RESUMEN
Carbons are ubiquitous electrocatalytic supports for various energy-related transformations, especially in fuel cells. Doped carbons such as Fe-N-C materials are particularly active towards the oxidation of hydrazine, an alternative fuel and hydrogen carrier. However, there is little discussion of the electrocatalytic role of the most abundant component - the carbon matrix - towards the hydrazine oxidation reaction (HzOR). We present a systematic investigation of undoped graphitic carbons towards the HzOR in alkaline electrolyte. Using highly oriented pyrolytic graphite electrodes, as well as graphite powders enriched in either basal planes or edge defects, we demonstrate that edge defects are the most active catalytic sites during hydrazine oxidation electrocatalysis. Theoretical DFT calculations support and explain the mechanism of HzOR on carbon edges, identifying unsaturated graphene armchair defects as the most likely active sites. Finally, these findings explain the 'double peak' voltammetric feature observed on many doped carbons during the HzOR.
RESUMEN
Fe-N-C electrocatalysts hold a great promise for Pt-free energy conversion, driving the electrocatalysis of oxygen reduction and evolution, oxidation of nitrogen fuels, and reduction of N2, CO2, and NOx. Nevertheless, the catalytic role of iron carbide, a component of nearly every pyrolytic Fe-N-C material, is at the focus of a heated controversy. We now resolve the debate by examining a broad range of Fe3C sites, spanning across many typical size distributions and carbon environments. Removing Fe3C selectively by a non-oxidizing acid reveals its inactivity towards two representative reactions in alkaline media, oxygen reduction and hydrazine oxidation. The activity is assigned to other pre-existing sites, most probably Fe-Nx. DFT calculations prove that the Fe3C surface binds O and N intermediates too strongly to be catalytic. By settling the argument on the catalytic role of Fe3C in alkaline electrocatalysis, we hope to spur innovation in this critical field.
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Porous carbon materials attract great interest in a wide range of applications such as batteries, fuel cells, and membranes, due to their large surface area, structural and compositional tunability, and chemical stability. While micropores are typically obtained when preparing carbon materials by pyrolysis, the fabrication of mesoporous, and especially macroporous carbons is more challenging, yet important for enhancing mass transport. Herein, template-free regular macroporous carbons are prepared from a mixture of unfolded (linear) and folded (single-chain nanoparticles, SCNP) polyvinylpyrrolidone chains. While having the same chemical composition, the different molecular architectures lead to phase separation even before pyrolysis, creating a dense cell architecture, which is retained upon carbonization. Upon increasing the SCNP content, the homogeneity of the pore network increases and the specific surface area is enlarged 3-5-fold, until ideal properties are obtained at 75% SCNP, as observed by high-resolution scanning electron microscopy and N2 physisorption porosimetry. The materials are further investigated as hydrazine oxidation electrocatalysts, demonstrating the link between the evolving morphology and current density. Importantly, this study demonstrates the role of polymer architecture in macroporosity templating in carbon materials, providing a new approach to develop complex carbon architectures without the need for external templating.
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We report an efficient electrocatalyst for the oxidation of hydrazine, a promising fuel for fuel cells and an important analyte for health and environmental monitoring. To design this material, we emulated natural nitrogen-cycle enzymes, focusing on designing a cooperative, multi-doped active site. The catalytic oxidation occurs on Fe2 MoC nanoparticles and on edge-positioned nitrogen dopants, all well-dispersed on a hierarchically porous, graphitic carbon matrix that provides active site exposure to mass-transfer and charge flow. The new catalyst is the first carbide with HzOR activity. It operates at the most negative onset potentials reported for carbon-based HzOR catalysts at pHâ 14 (0.28â V vs. RHE), and has good-to-excellent activity at pH values down to 0. It shows high faradaic efficiency for oxidation to N2 (3.6 e- /N2 H4 ), and is perfectly stable for at least 2000 cycles.
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Although HLA alleles are associated with type 1 diabetes, association with microvascular complications remains controversial. We tested HLA association with complications in multiplex type 1 diabetes families. Probands from 425 type 1 diabetes families from the Human Biological Data Interchange (HBDI) collection were analyzed. The frequencies of specific HLA alleles in patients with complications were compared with the frequencies in complications-free patients. The complications we examined were: retinopathy, neuropathy, and nephropathy. We used logistic regression models with covariates to estimate odds ratios. We found that the DRB1*03:01 allele is a protective factor for complications (OR=0.58; p=0.03), as is the DQA1*05:01-DQB1*02:01 haplotype found in linkage disequilibrium with DRB1*03:01 (OR=0.59; p=0.031). The DRB1*04:01 allele showed no evidence of association (OR=1.13; p=0.624), although DRB1*04:01 showed suggestive evidence when the carriers of the protective DRB1*03:01 were removed from the analysis. The class II DQA1*03:01-DQB1*03:02 haplotype was not associated with complications, but the class I allele B*39:06 (OR=3.27; p=0.008) suggested a strong positive association with complications. Our results show that in type 1 diabetes patients, specific HLA alleles may be involved in susceptibility to, or protection from, microvascular complications.
Asunto(s)
Diabetes Mellitus Tipo 1/genética , Nefropatías Diabéticas/genética , Neuropatías Diabéticas/genética , Retinopatía Diabética/genética , Predisposición Genética a la Enfermedad/genética , Antígenos HLA/genética , Alelos , Diabetes Mellitus Tipo 1/complicaciones , Nefropatías Diabéticas/etiología , Neuropatías Diabéticas/etiología , Retinopatía Diabética/etiología , Femenino , Frecuencia de los Genes , Genotipo , Antígenos HLA/clasificación , Antígenos HLA-B/genética , Cadenas alfa de HLA-DQ/genética , Cadenas HLA-DRB1/genética , Haplotipos , Humanos , Modelos Logísticos , Masculino , Oportunidad RelativaRESUMEN
Autoimmune thyroid diseases (AITD) are postulated to develop as a result of a complex interplay between several genetic and environmental influences. The pathogenesis of AITD is still not clearly defined. However, among the implicated triggers (e.g. iodine, infections, medications), more recent data confirmed strong associations of AITD with the hepatitis C virus (HCV) infection and interferon-α (IFNα) therapy. Moreover, it is likely that HCV and IFN act in synergism to trigger AITD in patients. Indeed, approximately 40% of HCV patients develop either clinical or subclinical disease while receiving IFNα. Interferon induced thyroiditis (IIT) can manifest as non-autoimmune thyroiditis (presenting as destructive thyroiditis, or non-autoimmune hypothyroidism), or autoimmune thyroiditis [presenting with clinical features of Graves' disease (GD) or Hashimoto's thyroiditis (HT)]. Although not yet clearly understood, it is thought that IFNα can induce thyroiditis via both immune stimulatory and direct toxic effects on the thyroid. In view of the high frequency of IIT, routine screening and surveillance of HCV patients receiving IFNα is recommended to avoid the complications, such as cardiac arrhythmias, associated with thyrotoxicosis. In summary, IIT is a common clinical problem that can be readily diagnosed with routine thyroid function screening of HCV patients receiving IFN. The treatment of IIT consists of the standard therapy for differing clinical manifestations of IIT such as GD, HT, or destructive thyroiditis. However, anti-thyroid medications are not recommended in this setting since they can potentially be hepatotoxic.
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Ambiente , Hepatitis C/complicaciones , Interferón-alfa/fisiología , Tiroiditis/etiología , Animales , Predisposición Genética a la Enfermedad , Hepatitis C/genética , Humanos , Interferón-alfa/efectos adversos , Modelos Biológicos , Tiroiditis/diagnóstico , Tiroiditis/genética , Tiroiditis/terapiaRESUMEN
This work was designed to study the role of surfactant protein D in the regulation of NO synthesis by "non-alveolar" microphages. We evaluated whether the effects of surfactant protein D depend on the phenotype of macrophages. In the absence of surfactant protein D, the LPS-induced iNOS response was shown to decrease in macrophages of native and proinflammatory phenotypes by 30%, and in macrophages of the antiinflammatory phenotype (by 63%). Under the influence of lipopolysaccharide in high doses (500 ng/ml), NO(2)*- production by mouse macrophages without surfactant protein D was reduced in native cells (by 25%), but increased in proinflammatory (by 40%) and antiinflammatory phenotypes (by 12% compared to mouse macrophages with surfactant protein D). Our results suggest that surfactant protein D is involved in the immune response in the whole organism, but not only in the lungs. The effect of surfactant protein D depends on the phenotype of macrophages.
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Lipopolisacáridos/toxicidad , Macrófagos/efectos de los fármacos , Macrófagos/fisiología , Óxido Nítrico/metabolismo , Cavidad Peritoneal/fisiopatología , Proteína D Asociada a Surfactante Pulmonar/metabolismo , Animales , Células Cultivadas , Citocinas/metabolismo , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Cavidad Peritoneal/citología , Proteína D Asociada a Surfactante Pulmonar/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de TiempoRESUMEN
Previously, we and others have demonstrated the association of a C/T single nucleotide polymorphism (SNP), in the Kozak sequence of CD40, with Graves' disease (GD). Here, using an expanded data set of patients, we confirm the association of the CD40 SNP with GD (n=210, P=0.002, odds ratio (OR)=1.8). Subset analysis of patients with persistently elevated thyroid peroxidase (TPO) and/or thyroglobulin (Tg) antibodies (Abs), (TPO/Tg Abs), after treatment (n=126), revealed a significantly stronger association of the SNP with disease (P=5.2 x 10(-5), OR=2.5) than in GD patients who were thyroid antibody-negative. However, the CD40 SNP was not associated with TPO/Tg Abs in healthy individuals. Next, we tested the CD40 SNP for association with Myasthenia Gravis (MG), which, like GD is an antibody-mediated autoimmune condition. Analysis of 81 MG patients found no association of the SNP with disease. Functional studies revealed significant expression of CD40 mRNA and protein in the thyroid (target tissue in GD) but not in skeletal muscle (target tissue in MG). Combined, our genetic and tissue expression data suggest that the CD40 Kozak SNP is specific for thyroid antibody production involved in the etiology of GD. Increased thyroidal expression of CD40 driven by the SNP may contribute to this disease specificity.
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Antígenos CD40/genética , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Polimorfismo de Nucleótido Simple , Regiones no Traducidas 5' , Adolescente , Adulto , Anciano , Autoanticuerpos/sangre , Autoantígenos/inmunología , Secuencia de Bases , Estudios de Casos y Controles , Cartilla de ADN/genética , Femenino , Expresión Génica , Humanos , Yoduro Peroxidasa/inmunología , Proteínas de Unión a Hierro/inmunología , Masculino , Persona de Mediana Edad , Modelos Inmunológicos , Miastenia Gravis/genética , Miastenia Gravis/inmunología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Distribución TisularRESUMEN
Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR beta1 chain conferring susceptibility to GD is unknown. Therefore, the aim of our study was to identify the critical sequence among the HLA-DRB1 amino-acid residues occupying the peptide-binding pocket, which conferred susceptibility to GD. We sequenced the HLA-DRB1 locus in 208 Caucasian GD patients and 149 Caucasian controls. Sequence analysis showed an increased frequency of DR beta-Arg-74 in GD patients compared to controls (41.8 and 13.4%, respectively; P=2.3 x 10(-8), OR=4.6). Moreover, subset analyses showed that DR beta-Arg-74 was also significantly more frequent in the HLA-DR3 negative GD patients than in controls (7.6 vs 0.8%, P=0.02, OR=10.5), suggesting that the association with DR beta-Arg-74 is independent of the association with HLA-DR3. Structural modeling studies demonstrated that the change at position 74 from the neutral amino acids Ala or Gln to the positively charged amino-acid Arg significantly modifies the three-dimensional structure of the DR peptide-binding pocket. Our results suggested that structural heterogeneity of the DR beta-chain peptide-binding pocket P4 at residue 74 predispose some at risk individuals to GD.
