Search

Variations in two genes of the tumour necrosis factor ( TNF) alpha pathway have been implicated in the pathogenesis of autoimmune diseases: polymorphisms in the TNFRSF1A gene, encoding TNF receptor 1, showed significant association with MS in genomewide association scans, and variation in or near the TNFAIP3 gene, coding for a negative regulator of NFkB, was associated with MS, systemic lupus erythematosus, diabetes and rheumatoid arthritis. This study aimed at investigating association of MS with variation in the TNFRSF1A gene as well as in the TNFAIP3 gene region in an independent German case-control cohort. Four hundred and ninety-seven unrelated patients with MS and 878 healthy controls were genotyped with restriction enzyme digestion or TaqMan assays for three polymorphisms in the TNFRSF1A gene and seven in the region of the TNFAIP3 gene. Allele, genotype and haplotype frequencies were compared between cases and controls by chi-square testing. We found significant association of rs10499194, located in the intergenic region upstream of TNFAIP3, with MS ( pc = 3.4 × 10−4). Further, the intronic SNP rs1800693 in TNFRSF1A showed moderate association ( pc = 0.033) with MS. In conclusion, evidence is accumulating that polymorphisms in both TNFAIP3 and TNFRSF1A genes play a role in MS pathogenesis. Additional studies are warranted to further elucidate the role of TNF pathway variation for MS development. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) and asthma are common complex diseases characterized by airflow obstruction and inflammatory processes in the small airways. lnterleukin 8 (IL-8) is a potent proinflammatory cytokine which interacts with the IL-8 receptora(IL8RA, CXCR1) andß(IL8RB, CXCR2), leading to activation and migration of leukocytes. In order to evaluate the role of the IL8RA gene in the pathogenesis of COPD and asthma, we screened the coding region of IL8RA for mutations by means of single-strand conformation polymorphism analysis in 50 COPD patients and identified three exchanges (M31R, S276T and R335C). These three polymorphisms were subsequently genotyped in 182 adult patients with COPD, 68 adult patients and 130 children with asthma as well as 454 healthy controls. The frequencies of the IL8RA 31R and 335C alleles were significantly increased in patients with COPD and in children with asthma compared to healthy controls (P=0.0073 and 0.023, respectively). Thus, these polymorphisms may play a role in the pathogenesis of COPD and asthma.Genes and Immunity (2005) 6, 225-230. doi:10.1038/sj.gene.6364181 Published online 17 March 2004 [ABSTRACT FROM AUTHOR]

To study the consequences of the interaction of respiratory syncytial virus (RSV) with dendritic cellsin vitro, we established a model of the primary immune response using dendritic cells, autologous naive T cells and the superantigen toxic shock syndrome toxin 1 (TSST 1). About 10% of the naive T cells express the T cell receptor chain Vβ2. These cells were stimulated by TSST 1 and could be analysed by flow cytometry. Cultures infected with RSV produced significantly less interferon-γ compared to uninfected cultures. In a first set of experiments we evaluated whether this culture model using isolated CD4+ CD45RA+ T cells, in fact, reflects the primary immune response. In a prospective study, cells were isolated from 13 children at birth, at 1 year of age and at 4 years of age. RSV reduced interferon-γ production at all the age groups analysed and the results were stable over time within a given individual. In a second set of experiments, we asked whether clinical differences in the course of RSV infection are due to variations in the cellular immune response. At the age of 1 year (5–9 months after the RSV epidemic) dendritic cells and naive T cells were obtained from 27 children with a history of bronchiolitis, from 15 children with a benign course of RSV infection and from 26 controls without RSV infection. The frequency of interferon-γ-producing cells in RSV infected cultures was significantly lower (P < 0·001) in cultures from children with a history of RSV bronchiolitis compared to children with mild RSV infection. Cultures from children without infection displayed a wide range of results. Overall, interferon-γ generation in this group was still lower (P < 0·05) than in the group with mild RSV infection. Because we have ruled out that memory cells play a role in the experiments performed, the most likely explanation for our results is that a high generation of interferon-γ in the primary immune response protects from severe RSV mediated disease. [ABSTRACT FROM AUTHOR]

