Pathogenesis of allergic airway inflammation

Abstract

Advances have been made in defining the mechanisms for the control of allergic airway inflammation in response to inhaled antigens. Several genes, including ADAM33, DPP10, PHF11, GPRA, TIM-1, PDE4D, OPN3, and ORMDL3, have been implicated in the pathogenesis and susceptibility to atopy and asthma. Growing evidence associates asthma with a systemic propensity for allergic T-helper type 2 cytokines. Disordered coagulation and fibrinolysis also exacerbate asthma symptoms. Balance among functionally distinct dendritic cell subsets contributes to the outcome of T-cell-mediated immunity. Allergen-specific T-regulatory cells play a pivotal role in the development of tolerance to allergens and immune suppression. The major emphasis on immunotherapy for asthma during the past decade has been to direct the immune response to a type 1 response, or immune tolerance. In this review, we discuss the current information on the pathogenesis of allergic airway inflammation and potential immunotherapy, which could be beneficial in the treatment of airway inflammation, allergy, and asthma.

Figure 1. Differentiation of CD4⁺ T helper cell and CD8⁺ cytotoxic T cells in allergic asthma

Differentiation of CD4⁺ T helper cells to effector Th1, Th2, Th17 cells or Treg cells depends upon environmental cytokine profile. Cytokines released from Th1 cells can antagonize differentiation and function of Th2 cells, and vice-versa. Undifferentiated Th0 cells can mature into Th1, Th2, Th17, or Treg cells in peripheral lymph organs, depending upon the costimulatory signals presented to them, along with antigen, by antigen-loaded dendritic cells. Functionally, CD8⁺ effector cytotoxic T cells (Tc) contain Tc1, Tc2, and CD8⁺Foxp3⁺ regulatory cells. Immunomodulators, such as Flt-3 ligand or CpR oligonucleotides, may preferentially increase the number of regulatory dendritic cells and/or T-regulatory cells inducing Th1 response, T cell anergy/tolerance to allergen. This could result in the prevention and/or reversal of atopy and/or asthma symptoms.