CD11a polymorphisms regulate TH2 cell homing and TH2-related disease

Abstract

Background: TH2-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.

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

Methods: We 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.

Results: Compared 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.

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

Keywords: AHR; Airway hyperreactivity; Asthma; CAMP; CD11a; Childhood Asthma Management Program; LD; LFA-1; Leukocyte function–associated antigen 1; Linkage disequilibrium; MIBD; Metal ion binding domain; OVA; Ovalbumin; PE; Phycoerythrin; Rag; Recombination-activating gene; SNP; Single nucleotide polymorphism; T(H)2 cell; WT; Wild-type; allele; allergic disease; biomarker; congenic; homing; polymorphism.