Mapping of asthma susceptibility in recombinant congenic mouse strains

Astma is een longziekte waarbij patiënten kortademigheid en hyperreactiviteit van de luchtwegen ontwikkelen. Onderzoek heeft uitgewezen dat genetische aanleg een belangrijke rol speelt in astma. Asthma is a pulmonary inflammatory disease in which patients suffer from wheezing and shortness of breath. Like all inflammatory disease it has shown to be influenced by many genes. We used recombinant congenic mouse strains to map asthma susceptibility genes on mouse chromosome 17. Recombinant congenic strains are series of strains which have inherited one or more chromosomal fragments from a donor strain and all other DNA from the background strain. First, we investigated the power of this approach for the mapping of asthma susceptibility using the CcS/Dem series. These strains show different intensities and types of asthmatic response, which indicates that this approach could successfully be used for asthma genetics. We then started to map asthma susceptibility in the Lmr series of recombinant congenic and subcongenic strains. We identified 3 strong asthma susceptibility loci, lmr1A, lmr1B and H2. Lmr1A was further fine-mapped in a F2 cross between the RC strains and their background strain. Based upon the literature, in silico SNP analysis and expression profiling, we were able to identify candidate genes in 2 of these loci: Pla2g7 in lmr1A and Apobec-2 in lmr1B. For the H2 locus different candidate genes remain. Further studies should be undertaken to investigate this. Our models were found to be a valuable tool to investigate this complex locus which, like Pla2g7, was also associated to human asthma in many studies. It also shows that genetic research in mice can generate data relevant to human.

L’église Saint-Jacques à Liège. Templum pulcherrimum. Une histoire, un patrimoine

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Un nouveau regard sur l’histoire millénaire de Saint-Jacques à Liège

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Indoleamine 2,3-dioxygenase-dependent tryptophan metabolites contribute to tolerance induction during allergen immunotherapy in a mouse model

Background: The tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in immune suppression and tolerance induction. Objective: We examined (1) whether IDO activity is required during tolerance induction by allergen immunotherapy or for the subsequent suppressive effects on asthma manifestations and (2) whether tryptophan depletion or generation of its downstream metabolites is involved. Methods: Ovalbumin (OVA)-sensitized and OVA-challenged BALB/c mice that display increased airway responsiveness to methacholine, serum OVA-specific IgE levels, bronchoalveolar eosinophilia, and T(H)2 cytokine levels were used as a model of allergic asthma. Sensitized mice received subcutaneous optimal (1 mg) or suboptimal (100 mu g) OVA immunotherapy. Results: Inhibition of IDO by 1-methyl-DL-tryptophan during immunotherapy, but not during inhalation challenge, partially reversed the suppressive effects of immunotherapy on airway eosinophilia and T(H)2 cytokine levels, whereas airway hyperresponsiveness and serum OVA-specific IgE levels remained suppressed. Administration of tryptophan during immunotherapy failed to abrogate its beneficial effects toward allergic airway inflammation. Interestingly, administration of tryptophan or its metabolites, kynurenine, 3-hydroxykynurenine, and xanthurenic acid, but not 3-hydroxyanthranilinic acid, quinolinic acid, and kynurenic acid, during suboptimal immunotherapy potentiated the reduction of eosinophilia. These effects coincided with reduced T(H)2 cytokine levels in bronchoalveolar lavage fluid, but no effects on IgE levels were detected. Conclusion: During immunotherapy, the tryptophan metabolites kynurenine, 3-hydroxykynurenine, and xanthurenic acid generated through IDO contribute to tolerance induction regarding T(H)2-dependent allergic airway inflammation

Identification of the Mhc Region as an Asthma Susceptibility Locus in Recombinant Congenic Mice

Mouse models of allergic asthma are characterized by airway hyperreactivity (AHR), Th2-driven eosinophilic airway inflammation, high allergen-specific IgE (anti-OVA IgE) levels in serum, and airway remodeling. Because asthma susceptibility has a strong genetic component, we aimed to identify new asthma susceptibility genes in the mouse by analyzing the asthma phenotypes of the Leishmania major resistant (lmr) recombinant congenic (RC) strains. The lmr RC strains are derived from C57BL/6 and BALB/c intercrosses and carry congenic loci on chromosome 17 (lmr1) and 9 (lmr2) in both backgrounds. Whereas the lmr2 locus on chromosome 9 contributes to a small background-specific effect on anti-OVA IgE and AHR, the lmr1 locus on chromosome 17 mediates a strong effect on Th2-driven eosinophilic airway inflammation and background-specific effects on anti-OVA IgE and AHR. The lmr1 locus contains almost 600 polymorphic genes. To narrow down this number of candidate genes, we performed genome-wide transcriptional profiling on lung tissue from C. lmr1 RC mice and BALB/c control mice. We identified a small number of differentially expressed genes located within the congenic fragment, including a number of Mhc genes, polymorphic between BALB/c and C57Bl/6. The analysis of asthma phenotypes in the C.B10-H2b RC strain, carrying the C57Bl/6 haplotype of the Mhc locus in a BALB/c genetic background, reveals a strikingly similar asthma phenotype compared with C. lmr1, indicating that the differentially expressed genes located within the C.B10-H2b congenic fragment are the most likely candidate genes to contribute to the reduced asthma phenotypes associated with the C57Bl/6 allele of lmr1