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Alelos , Arginina/genética , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Antígenos HLA-DR/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Arginina/química , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Enfermedad de Graves/epidemiología , Cadenas HLA-DRB1 , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Población BlancaRESUMEN
The cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) gene on 2q33 is associated with autoimmune thyroid diseases (AITDs). Our earlier study in 56 families showed linkage of 2q33 to the presence of thyroid antibodies (TAbs). The goals of this study were to confirm the linkage of the 2q33 region to TAbs, to fine map this region, and study the ICOS gene. We performed a linkage study in an expanded data set of 99 multiplex AITD-TAb families (529 individuals). The highest two-point LOD score of 2.9 was obtained for marker D2S325 on 2q33. To fine map this locus, we genotyped 238 Caucasian AITD patients and 137 controls for five additional markers in the linked locus, which contained the CTLA-4, CD28, and ICOS genes. The A/G single-nucleotide polymorphism at position 49 of CTLA-4 was associated with AITD (P=0.01, OR=1.5), while markers inside CD28 and ICOS were not. Functional studies have shown that the G allele was associated with reduced inhibition of T-cell proliferation by CTLA-4. We concluded that: (1) the AITD gene in the 2q33 locus is the CTLA-4 gene and not the CD28 or ICOS genes; and (2) the G allele is associated with decreased function of CTLA-4.
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Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación/genética , Antígenos CD28/genética , Cromosomas Humanos Par 2/genética , Tiroiditis Autoinmune/genética , Alelos , Antígenos CD , Antígeno CTLA-4 , Mapeo Cromosómico , Femenino , Genotipo , Humanos , Proteína Coestimuladora de Linfocitos T Inducibles , Funciones de Verosimilitud , Escala de Lod , Masculino , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido Simple/genética , Linfocitos T/inmunología , Tiroiditis Autoinmune/inmunología , Población BlancaRESUMEN
There is abundant evidence for a genetic influence on the development of autoimmune thyroid diseases (AITD). One measure of the magnitude of genetic contribution to the development of a disease is the sibling risk ratio (lambda(s)). Recent accurate prevalence data for hypothyroidism and hyperthyroidism in the United States reported from the National Health and Nutrition Examination Survey III (NHANES III) study have now allowed us to compute the sibling recurrence risk for AITD. Patients were recruited from our endocrine clinic on the basis of having AITD. The inclusion of patients in this study was unambiguously single ascertainment. We studied 155 patients (131 with Graves' disease [GD] and 24 with Hashimoto's thyroiditis [HT]) who had reliable information on the presence or absence of AITD in siblings. Nine probands had siblings with GD and 13 probands had siblings with HT. Using the prevalence rates from NHANES III for clinical hyperthyroidism and hypothyroidism, the calculated lambda(s) was 16.9 for AITD, 11.6 for GD, and 28.0 for HT. These results confirm the significant contribution of genetic factors to the development of AITD.
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Hermanos , Tiroiditis Autoinmune/epidemiología , Tiroiditis Autoinmune/genética , Enfermedad de Graves/epidemiología , Enfermedad de Graves/genética , Humanos , Hipertiroidismo/epidemiología , Hipertiroidismo/genética , Hipotiroidismo/epidemiología , Hipotiroidismo/genética , Prevalencia , Factores de RiesgoRESUMEN
AIM: To understand the modern approach to finding the genes responsible for complex diseases when compared to simple Mendelian inheritance. To define the autoimmune thyroid diseases as we now understand them and introduce the concept of disease heterogeneity. To review the evidence for a genetic contribution to autoimmune thyroid disease as opposed to environmental factors and to be aware of new information generated from recent studies concerning the role of HLA, immune modulators, and new loci of interest providing susceptibility to the autoimmune thyroid diseases.
