CD11a polymorphisms regulate TH2 cell homing and TH2-related disease

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:133

Article

Knight, John M.¹  Lee, Seung-Hyo⁴  Roberts, Luz²  Smith, C. Wayne^1,3  Weiss, Scott T.^5,6  Kheradmand, Farrah^1,2  Corry, David B.^1,2 

[1] Baylor Coll Med, Dept Pathol & Immunol, Houston, TX 77030 USA

[2] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[3] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[4] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Taejon 305701, South Korea

[5] Brigham & Womens Hosp, Dept Med, Channing Lab, Div Network Med, Boston, MA USA

[6] Harvard Univ, Sch Med, Boston, MA USA

关键词: Asthma;    allergic disease;    CD11a;    T(H)2 cell;    homing;    polymorphism;    allele;    congenic;    biomarker;   

DOI  :  10.1016/j.jaci.2013.03.049

来源: Elsevier

【 摘 要 】

Background: T(H)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 T(H)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 T(H)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 T(H)2 cell homing and diverse T(H)2-dependent immunopathologic states in mice and potentially influence the expression of human allergic disease.

【 授权许可】

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