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.
Laboratory of Allergology & Pulmonary Diseases, Department of Pathology and Medical Biology, GRIAC Research Institute, University Medical Centre Groningen, University of Groningen, the Netherlands.
Martijn C
MC
Nawijn
Benoit J A
BJ
Piavaux
Prescilla V
PV
Jeurink
Renée
R
Gras
Marjan A
MA
Reinders
Timothy
T
Stearns
Simon
S
Foote
Machteld N
MN
Hylkema
Peter C
PC
Groot
Ron
R
Korstanje
Antoon J M Van
AJ
Oosterhout
D056151:Airway Remodeling / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000235:genetics* / Q000276:immunology / Q000821:virology; D015415:Biomarkers / Q000378:metabolism; D016535:Bronchial Hyperreactivity / Q000235:genetics* / Q000276:immunology / Q000821:virology; D001992:Bronchoalveolar Lavage Fluid; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D004802:Eosinophilia / Q000235:genetics / Q000276:immunology / Q000821:virology; D004804:Eosinophils / Q000276:immunology / Q000821:virology; D005260:Female; D020869:Gene Expression Profiling; D007073:Immunoglobulin E / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000276:immunology / Q000821:virology; D018320:Leishmania major; D007896:Leishmaniasis / Q000235:genetics* / Q000276:immunology / Q000821:virology; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010047:Ovalbumin / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015415:Biomarkers; D012333:RNA, Messenger; D007073:Immunoglobulin E; D010047:Ovalbumin