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Enfermedades Autoinmunes/genética , Enfermedades de la Tiroides/genética , Enfermedades de la Tiroides/inmunología , Ligamiento Genético , Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Enfermedad de Graves/inmunología , Antígenos HLA/genética , Humanos , Tiroiditis Autoinmune/genéticaRESUMEN
OBJECTIVES: The autoimmune thyroid diseases (AITDs) comprising Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases, which result from an interaction between predisposing genes and environmental triggers. The aim of our study was to dissect the genetic predisposition to GD and HT in one large Chinese family with multiple members affected with AITD. PATIENTS: We completed a whole genome screen of a large multiplex Chinese-American family. We enrolled 27 family members from three generations. Eight members were affected with AITD, six had GD and two had HT. DESIGN: We determined the information limits of the family. Power calculations indicated that the maximum attainable LOD scores were 5.1 assuming dominant inheritance, and 3.4 assuming recessive inheritance. These estimates both assumed 100% penetrance and one gene. Whole genome screening was performed using 400 highly polymorphic and densely spaced microsatellite markers spanning the entire human genome (intermarker distance < 10 cM). Linkage analysis was performed using two-point and multipoint parametric and nonparametric methods. RESULTS: Initial whole genome screening performed with 400 microsatellite markers identified two markers that showed evidence for linkage to AITD in this family, D11S4191 and D9S175, with two-point LOD scores of 2.31 and 2.05, respectively. Multipoint linkage analysis focusing on the regions containing these markers revealed a maximum multipoint LOD score (MLS) of 2.13 and a nonparametric linkage score (NPL) of 6.1 for D11S4191 and an MLS of 2.01 and NPL of 7.5 for D9S175. CONCLUSIONS: These results showed that this Chinese family harboured susceptibility loci for AITD which were distinct from those previously found in the Caucasian population. This suggests that different susceptibility loci exist between different ethnic groups. Furthermore, even within a single family from a genetically homogenous population, more than one gene was involved in the genetic susceptibility to AITD, supporting the notion that AITDs are caused by multiple genes of varying influences.
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Predisposición Genética a la Enfermedad , Enfermedad de Graves/genética , Tiroiditis Autoinmune/genética , Adolescente , Adulto , China/etnología , Femenino , Ligamiento Genético , Enfermedad de Graves/etnología , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Tiroiditis Autoinmune/etnología , Estados UnidosRESUMEN
Interleukin (IL)-9 is a T helper (Th) 2 cytokine recently implicated as an essential factor in determining susceptibility to asthma. Transgenic mice overexpressing IL-9 exhibit many features that are characteristic of human asthma. To better understand the mechanism by which IL-9 mediates the various biologic activities in asthma, we performed suppressive subtraction hybridization with whole lung from IL-9 transgenic and control mice. Here we report the identification of mCLCA3, a calcium-activated chloride channel that was specifically induced in the lung epithelium of IL-9 transgenic mice. Expression of mCLCA3 could also be induced by intratracheal administration of IL-9 or other Th2 cytokines (IL-4, IL-13), but not by interferon-gamma. Moreover, expression of mCLCA3 was induced in the lung of antigen-exposed mice, and this induction could be suppressed by neutralizing IL-9 antibody treatment, indicating IL-9 is both necessary and sufficient to induce mCLCA3 in this experimental model of asthma. Finally, we demonstrate that hCLCA1 is the human counterpart to mCLCA3 and is also induced in vitro in human primary lung cells by Th2 cytokine treatment. Together, these data strongly implicate the involvement of mCLCA3 (in mice) and hCLCA1 (in humans) in the pathogenesis of Th2 cytokine-mediated asthmatic disorders.
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Asma/metabolismo , Canales de Cloruro/metabolismo , Citocinas/metabolismo , Interleucina-9/genética , Mucoproteínas/metabolismo , Células Th2/metabolismo , Secuencia de Aminoácidos , Animales , Anticuerpos Monoclonales/farmacología , Canales de Cloruro/genética , Clonación Molecular , Humanos , Hibridación in Situ/métodos , Interleucina-9/inmunología , Interleucina-9/metabolismo , Pulmón/fisiología , Ratones , Ratones Endogámicos , Ratones Transgénicos , Datos de Secuencia Molecular , Mucoproteínas/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Mucosa Respiratoria/fisiología , Transducción de SeñalRESUMEN
BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA4) has been shown to play a critical role in the down-regulation of the immune response. We retrospectively examined the association between acute rejection and two polymorphisms in the CTLA4 gene, the dinucleotide (AT)n repeat polymorphism in exon 3 and the single nucleotide polymorphism A/G at position 49 in exon 1, in a cohort of liver and kidney transplant recipients. METHODS AND RESULTS: A total of 207 liver and 167 renal transplant recipients were analyzed. In the case of the (AT)n repeat polymorphism we found an increased incidence of acute rejection in association with allele 3 and 4 in both liver and kidney (P=0.002 and 0.05, respectively). In addition, in liver transplant recipients, allele 7 was associated with acute rejection independent of ethnicity (P<0.05). Allele 1 was less frequently observed in African American as compared with Caucasian liver and kidney transplant recipients, with a frequency of 33.8% and 69%, respectively (P<0.0001). Those patients with allele 1 had a tendency toward a lower rate of rejection at 42% versus 57.8% (P=0.058), suggesting a potential protective effect of allele 1. Analysis of the A/G single nucleotide polymorphism demonstrated no association between either allele and the incidence of acute rejection in the patients studied. CONCLUSION: These initial observations provide the necessary basis to further investigate the risk stratification of transplant recipients based on specific CTLA4 gene polymorphisms.
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Antígenos de Diferenciación/genética , Rechazo de Injerto/genética , Rechazo de Injerto/inmunología , Inmunoconjugados , Polimorfismo Genético , Abatacept , Enfermedad Aguda , Alelos , Antígenos CD , Antígeno CTLA-4 , Estudios de Casos y Controles , Estudios de Cohortes , Repeticiones de Dinucleótido , Etnicidad/genética , Exones , Femenino , Genotipo , Rechazo de Injerto/etiología , Humanos , Trasplante de Riñón/efectos adversos , Trasplante de Riñón/inmunología , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/inmunología , Masculino , Polimorfismo de Nucleótido SimpleRESUMEN
The differential regulation of pulmonary surfactant proteins (SPs) is demonstrated in a murine model of Aspergillus fumigatus (Af )-induced allergic airway inflammation and hyperresponsiveness. BALB/c mice were sensitized intraperitoneally and challenged intranasally with Af extract. Enzyme-linked immunosorbent assay analysis of serum immunoglobulin (Ig) levels in these mice showed markedly increased total IgE and Af-specific IgE and IgG1. This was associated with peribronchial/perivascular tissue inflammation, airway eosinophilia, and secretion of interleukin (IL)-4 and IL-5 into the bronchoalveolar lavage fluid (BALF). Functional analysis revealed that in comparison with nonsensitized mice, allergic sensitization and challenge resulted in significant increases in acetylcholine responsiveness. To analyze levels of SPs, the cell-free supernate of the BALF was further fractionated by high-speed (20,000 x g) centrifugation. After sensitization and challenges, the pellet (large-aggregate fraction) showed a selective downregulation of hydrophobic SPs SP-B and SP-C by 50%. This reduction was reflected by commensurate decreases in SP-B and SP-C messenger RNA (mRNA) expression of the lung tissue of these animals. In contrast, there was a 9-fold increase in SP-D protein levels in the 20,000 x g supernate without changes in SP-D mRNA. The increased levels of SP-D showed a significant positive correlation with serum IgE (r = 0.85, P < 0.001). Tissue mRNA and protein levels of SP-A in either the large- or the small-aggregate fractions were unaffected. Our data indicate that allergic airway inflammation induces selective inhibition of hydrophobic SP synthesis accompanied by marked increases in the lung collectin SP-D protein content of BALF. These changes may contribute significantly to the pathophysiology of Af-induced allergic airway hyperresponsiveness.
