at this locus in 772 Caucasian and African American patients with asthma of varying severity, and we used multiple regression analysis to relate genotypic findings to FEV(1). Among white individuals, the homozygous presence of the C-589T IL-4 promoter genotype (TT) was associated with a FEV(1) below 50% of predicted (p = 0.013; OR, 1.44; 95% CI: 1.09 to 1.90). Subjects with the TT genotype had mean FEV(1) (% predicted) values 4.5% lower than those of subjects with the wild-type (CC) genotype at this locus. FEV(1) values of white patients with a CC or CT genotype were broadly distributed, whereas the TT genotype was associated with a narrow distribution of low FEV(1) values. The frequency of the T allele was significantly greater (p = 1 x 10(-)(23)) among African American asthmatics (0.544) than among white asthmatics (0.183). These data provide the first evidence associating FEV(1) in patients with asthma and genetic determinants at any locus. Our data are consistent with the idea that the FEV(1) in asthma is the result of multiple factors; one of these factors is the genotype at the IL-4 C-589T locus. This locus is associated with a small but significant decrement in pulmonary function among white asthmatic subjects.
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Asma/genética , Volumen Espiratorio Forzado , Genes/genética , Interleucina-4/genética , Adulto , Alelos , Asma/sangre , Asma/fisiopatología , Estudios de Cohortes , Interpretación Estadística de Datos , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Inmunoglobulina E/sangre , Masculino , Reacción en Cadena de la Polimerasa , Regiones Promotoras Genéticas/genéticaRESUMEN
LEARNING OBJECTIVES: This article summarizes the latest information regarding the role of genetic influences in the development of allergic disorders and asthma and reviews our current information on some of the most likely genes responsible for these conditions. After reading this article, the reader will have a better understanding of the current molecular biologic techniques that are being used to understand complex genetic disorders such as allergies and asthma. The reader should understand the value of how this genetic insight will lead to the recognition of the presence of specific subtypes of these disorders that require unique therapeutic interventions. This information can also be used to identify genetically at risk children and thereby offer earlier intervention. Finally, understanding the genetic causes of allergies and asthma will lead to the development of the next--hopefully curative--generation of asthma and allergy therapeutics. DATA SOURCES: A detailed literature search was conducted. Studies considered relevant, well performed, and appropriately controlled were used. Only human studies are included and only the English language literature was reviewed. Some of the information presented is based on the author's own research experience. STUDY SELECTION: Material was only taken from peer-reviewed journals and appropriate reviews. RESULTS AND CONCLUSIONS: Asthma and allergic diseases are examples of disorders having an unmistakable genetic predisposition, but in the absence of a classic Mendelian inheritance pattern. These "complex" genetic disorders are caused by the interactions of multiple interacting genes some having protective value and some contributing to disease development and with each gene having its own variable tendency to be expressed. In addition, these disorders require the presence of appropriate environmental triggers for their expression. One approach to identifying the genetic basis for these conditions is to perform a genome-wide search in which the location of the disease-causing gene on a human chromosome is identified and nearby genes that may be responsible are subsequently identified. An alternative approach to identifying heritable components to asthma and allergy is to evaluate disordered structure or regulation within genes known to be involved in these disorders. Using these approaches, studies have suggested that genes within the cytokine gene cluster on chromosome 5 (including interleukins-3, -4, -5, -9, and -13), chromosome 11 (the beta chain of the high affinity IgE receptor), chromosome 16 (the IL-4 receptor), and chromosome 12 (stem cell factor, interferon-gamma, insulin growth factor, and Stat 6 [IL-4 Stat]) may contribute to asthma and allergy development. In addition, data support involvement of genes involved in antigen-presentation (MHC class II genes) and T cell responses (the T cell receptor alpha chain). Finally, disease-contributing alleles may be present on genes for the beta-adrenergic receptor, 5-lipoxygenase, and leukotriene C4 synthase.
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Asma/genética , Hipersensibilidad/genética , Presentación de Antígeno/genética , Predisposición Genética a la Enfermedad , HumanosRESUMEN
Interleukin-10 (IL-10) and transforming growth factor beta (TGF-beta) are inhibitory for B and T cells, IgE production, and mast cell proliferation, and they induce apoptosis in eosinophils. These cytokines are therefore candidate genes which could contribute to the development of asthma or allergies. We investigated the hypothesis that polymorphic nucleotides within the IL-10 and TGF-beta gene promoters would link to the expression of allergies and asthma. DNA taken from families with an asthmatic proband was examined for base exchanges by single-stranded conformational polymorphism (SSCP). We demonstrated the presence of a polymorphism in the promoter region of the IL-10 gene and four in the TGF-beta gene promoters (3 in TGF-beta1 and 1 in TGF-beta2). The IL-10 gene polymorphism was a C-to-A exchange 571 base pairs upstream from the translation start site and was present between consensus binding sequences for Sp1 and elevated total serum. This polymorphism was associated with elevated total serum IgE in subjects heterozygotic or homozygotic for this base exchange (p < 0.009). The base exchange at -509 (from the transcription initiation site) in the TGF-beta promoter also linked to elevated total IgE (p < 0.01). This polymorphism represented a C-to-T base exchange which induced a YY1 consensus sequence and is present in a region of the promoter associated with negative transcription regulation.
