CD11a polymorphisms regulate TH 2 cell homing and TH 2-related disease

• Published in: Journal of allergy and clinical immunology Vol. 133; no. 1; pp. 189 - 197.e8
• Main Authors: Knight, John M., PhD, Lee, Seung-Hyo, PhD, Roberts, Luz, BS, Smith, C. Wayne, MD, Weiss, Scott T., MD, MS, Kheradmand, Farrah, MD, Corry, David B., MD
• Format: Journal Article
• Language: English
• Published: 2013
• Subjects: Allergy and Immunology; Linkage disequilibrium; polymorphism; AHR; Leukocyte function–associated antigen 1; CD11a; congenic; T H2 cell; SNP; Recombination-activating gene; homing; allergic disease; Metal ion binding domain; WT; CAMP; Ovalbumin; LFA-1; Childhood Asthma Management Program; Airway hyperreactivity; biomarker; Wild-type; Asthma; PE; allele; Phycoerythrin; LD; Rag; MIBD; OVA; Single nucleotide polymorphism
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2013.03.049

Background TH 2-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 TH 2 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 TH 2 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 TH 2 cell homing and diverse TH 2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease.