Genetics of atopy in a mouse model: polymorphism of the IL-5 receptor alpha chain

To study the genetics of atopy systematically we established a mouse model that provides the general phenotype of atopy: the early response characteri stic of IgE-dependent eczema or atopic dermatitis, and the diagnostic test of atopy, the skin-prick test. Using an immediate cutaneous hypersensitivit y test (ICHS) against birch pollen extract we could classify A/J and C57BL/ 6 (B6) inbred mouse strains respectively as high responder and low responde rs. The Fl hybrids were found to be high responders with incomplete penetra nce. Backcrossing F1 mice to the low responder B6 strain yielded three clas ses of responders, high, intermediate, and low. A genome-wide microsatellit e screen of the backcross progeny disclosed suggestive linkage to a microsa tellite marker on chromosome 6 close to the locus of the IL-5 receptor alph a chain. Its allelic variation in A/J and B6 strains was investigated and t wo major differences were detected. Firstly, a nucleotide exchange in the 5 ' untranslated region of B6 mRNA resulted in increased transcription/transl ation of a reporter construct. Higher expression of the receptor on the cel l surface would be expected to favor an allergic immune response. Secondly, the two alleles are differentially spliced so as to yield two soluble isof orms in A/J mice versus one in B6 mice. Higher expression of soluble IL-5R would be expected to reduce the level of allergy through capture of IL-5. T hus both findings conform to the expectation based on susceptibility to ato py and thus identify the IL-5R alpha chain as a likely contributor to the g enetics of atopy.