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Asma/genética , Hipersensibilidad/genética , Interleucina-10/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Factor de Crecimiento Transformador beta/genética , Adenina , Apoptosis , Linfocitos B/inmunología , Emparejamiento Base , Secuencia de Bases , División Celular , Niño , Preescolar , Secuencia de Consenso , Citosina , Eosinófilos/inmunología , Eosinófilos/patología , Regulación de la Expresión Génica , Humanos , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Mastocitos/inmunología , Mastocitos/patología , Polimorfismo Conformacional Retorcido-Simple , Biosíntesis de Proteínas , Factor de Transcripción Sp1/genética , Linfocitos T/inmunología , TiminaRESUMEN
BACKGROUND: We investigated a role for allergic inflammation and psychologic parameters in the development of chronic fatigue syndrome (CFS). METHODS: The design was a comparison between subjects with CFS and age- and sex-matched control cohorts. Studies were performed on CFS subjects (n = 18) and control cohorts consisting of normal subjects (n = 11), allergic subjects (n = 14), and individuals with primary depression (n = 12). We quantified cytokines at baseline as cell-associated immunoreactive peptides and as transcripts evaluated by means of semiquantitative RNA-based polymerase chain reactions. Psychologic evaluations included administration of the Diagnostic Interview Schedule, the Structured Clinical Interview, and the Symptom Checklist 90-Revised. RESULTS: Increases in tumor necrosis factor (TNF)-alpha were identified in individual subjects with CFS (50.1 +/- 14.4 pg TNF-alpha per 10(7) peripheral blood mononuclear cells [PBMCs]; mean +/- SEM) and allergic subjects (41.6 +/- 7.6) in comparison with normal subjects (13.1 +/- 8.8) (P < .01 and P < .05, respectively). Similar trends were observed for interferon (IFN)-alpha in allergic subjects (3.0 +/- 1.7 pg/10(7) PBMCs) and subjects with CFS (6.4 +/- 3.4) compared with normal subjects (1.9 +/- 1.4). A significant increase (P < .05) in TNF-alpha transcripts was demonstrated between subjects with CFS and depressed subjects. In contrast to these proinflammatory cytokines, both subjects with CFS (2.6 +/- 1.8 pg/10(7) PBMCs) and allergic subjects (3.4 +/- 2.8) were associated with a statistically significant (P < .01) decrease in IL-10 concentrations compared with normal subjects (60.2 +/- 18.2). As shown in other studies, most of our subjects with CFS were allergic (15 of 18) and therefore presumably demonstrated cytokine gene activation on that basis. The seasonal exacerbation of allergy was associated with a further increase in cellular IFN-alpha (from 2.1 +/- 1.2 to 14.2 +/- 4.5 pg/107 PBMCs; P < .05) but no further modulation of TNF-alpha or IL-10. Similarly, self-reported exacerbations of CFS were associated with a further increase in IFN-alpha (from 2.5 +/- 1.0 to 21.9 +/- 7.8; P < .05) and occurred at times of seasonal exposures to allergens. This linkage does not permit making any definitive conclusions regarding a causative influence of either seasonal allergies or the increase in cellular IFN-alpha with the increase in CFS symptoms. The close association between atopy and CFS led us to speculate that CFS may arise from an abnormal psychologic response to the disordered expression of these proinflammatory and antiinflammatory cytokines. Psychologic variables were predictive of immune status within the CFS sample (65.9% of the variance in immune status; F (3,10) = 6.44, P < .05). Specifically, the absence of a personality disorder but greater endorsement of global psychiatric symptoms was predictive of immune activation. CONCLUSIONS: Most of our subjects with CFS were allergic, and the CFS and allergy cohorts were similar in terms of their immune status. However, the CFS subjects could be discriminated by the distinct psychologic profiles among subjects with and without immune activation. We propose that in at least a large subgroup of subjects with CFS who had allergies, the concomitant influences of immune activation brought on by allergic inflammation in an individual with the appropriate psychologic profile may interact to produce the symptoms of CFS. In a psychologically predisposed individual, symptoms associated with allergic inflammation are recognized as illness.