Availability of 25-hydroxyvitamin D(3) to APCs controls the balance between regulatory and inflammatory T cell responses.

1,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], the active form of vitamin D, exerts potent effects on several tissues including cells of the immune system, where it affects T cell activation, differentiation and migration. The circulating, inactive form of vitamin D, 25(OH)D(3), is generally used as an indication of vitamin D status. However, use of this precursor depends on its uptake by cells and subsequent conversion by the enzyme 25(OH)D(3)-1α-hydroxylase (CYP27B1) into active 1,25(OH)(2)D(3). Using human T cells, we show in this study that addition of inactive 25(OH)D(3) is sufficient to alter T cell responses only when dendritic cells (DCs) are present. Mechanistically, CYP27B1 is induced in DCs upon maturation with LPS or upon T cell contact, resulting in the generation and release of 1,25(OH)(2)D(3), which subsequently affects T cell responses. In most tissues, vitamin D binding protein acts as a carrier to enhance the use of vitamin D. However, we show that vitamin D binding protein modulates T cell responses by restricting the availability of inactive 25(OH)D(3) to DC. These data indicate that the level of free 25(OH)D(3) available to DCs determines the inflammatory/regulatory balance of ensuing T cell responses.

Variability of sputum inflammatory mediators in COPD and α1-antitrypsin deficiency.

There is inherent daily variability of sputum inflammatory mediators in stable-state patients with usual chronic obstructive pulmonary disease (COPD). The variability of pulmonary inflammation in patients with α(1)-antitrypsin deficiency (A1ATD) is unknown. Our study aimed to quantify this variability, in comparison to patients with usual COPD, in order to facilitate power calculations for proof of concept trials of putative specific anti-inflammatory agents in both groups. Sputum interleukin (IL)-8, myeloperoxidase (MPO), leukotriene B(4) (LTB(4)) and differential cell counts were measured in 12 usual COPD patients and 12 A1ATD patients on nine occasions over a 1-month period. All samples were obtained in the stable clinical state. There was significant daily variability in all mediators in all patients. A1ATD patients had higher sputum concentrations of IL-8 and LTB(4) compared with usual COPD, but lower levels of MPO and absolute neutrophil counts. Patients with usual COPD had more intra-patient variability, A1ATD patients demonstrated greater inter-patient variability. There are increased concentrations of pulmonary inflammatory mediators but fewer sputum neutrophils in A1ATD compared with usual COPD. The daily variability of inflammatory mediators and cell counts was significantly reduced in both groups by averaging sequential samples. This can be utilised to perform power calculations for future proof of concept studies; averaging three sequential samples appears optimum.

Association of IREB2 and CHRNA3 polymorphisms with airflow obstruction in severe alpha-1 antitrypsin deficiency.

BACKGROUND: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency. METHODS: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2 were selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative phenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication set, general linear models were used for quantitative phenotypes and logistic regression models were used for the presence/absence of emphysema or COPD. RESULTS: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with pre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and rs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC ratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly associated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed. CONCLUSIONS: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe AAT deficiency and may be sex-specific in their impact.

Tumor necrosis factor-{alpha} rs361525 polymorphism is associated with increased local production and downstream inflammation in chronic obstructive pulmonary disease.

RATIONALE: Chronic obstructive pulmonary disease (COPD) has a genetic component, explaining susceptibility. Tumor necrosis factor (TNF)-alpha polymorphisms have been associated with COPD, but it is unclear if genotype influences clinical phenotype, protein expression, and bioactivity. OBJECTIVES: To determine if a functional polymorphism was important by assessing TNF-alpha expression and activity and its association with clinical severity over time. METHODS: Patients with COPD with rs361525 polymorphism were matched to patients with COPD without rs361525 polymorphism. TNF-alpha, its antagonists, and downstream mediators were measured in plasma and sputum. To determine TNF-alpha bioactivity, IL-8 secretion from primary bronchial epithelial cells (PBECs) was measured, and neutrophil migration was assessed using sputum from both subject groups in the presence and absence of TNF-alpha antibody. Subjects were followed annually and compared. MEASUREMENTS AND MAIN RESULTS: Patients with polymorphism had more chronic bronchitis, a lower body mass index, and a greater annual decline in FEV(1) than patients with COPD without rs361525 polymorphism. TNF-alpha concentrations were 100-fold higher in airway secretions from the patients with the rs361525 polymorphism, with no difference in TNF-alpha antagonists. Their lung secretions contained more IL-8 and myeloperoxidase, consistent with downstream inflammation. Sputum from patients with rs361525 polymorphism induced greater secretion of IL-8 from PBECs and increased neutrophil migration. These effects could be abrogated by TNF-alpha antibody, demonstrating the bioactivity of TNF-alpha in lung secretions from this group. CONCLUSIONS: This TNF-alpha polymorphism is associated with clinical features of disease including progression. There is clear evidence of TNF-alpha overexpression and bioactivity with neutrophilic inflammation. The polymorphism is likely to be a factor that influences a COPD disease phenotype and its progression.

Outdoor air pollution is associated with rapid decline of lung function in alpha-1-antitrypsin deficiency.

INTRODUCTION: Outdoor air pollutants are associated with respiratory morbidity and mortality, but little longitudinal work has been undertaken in this area in chronic obstructive pulmonary disease (COPD). Patients with alpha-1-antitrypsin deficiency (AATD) typically exhibit faster decline of lung function than subjects with usual COPD and thus represent a group in whom studies of factors influencing decline may be more easily clarified. METHODS: Decline of FEV(1) and KCO in subjects of the PiZZ genotype from the UK AATD registry were studied. Pollution levels (PM(10), ozone, sulphur dioxide, nitrogen dioxide) during the exposure window were extracted from GIS maps, matching the measurement to each patient's home address. Clinical predictors of decline were sought using generalised estimating equations, and pollutants added to these subsequently. Single pollutant models were used due to multicollinearity. RESULTS: In the FEV(1) decline analysis, higher baseline FEV(1) was associated with rapid decline of FEV(1) (p<0.001). High PM(10) exposure predicted more rapid decline of FEV(1) (p=0.024). In a similar analysis for KCO decline, higher baseline KCO predicted rapid decline (p<0.001) as did higher exposure to ozone (p=0.018). High PM(10) exposure also showed a trend towards this effect (p=0.056). CONCLUSIONS: Exposure to ozone and PM(10) predicts decline of lung function in AATD.

The TNFalpha gene relates to clinical phenotype in alpha-1-antitrypsin deficiency.

BACKGROUND: Genetic variation may underlie phenotypic variation in chronic obstructive pulmonary disease (COPD) in subjects with and without alpha 1 antitrypsin deficiency (AATD). Genotype specific sub-phenotypes are likely and may underlie the poor replication of previous genetic studies. This study investigated subjects with AATD to determine the relationship between specific phenotypes and TNFalpha polymorphisms. METHODS: 424 unrelated subjects of the PiZZ genotype were assessed for history of chronic bronchitis, impairment of lung function and radiological presence of emphysema and bronchiectasis. A subset of subjects with 3 years consecutive lung function data was assessed for decline of lung function. Four single nucleotide polymorphisms (SNPs) tagging TNFalpha were genotyped using TaqMan(R) genotyping technologies and compared between subjects affected by each phenotype and those unaffected. Plasma TNFalpha levels were measured in all PiZZ subjects. RESULTS: All SNPs were in Hardy-Weinberg equilibrium. A significant difference in rs361525 genotype (p = 0.01) and allele (p = 0.01) frequency was seen between subjects with and without chronic bronchitis, independent of the presence of other phenotypes. TNFalpha plasma level showed no phenotypic or genotypic associations. CONCLUSION: Variation in TNFalpha is associated with chronic bronchitis in AATD.

Phenotypic differences in alpha 1 antitrypsin-deficient sibling pairs may relate to genetic variation.

Alpha-1-antitrypsin deficiency is associated with variable development of airflow obstruction and emphysema. Index patients have greater airflow obstruction than subjects detected by screening, but it is unclear if this reflects smoking differences and/or ascertainment bias, or is due to additional genetic factors. In this study 72 sibling pairs with alpha-1-antitrypsin deficiency were compared using lung function measurements and HRCT chest. Tag single nucleotide polymorphisms to cover all common variation in four genes involved in relevant inflammatory pathways (Tumour necrosis factor alpha, Transforming growth Factor beta, Surfactant protein B and Vitamin D binding protein) were genotyped using TaqMan technology and compared between pairs for their frequency and relationship to lung function. 63.5% of non-index siblings had airflow obstruction and 59.5% an FEV(1) < 80% predicted. Index siblings had lower FEV(1) and FEV(1)/FVC ratio, a higher incidence of emphysema (all P

The genetics of chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation.

Chronic obstructive pulmonary disease: towards pharmacogenetics.

Chronic obstructive pulmonary disease (COPD) is a common problem worldwide, and it is recognized that the term encompasses overlapping sub-phenotypes of disease. The development of a sub-phenotype may be determined in part by an individual's genetics, which in turn may determine response to treatment. A growing understanding of the genetic factors that predispose to COPD and its sub-phenotypes and the pathophysiology of the condition is now leading to the suggestion of individualized therapy based on the patients' clinical phenotype and genotype. Pharmacogenetics is the study of variations in treatment response according to genotype and is perhaps the next direction for genetic research in COPD. Here, we consider how knowledge of the pathophysiology and genetic risk factors for COPD may inform future management strategies for affected individuals.

Matrix metalloprotease polymorphisms are associated with gas transfer in alpha 1 antitrypsin deficiency.

UNLABELLED: Alpha-1-antitrypsin deficiency [AATD] is associated with variable development of emphysema and other features of chronic obstructive pulmonary disease [COPD]. Matrix metalloproteinases [MMPs] are believed to be important in the pathophysiology of COPD, and may therefore confer susceptibility to this phenotype in patients with AATD. OBJECTIVES: to assess the role of polymorphism of MMP1, MMP3 and MMP12 in AATD phenotypes. METHODS: 424 PiZZ subjects from the UK AATD Registry were assessed for history of chronic bronchitis [CB], post-bronchodilator lung function impairment and decline of lung function. Tag single nucleotide polymorphisms (SNPs) for MMP1, MMP3 and MMP12 were chosen using HapMap [r(2)>0.8, MAF>0.05] and were genotyped using TaqMan genotyping technologies. Quantitative genetic association was assessed using regression modelling to correct for covariates. RESULTS: in patients with AATD, carriers of the G allele of rs678815 [MMP3] had lower gas transfer [KCO] [P = 0.025, B =-7.766] than the homozygous wild type, while carriers of the T allele of rs470358 [MMP1] had higher KCO [P = 0.025, B = 6.130]. CONCLUSIONS: variations in MMP1 and MMP3 are associated with gas transfer in AATD, supporting a previous family study showing linkage of KCO to this gene region. Replication of these preliminary data is now required particularly if MMP inhibitors are to be considered as a therapeutic option.

Alpha one antitrypsin deficiency: from gene to treatment.

Alpha1-antitrypsin deficiency is a genetic disorder which contributes to the development of chronic obstructive pulmonary disease, bronchiectasis, liver cirrhosis and panniculitis. The discovery of alpha1-antitrypsin and its function as an antiprotease led to the protease-antiprotease hypothesis, which goes some way to explaining the pathogenesis of emphysema. This article will review the clinical features of alpha1-antitrypsin deficiency, the genetic mutations known to cause it, and how they do so at a molecular level. Specific treatments for the disorder based on this knowledge will be reviewed, including alpha1-antitrypsin replacement, gene therapy and possible future therapies, such as those based on stem cells.