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Genetic Analysis of Antigen-Induced Airway Manifestations of Asthma Using Recombinant Congenic Mouse Strains
J Biol Chem 1999; 274:21499 –21502 104 Rioux J, Stone V, Daly M, et al. Familial eosinophilia maps to the cytokine gene cluster on human chromosomal region 5q31– q33. Am J Hum Genet 1998; 63:1086 –1094 105 Jani K, Kempski H, Reeves B. A case of myelodysplasia with eosinophilia having a translocation t(5; 12) (q31; q13) restricted to myeloid cells but not involving eosinophils. Br J Haematol 1994; 87:57– 60 106 Sato H, Saito H, Ikebuchi K, et al. Biological characteristics of chronic eosinophilic leukemia cells with a t(2; 5)(p23; q35) translocation. Leuk Lymphoma 1995; 19: 499 –505 107 Grimbacher B, Schaffer AA, Holland SM, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet 1999; 65:735–744 108 Moffatt MF, Traherne JA, Abecasis GR, et al. Single nucleotide polymorphism and linkage disequilibrium within the TCR alpha/delta locus. Hum Mol Genet 2000; 9:1011–1019
Genetic Analysis of AntigenInduced Airway Manifestations of Asthma Using Recombinant Congenic Mouse Strains* Antoon J.M. Van Oosterhout, PhD; Prescilla V. Jeurink; Peter C. Groot, PhD; Gerard A. Hofman; Frans P. Nijkamp, PhD; and Peter Demant, PhD
(CHEST 2002; 121:13S) Abbreviation: OVA ⫽ ovalbumin
asthma is a heterogeneous and genetically A llergic complex disease that is characterized by the pres-
ence of allergen-specific IgE, eosinophilic airway inflammation, and hyperresponsiveness to bronchospasmogenic stimuli. To facilitate the mapping of genes controlling complex asthma traits, we have used a powerful tool, the recombinant congenic strains of mice, which transforms a multigenic difference into a set of monogenic or oligogenic differences.1 This approach offers a higher resolution power than do the standard mouse crosses in mapping segregating quantitative trait loci and in the detection of their potential interactions. In the present study, we compared 4 strains (Ccs/DEM-5, Ccs/DEM-11, Ccs/DEM-12, and Ccs/DEM-18) from a series of 20 strains, each of which carries a random set of 12.5% of genes from the T-helper cell type 1 responder strain STS and 87.5% of
Table 1—Lung Function and Inflammation* Strain 5 11 12 18
(n ⫽ 13) (n ⫽ 4) (n ⫽ 12) (n ⫽ 8)
Penh Maximum 2.6 ⫾ 0.3 2.5 ⫾ 0.2 3.3 ⫾ 0.3 2.7 ⫾ 0.3
vs vs vs vs
⌬ED300
3.5 ⫾ 0.5† ⫺ 1.1 ⫾ 4.4 3.0 ⫾ 0.3† ⫺ 33.2 ⫾ 8.3† 3.0 ⫾ 0.4 ⫹ 6.6 ⫾ 5.1 6.0 ⫾ 1.1† ⫺ 6.3 ⫾ 3.7
Eosinophils, ⫻ 105 1.0 ⫾ 0.4 2.9 ⫾ 1.5 5.1 ⫾ 1.2 6.0 ⫾ 1.5
*Values given as mean ⫾ SEM. ED300 ⫽ dose of methacholine needed to increase baseline values of enhanced pause by 300%; Penh ⫽ enhanced pause. †p ⬍ 0.05, as determined by Student’s t test.
genes from the T-helper cell type 2 responder strain BALB/c. Mice were sensitized with ovalbumin (OVA), and later on were repeatedly challenged by the inhalation of an OVA aerosol. Before and after the OVA challenges, serum samples were obtained and the airway responsiveness to nebulized methacholine (dose range, 1.5 to 50 mg/mL) was determined. Finally, BAL was performed, and the number of leukocytes were determined (Table 1). All mouse strains showed increased serum levels of OVA-specific IgE as a result of the OVA inhalation challenge (data not shown). It appears that there is no correlation between the number of BAL eosinophils and the extent of airway hyperresponsiveness. Strain 12 displayed airway eosinophilia but a resistance to hyperresponsiveness. However, the baseline airway responsiveness of strain 12 was higher than that of the other strains. In strain 11, airway hyperresponsiveness was determined predominantly by an increased sensitivity (ie, the dose of methacholine needed to increase baseline values of enhanced pause by 300%) to methacholine, whereas in strains 5 and 18 only a significant increase in the maximal response could be observed. These data demonstrate that different asthma traits like the presence of IgE, eosinophilia, and hyperresponsiveness may be genetically dissociated. Further mapping studies will be carried out to localize the modifier genes involved in specific traits.
