CD11a polymorphisms regulate TH2 cell homing and TH2-related disease.

backgroundTH2-dependent diseases vary in severity according to genotype, but relevant gene polymorphisms remain largely unknown. The integrin CD11a is a critical determinant of allergic responses, and allelic variants of this gene might influence allergic phenotypes.

objectiveWe sought to determine major CD11a allelic variants in mice and human subjects and their importance to allergic disease expression.

methodsWe sequenced mouse CD11a alleles from C57BL/6 and BALB/c strains to identify major polymorphisms; human CD11a single nucleotide polymorphisms were compared with allergic disease phenotypes as part of the international HapMap project. Mice on a BALB/c or C57BL/6 background and congenic for the other strain's CD11a allele were created to determine the importance of mouse CD11a polymorphisms in vivo and in vitro.

resultsCompared with the C57BL/6 allele, the BALB/c CD11a allele contained a nonsynonymous change from asparagine to aspartic acid within the metal ion binding domain. In general, the BALB/c CD11a allele enhanced and the C57BL/6 CD11a allele suppressed TH2 cell-dependent disease caused by the parasite Leishmania major and allergic lung disease caused by the fungus Aspergillus niger. Relative to the C57BL/6 CD11a allele, the BALB/c CD11a allele conferred both greater T-cell adhesion to CD54 in vitro and enhanced TH2 cell homing to lungs in vivo. We further identified a human CD11a polymorphism that significantly associated with atopic disease and relevant allergic indices.

conclusionsPolymorphisms in CD11a critically influence TH2 cell homing and diverse TH2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease.