title: Alpha4 and beta2 integrins have nonredundant roles for asthma development, but for optimal allergen sensitization only alpha4 is critical.
abstract: OBJECTIVE
  Recruitment of effector cell subsets to inflammatory lung, together with airway resident cells responsive to secreted products, play pivotal roles in developing and maintaining asthma. Differential use of adhesion molecules dictates the recruitment patterns of specific cell subsets, yet a clear understanding of the distinctive adhesive molecular pathways guiding them to lung is lacking. To provide further insight into the role of alpha4beta1/VCAM-1 pathway and to compare this to the role of beta2 integrin in the development of acute asthma phenotype, we used genetically deficient mice, in contrast to previous studies with anti-functional antibodies yielding ambiguous results.
  
  
  METHODS
  Allergen-dependent airway inflammation and hyperresponsiveness was induced in conditional alpha4(Delta/Delta), VCAM-1(-/-), and beta2(-/-) mice. Cytology, immunocytochemistry, cytokine and immunoglobulin measurements, and cell type accumulation in lung, BAL fluid, plasma, and hemopoietic tissues were carried out.
  
  
  RESULTS
  Asthma phenotype was totally abrogated in alpha4- or beta2-deficient mice. Adoptive transfer of sensitized alpha4(Delta/Delta) CD4(+) cells into challenged normal mice failed to induce asthma, whereas alpha4(+/+) CD4(+) cells were able to induce asthma in challenged alpha4(Delta/Delta) mice. Parallel studies with beta2(-/-) or VCAM-1(-/-) mice uncovered novel mechanistic insights in primary sensitization and into redundant or unique functional roles of these adhesion pathways in allergic asthma.
  
  
  CONCLUSIONS
  The lack of alpha4 integrin not only impedes the migration of all white cell subsets to lung and airways, but also prevents upregulation of vascular cell adhesion molecule-1 (VCAM-1) in inflamed lung vasculature and, unlike beta2, attenuates optimal sensitization and ovalbumin-specific IgE production in vivo. As VCAM-1 deficiency did not protect mice from asthma, interactions of alpha4beta1(+) or alpha4beta7(+) cells with other ligands are suggested.
authors: Divisions of Allergy and Infectious Diseases, University of Washington, Seattle, WA, USA.
authors: Ena Ray
authors: ER
authors: Banerjee
authors: Yi
authors: Y
authors: Jiang
authors: William R
authors: WR
authors: Henderson
authors: Linda M
authors: LM
authors: Scott
authors: Thalia
authors: T
authors: Papayannopoulou
mesh_terms: D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D018821:CD18 Antigens / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D039441:Integrin alpha4 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000008:administration & dosage*; D010641:Phenotype; D012129:Respiratory Function Tests; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000485:Allergens; D018821:CD18 Antigens; D016207:Cytokines; D019010:Vascular Cell Adhesion Molecule-1; D039441:Integrin alpha4; D010047:Ovalbumin