Old dogs—new tricks: immunoregulatory properties of C3 and C5 cleavage fragments

Abstract

The activation of the complement system by canonical and non-canonical mechanisms results in the generation of multiple C3 and C5 cleavage fragments including anaphylatoxins C3a and C5a as well as opsonizing C3b/iC3b. It is now well appreciated that anaphylatoxins not only act as pro-inflammatory mediators but as immunoregulatory molecules that control the activation status of cells and tissue at several levels. Likewise, C3b/iC3b is more than the opsonizing fragment that facilitates engulfment and destruction of targets by phagocytes. In the circulation, it also facilitates the transport and delivery of bacteria and immune complexes to phagocytes, through a process known as immune adherence, with consequences for adaptive immunity. Here, we will discuss non-classical immunoregulatory properties of C3 and C5 cleavage fragments. We highlight the influence of anaphylatoxins on Th2 and Th17 cell development during allergic asthma with a particular emphasis on their role in the modulation of CD11b conventional dendritic cells and monocyte-derived dendritic cells. Furthermore, we discuss the control of anaphylatoxin-mediated activation of dendritic cells and allergic effector cells by adaptive immune mechanisms that involve allergen-specific IgG1 antibodies and plasma or regulatory T cell-derived IL-10 production. Finally, we take a fresh look at immune adherence with a particular focus on the development of antibacterial cytotoxic T-cell responses.

Alarmins and immunity

“…For example, serum amyloid A (SAA) is chemotactic for DCs and other leucocytes and also activates DCs, and can therefore be considered an alarmin. Similarly, some components generated by the complement cascade such as C3a and C5a have both chemotactic and activating effects on leucocytes and are therefore likely to be alarmins. These considerations enable us to expand and redefine our view of some well‐known proinflammatory intercellular signals.…”

Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

“…Alongside their regulatory activities, some of the membrane‐bound RCAs also act as adhesion and/or signaling receptors. For example, CR1 on erythrocytes is important for shuttling C3b‐opsonized particles to the spleen and liver and is known to facilitate antibody‐mediated phagocytosis via Fc‐receptors . The interaction of CD46 with C3b, on the other hand, can induce or modulate intracellular signaling events on various lymphocytes, including the induction of a productive Th1 phenotype in T cells .…”

“…C3b-opsonized particles to the spleen and liver and is known to facilitate antibody-mediated phagocytosis via Fc-receptors. 6,109 The interaction of CD46 with C3b, on the other hand, can induce or modulate intracellular signaling events on various lymphocytes, including the induction of a productive Th1 phenotype in T cells. 110,111 Finally, the binding of CRIg to the key ring of C3b enables phagocytic clearance of opsonized particles by Kupffer cells and other tissue-resident phagocytes 94,112 ; of note, CRIg may also exert AP-specific regulatory functions by interfering with the binding of C3 to C3bBb and was recently reported to act as a direct PRM for Gram-positive bacteria.…”

Chemical Approaches to Modulating Complement-Mediated Diseases

“…MAC formation in organisms and infected or damaged cells enables cell lysis leading to death and elimination of debris. 4,8,17,18 The purpose of Complement activation is to protect the host but, if not appropriately regulated, it can also lead to deleterious effects.…”