Reference 1 Groot PC, Moen CJ, Dietrich W, et al. The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 1992; 6:2826 –2835
*From the Department of Pharmacology and Pathophysiology (Drs. Van Oosterhout, Groot, and Nijkamp, Ms. Jeurink, and Mr. Hofman), Faculty of Pharmacy, Utrecht University, Utrecht, Netherlands; Division of Molecular Genetics (Dr. Demant), Netherlands Cancer Institute, Amsterdam, Netherlands. This research was supported by a research grant (AF99.23) of the Dutch Asthma Foundation. Correspondence to: Antoon J.M. Van Oosterhout, PhD, Department of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University, PO box 80.082, 3508TB Utrecht, Netherlands; e-mail: [email protected] CHEST / 121 / 3 / MARCH, 2002 SUPPLEMENT
13S
Genetic Analysis of AntigenInduced Airway Manifestations of Asthma Using Recombinant Congenic Mouse Strains* Antoon J.M. Van Oosterhout, PhD; Prescilla V. Jeurink; Peter C. Groot, PhD; Gerard A. Hofman; Frans P. Nijkamp, PhD; and Peter Demant, PhD
(CHEST 2002; 121:13S) Abbreviation: OVA ⫽ ovalbumin
asthma is a heterogeneous and genetically A llergic complex disease that is characterized by the pres-
ence of allergen-specific IgE, eosinophilic airway inflammation, and hyperresponsiveness to bronchospasmogenic stimuli. To facilitate the mapping of genes controlling complex asthma traits, we have used a powerful tool, the recombinant congenic strains of mice, which transforms a multigenic difference into a set of monogenic or oligogenic differences.1 This approach offers a higher resolution power than do the standard mouse crosses in mapping segregating quantitative trait loci and in the detection of their potential interactions. In the present study, we compared 4 strains (Ccs/DEM-5, Ccs/DEM-11, Ccs/DEM-12, and Ccs/DEM-18) from a series of 20 strains, each of which carries a random set of 12.5% of genes from the T-helper cell type 1 responder strain STS and 87.5% of
Table 1—Lung Function and Inflammation* Strain 5 11 12 18
(n ⫽ 13) (n ⫽ 4) (n ⫽ 12) (n ⫽ 8)
Penh Maximum 2.6 ⫾ 0.3 2.5 ⫾ 0.2 3.3 ⫾ 0.3 2.7 ⫾ 0.3
vs vs vs vs
⌬ED300
3.5 ⫾ 0.5† ⫺ 1.1 ⫾ 4.4 3.0 ⫾ 0.3† ⫺ 33.2 ⫾ 8.3† 3.0 ⫾ 0.4 ⫹ 6.6 ⫾ 5.1 6.0 ⫾ 1.1† ⫺ 6.3 ⫾ 3.7
Eosinophils, ⫻ 105 1.0 ⫾ 0.4 2.9 ⫾ 1.5 5.1 ⫾ 1.2 6.0 ⫾ 1.5
*Values given as mean ⫾ SEM. ED300 ⫽ dose of methacholine needed to increase baseline values of enhanced pause by 300%; Penh ⫽ enhanced pause. †p ⬍ 0.05, as determined by Student’s t test.
genes from the T-helper cell type 2 responder strain BALB/c. Mice were sensitized with ovalbumin (OVA), and later on were repeatedly challenged by the inhalation of an OVA aerosol. Before and after the OVA challenges, serum samples were obtained and the airway responsiveness to nebulized methacholine (dose range, 1.5 to 50 mg/mL) was determined. Finally, BAL was performed, and the number of leukocytes were determined (Table 1). All mouse strains showed increased serum levels of OVA-specific IgE as a result of the OVA inhalation challenge (data not shown). It appears that there is no correlation between the number of BAL eosinophils and the extent of airway hyperresponsiveness. Strain 12 displayed airway eosinophilia but a resistance to hyperresponsiveness. However, the baseline airway responsiveness of strain 12 was higher than that of the other strains. In strain 11, airway hyperresponsiveness was determined predominantly by an increased sensitivity (ie, the dose of methacholine needed to increase baseline values of enhanced pause by 300%) to methacholine, whereas in strains 5 and 18 only a significant increase in the maximal response could be observed. These data demonstrate that different asthma traits like the presence of IgE, eosinophilia, and hyperresponsiveness may be genetically dissociated. Further mapping studies will be carried out to localize the modifier genes involved in specific traits.
Reference 1 Groot PC, Moen CJ, Dietrich W, et al. The recombinant congenic strains for analysis of multigenic traits: genetic composition. FASEB J 1992; 6:2826 –2835
*From the Department of Pharmacology and Pathophysiology (Drs. Van Oosterhout, Groot, and Nijkamp, Ms. Jeurink, and Mr. Hofman), Faculty of Pharmacy, Utrecht University, Utrecht, Netherlands; Division of Molecular Genetics (Dr. Demant), Netherlands Cancer Institute, Amsterdam, Netherlands. This research was supported by a research grant (AF99.23) of the Dutch Asthma Foundation. Correspondence to: Antoon J.M. Van Oosterhout, PhD, Department of Pharmacology and Pathophysiology, Faculty of Pharmacy, Utrecht University, PO box 80.082, 3508TB Utrecht, Netherlands; e-mail: [email protected] CHEST / 121 / 3 / MARCH, 2002 SUPPLEMENT
13S