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.

Shifting of Immune Responsiveness to House Dust Mite by Influenza A Infection: Genomic Insights

“…Anaphylatoxins are involved in the recruitment and activation of a number of leukocytes, including mast cells, eosinophils, and basophils, and were also implicated in the regulation of DC and T cell signaling (27). Thus, Flu infection enhanced the expression of a substantial number of innate molecules involved in the sensing and response to HDM.…”

Complement 5a Receptor Inhibition Improves Renal Allograft Survival

“…Such reduced T cell priming by C5aRA may be mediated via the ability of C5a/C5aR to induce tolerogenic DC subsets. 47,48 Another mechanism linking complement to T cell function is the decay accelerating factor. Decay accelerating factor-regulated IL-12 production and subsequent T cell differentiation into IFN-␥-producing effectors was prevented by the deficiency of either C3aR or C5aR in antigenpresenting cells.…”

Surfactant protein D inhibits TNF-α production by macrophages and dendritic cells in mice

“…Plasmacytoid dendritic cells make up the majority under baseline conditions, 23 and these cells were shown to be tolerogenic in allergen-induced inflammation. [24][25][26] On the other hand, myeloid dendritic cells migrate rapidly to the lung during T H 2-type inflammation and exert potent T H 2 cell activation. [24][25][26] Dendritic cells are generally differentiated by the membrane marker CD11c, although this marker is shared with alveolar macrophages.…”