Complement activation pathways: a bridge between innate and adaptive immune responses in asthma

Abstract

Although it is widely accepted that allergic asthma is driven by T helper type 2 (Th2)-polarized immune responses to innocuous environmental allergens, the mechanisms driving these aberrant immune responses remain elusive. Recent recognition of the importance of innate immune pathways in regulating adaptive immune responses have fueled investigation into the role of innate immune pathways in the pathogenesis of asthma. The phylogenetically ancient innate immune system, the complement system, is no exception. The emerging paradigm is that C3a production at the airway surface serves as a common pathway for the induction of Th2-mediated inflammatory responses to a variety of environmental triggers of asthma (i.e., allergens, pollutants, viral infections, cigarette smoke). In contrast, C5a plays a dual immunoregulatory role by protecting against the initial development of a Th2-polarized adaptive immune response via its ability to induce tolerogenic dendritic cell subsets. On the other hand, C5a drives type 2-mediated inflammatory responses once inflammation ensues. Thus, alterations in the balance of generation of the various components of the complement pathway either due to environmental exposure changes or genetic alterations in genes of the complement cascade may underlie the recent rise in asthma prevalence in westernized countries.

Figure 1.

Immunoregulatory role of complement activation pathways in asthma. (A) C5/C5a production driven either by microbial infections or their by-products or allergens during allergen sensitization leads to development of immune tolerance to inhaled antigens through the preferential recruitment, survival, or activation of plasmacytoid dendritic cells (pDCs). pDCs suppress the generation of effector cells by myeloid dendritic cells (mDCs) by sending an unknown inhibitory signal to mDCs and to T lymphocytes (perhaps in the form of B7-H1:PD-1 [programmed death ligand-1] ligation). Alternatively, pDCs may directly stimulate the differentiation of Tregs (CD4+ CD25+ T lymphocytes), leading to the development of tolerance to inhaled antigens. (B) C5 deficiency or C5aR blockade during initial exposure to allergens leads to an increase in the numbers of mDCs compared with pDCs, leading to sensitization to inhaled antigens, thus releasing the inhibitory “brake” on T cell stimulation. mDCs also produce the Th2-selective chemokines CCL17 and CCL22, further intensifying Th2 effector cytokine production. Direct production of C3a or as a result of C5a blockade may also result in enhanced Th2 cytokine production through as yet unknown mechanisms. (C) During the effector phase, both C3a and C5a are generated through activation of the classical pathway, and through proteases released from inflammatory cells. C3 is further amplified through the direct induction by IL-4 and IL-13 in the airway epithelium. Both C5a and C3a are pro-allergic and play an important role in the recruitment and activation of inflammatory cells (i.e., eosinophils, mast cells) known to be important in the induction of the cardinal features of asthma, including airway hyperresponsiveness, mucus metaplasia, and airway remodeling.