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Aspergillus fumigatus/fisiología , Bronquitis/microbiología , Homeostasis , Hipersensibilidad/microbiología , Surfactantes Pulmonares/metabolismo , Animales , Antígenos Fúngicos/inmunología , Aspergillus fumigatus/inmunología , Líquido del Lavado Bronquioalveolar , Femenino , Glicoproteínas/metabolismo , Ratones , Ratones Endogámicos BALB C , Proteína D Asociada a Surfactante PulmonarRESUMEN
One of the hallmarks of the human autoimmune thyroid diseases (AITDs) is the production of high titers of autoantibodies against thyroglobulin and thyroid peroxidase that often precedes the development of clinical disease. A high percentage of family members of patients with AITDs have significant titers of thyroid antibodies (TAbs), suggesting a genetic predisposition for their development, and segregation analyses have favored a dominant mode of inheritance. The aim of the present study was to identify the susceptibility genes for TAb production. We completed a genome-wide scan in 56 multiplex families (323 individuals) in which all family members with AITDs and/or detectable TAbs were considered affected. The highest 2-point logarithm of odds (LOD) score of 3.6 was obtained for marker D2S325 on chromosome 2q33 at 210.9 centimorgans. This locus showed no evidence for linkage to Graves' disease or Hashimoto's thyroiditis (2-point LOD scores, 0.42 for Graves' disease and -0.60 for Hashimoto's thyroiditis), demonstrating that the gene in this region conferred susceptibility to TAbs, but that clinical disease development required additional genetic and/or environmental factors. We then fine-mapped the region linked with TAbs using 11 densely spaced microsatellite markers. Multipoint linkage analysis using these markers showed a maximum LOD score of 4.2 obtained for marker D2S155 at 209.8 centimorgans (with heterogeneity, alpha = 0.41). As the linked region contained the CTLA-4 and CD28 genes, we then tested whether they were the susceptibility genes for TAbs on chromosome 2q33. The CD28 gene was sequenced in 15 individuals, and a new C/T single nucleotide polymorphism (SNP) was identified in intron 3. Analysis of this SNP revealed no association with TAbs in the probands of the linked families (families that were linked with D2S155) compared with controls. The CTLA-4 gene was analyzed using the known A/G(49) SNP, and the results showed a significantly increased frequency of the G allele in the probands of the linked families compared with the probands of the unlinked families or with controls (P = 0.02). We concluded that 1) a major gene for thyroid autoantibody production was located on chromosome 2q33; 2) the TAb gene on chromosome 2q33 was most likely the CTLA-4 gene and not the CD28 gene; and 3) CTLA-4 contributed to the genetic susceptibility to TAb production, but there was no evidence that it contributed specifically to Graves' or Hashimoto's diseases.
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Antígenos de Diferenciación/genética , Autoanticuerpos/inmunología , Antígenos CD28/genética , Predisposición Genética a la Enfermedad/genética , Inmunoconjugados , Glándula Tiroides/inmunología , Abatacept , Alelos , Formación de Anticuerpos , Antígenos CD , Autoanticuerpos/genética , Antígeno CTLA-4 , Mapeo Cromosómico , Cromosomas Humanos Par 2/genética , Femenino , Frecuencia de los Genes , Pruebas Genéticas , Genoma , Humanos , MasculinoRESUMEN
The polycystic ovary syndrome (PCOS) is one of the commonest female endocrinopathies affecting 5-10% of women of reproductive age. The disorder, characterized by chronic anovulation and signs of hyperandrogenism, results from a complex interaction between genetic predisposing factors and environmental triggers. We have studied 85 Caucasian PCOS patients and 87 age-matched Caucasian control women for associations with four candidate genes: follistatin, CYP19 (aromatase), CYP17a, and the insulin receptor (INSR). These genes were analyzed using microsatellite markers located near or inside the genes. We found that only the insulin receptor gene marker D19S884 was significantly associated with PCOS (p=0.006 and even after a conservative correction p=0.042). The INSR gene region was then fine mapped with an additional panel of 9 markers but only marker D19S884, located 1 cM telomeric to the INSR gene, was again associated with PCOS. In conclusion, our results suggested that a susceptibility gene for PCOS was located on chromosome 19p13.3 in the insulin receptor gene region. It remains to be determined if this susceptibility gene is the insulin receptor gene itself or a closely located gene. Since insulin stimulates androgen secretion by the ovarian stroma it is likely that INSR function in the ovary is involved in the genetic susceptibility ot PCOS.