Chronic inflammation in cystic fibrosis (CF) airways leads to high concentrations of deoxyribonucleic acid (DNA) and neutrophil elastase (NE). Both play a major role in CF lung pathophysiology and are aims of new therapeutic approaches: rhDNase degrades highly viscosic DNA and a1-proteinase inhibitor (a1-PI) inhibits NE activity and thereby pulmonary inflammation and hypersecretion. Given the reports on increased sputum NE concentrations upon rhDNase inhalation, there is a rationale for a combined rhDNase/a1-PI treatment. With the question of whether a combined therapy is feasible, we first investigated in vitro whether incubation of CF sputum with rhDNase changes proteolytic and secretagogue activity of sputum supernatants and its inhibition by a1-PI. Next, we studied whether incubation of a1-PI with rhDNase impairs the inhibitory effect of a1-PI on proteolytic activity of NE and the inhibitory effect of a1-PI on NE-induced secretion from a human mucoepidermoid cell line. Incubation of CF sputum with rhDNase led to a twofold increase in sputum NE activity. Correspondingly, the inhibitory effect of a1-PI on sputum NE activity and on secretion induced by these sputum samples was significantly reduced by rhDNase. Preincubation of a1-PI with rhDNase significantly reduced the inhibitory effect of a1-PI on purified NE activity and on NE-induced secretion. However, this effect was limited to a1-PI concentrations lower than those achievable after inhalation. Therefore, impairment of a1-PI function by rhDNase is not likely to be relevant in vivo, provided that a sufficient dosage of a1-PI is inhaled. [ABSTRACT FROM AUTHOR]

Abstract Background For allergic disorders, the increasing prevalence over the past decade has been attributed in part to the lack of microbial burden in developed countries ('hygiene hypothesis'). Variation in genes encoding toll-like receptors (TLRs) as the receptor system for the first innate immune response to microbial stimuli has been implicated in various inflammatory diseases. We evaluated here the role of a coding variation, Ser249Pro, in the TLR6 gene in the pathogenesis of asthma, atopic dermatitis (AD) and chronic obstructive pulmonary disease (COPD). Methods Genotyping of the Ser249Pro polymorphism in 68 unrelated adult patients and 132 unrelated children with asthma, 185 unrelated patients with COPD, 295 unrelated individuals with AD and 212 healthy control subjects was performed by restriction enzyme digestion. Results We found a weak association of the 249Ser allele with childhood asthma (p = 0.03). Yet, significance was lost after Bonferroni correction. No association was evident for AD or COPD. Conclusion Variation in TLR6 might play a role in the pathogenesis of childhood asthma.

Abstract Hundreds of genetic association studies on asthma-related phenotypes have been conducted in different populations. To date, variants in 64 genes have been reported to be associated with asthma or related traits in at least one study. Of these, 33 associations were replicated in a second study, 9 associations were not replicated either in a second study or a second sample in the same study, and 22 associations were reported in just a single published study. These results suggest the potential for a great amount of heterogeneity underlying asthma. However, many of these studies are methodologically limited and their interpretation hampered by small sample sizes.

Pathogenic variants in the ryanodine receptor 1 ( RYR1 ) gene are causative for a wide spectrum of muscular phenotypes, ranging from malignant hyperthermia over mild, non-progressive to severe congenital myopathy. Both autosomal dominant and recessive inheritance can occur, with the more severe forms usually showing recessive inheritance. However, genotype-phenotype correlations are complicated due to the large size of the gene and heterogeneous phenotypes. We present a 6-year-old patient with severe congenital myopathy, carrying a heterozygous pathogenic RYR1 variant inherited from the healthy mother. Through whole genome sequencing we identified a second, deep intronic RYR1 variant that has recently been described in another patient with severe congenital myopathy and shown to affect splicing. Segregation analyses confirmed the variants to be compound heterozygous. We compared our patient's phenotype to that of the patient from the literature as well as five additional patients with compound heterozygous RYR1 variants from our center. The main overlapping features comprised congenital onset, predominant muscular hypotonia, and normal creatine kinase (CK) levels, while overall clinical expression varied substantially. Interestingly, both patients carrying the new intronic splice variant showed a very severe disease course. More widespread use of genome sequencing will open the way for better genotype-phenotype correlations., Competing Interests: The authors declare no conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams., (© 2024. The Author(s).)