A complex role for complement in allergic asthma

Abstract

Allergic asthma is a chronic inflammatory disease of the upper airway. It is well appreciated that maladaptive Th2 immunity promotes the allergic phenotype, the underlying mechanisms of which remain elusive. The disease is associated with activation of complement, an ancient danger-sensing component of the innate immune system. Different models of experimental allergic asthma suggest that the small complement fragments of C3 and C5, the anaphylatoxins C3a and C5a, not only promote proallergic effector functions during the allergic effector phase but regulate the development of Th2 immunity during allergen sensitization. The available data support a concept in which C5a is dominant during allergen sensitization and protects against the development of maladaptive Th2 immunity. By contrast, C3a and C5a appear to act synergistically and drive allergic inflammation during the effector phase. In this article, we will review the recent findings in the field to judge the benefit of complement targeting in allergic asthma.

Keywords: Th2 cytokine; allergic asthma; anaphylatoxin; complement; dendritic cell; innate immunity.

Conflict of interest statement

Financial & competing interests disclosure

This work has been supported by NIH grant AI057839 and DFG Transregio 22 project A21 to Jörg Köhl. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1. Complement system sensing of exogenous and endogenous danger in the fluid phase

The immunosensors C1q and MBL are soluble proteins that recognize exogenous and endogenous danger-associated molecular patterns (DAMPs). Recent data suggest that properdin may also serve as an immunosensor for exogenous and endogenous DAMPs. Exogenous DAMPs are mainly of microbial origin. They are often released from injured or apoptotic cells or can be altered self-molecules on the cell surface. The complement-derived danger sensors not only recognize DAMPs but translate the danger information into specific cellular responses by directly interacting with specific receptors on cells or activation of the complement cascade, which generates split products of C3 and C5 that target cells through a panel of complement receptors (danger transmission; lower right). C3 acts as a ubiquitous danger sensor that becomes activated through nucleophilic attack of its thioester. Once activated, it covalently binds as C3b to its activator surface. Specificity is gained by the environment of the activator surface, that is, the availability of complement regulator molecules, which ultimately decides the fate of the C3b molecule. This can be either termination of further C3 cleavage, or amplification of C3 cleavage to generate huge amounts of C3b and its degradation products iC3b, C3dg and C3a. The latter outcome results in danger transmission through activation of C3 cleavage product-specific receptors (danger transmission: lower right). C3aR: C3a receptor; C5aR: C5a receptor; CD46: Membrane cofactor protein; CR1–4: Complement receptors 1–4; CRIg: Complement receptor of the Ig superfamily; MAC: Membrane attack complex; MBL: Mannan-binding lectin. Modified with permission from [69].

Figure 2. Potential mechanisms underlying the immunoregulatory functions of anaphylatoxin receptor signaling during allergen sensitization

(A) Upon allergen exposure, pulmonary mDCs stimulate naive CD4+ T cells (Th0) through antigen presentation, upregulation of costimulatory molecules and secretion of proinflammatory cytokines, resulting in Th2 proliferation and activation. C5aR signaling in mDCs promotes mDC-mediated activation of naive T cells. C3aR signaling in mDCs is dispensable for mDC-mediated T-cell activation, but modulates the expression of C5aR in pulmonary DCs to regulate T-cell priming indirectly. (B) The absence of C5aR signaling negatively regulates the accumulation of pDCs expressing inhibitory B7-H1 and B7-DC molecules. Such pDCs are required to block the development of Th2-biased immune responses directly by negatively regulating mDC–T-cell interactions or indirectly by promoting the generation of immunosuppressive Treg cells. The decrease of tolerogenic pDCs results in enhanced polarization and proliferation of Th2 effector cells. In summary, anaphylatoxin receptors play critical roles at the DC/T-cell interface to regulate polarization of the Th2 lineage in response to initial allergen exposure. Solid arrows represent pathways that are triggered when C5aR signaling is intact. Dotted lines represent arrows that are favored in the absence of C5aR signaling. C3aR: C3a receptor; C5aR: C5a receptor; HDM: House dust mite; mDC: Myeloid dendritic cell; pDC: Plasmacytoid dendritic cell; TLR: Toll-like receptor; Treg: Regulatory T cell.