The Role of Anaphylatoxins C3a and C5a in Regulating Innate and Adaptive Immune Responses

Abstract

C3a and C5a, the small (approximately 10KDa) cleavage fragments released by complement activation, are potent mediators of inflammation. They are anaphylatoxins and act as cell activators with nanomolar affinity, exerting their functions through binding to specific receptors (C3aR and C5aR or C5L2 respectively). Recent studies suggest that locally generated complement effector molecules including C3a and C5a contribute to pathological processes in inflammatory and immunological diseases as well as adaptive immune response besides its host defence mechanism. Targeting the receptors and/or their ligands can reduce undesired inflammatory responses and tissue damage in certain pathological conditions. In this article we describe the recent developments in this important area and focus on the role of C3a/C5a in inflammatory and autoimmune diseases and in adaptive immune responses.

Elevated plasma neutrophil elastase concentration is associated with disease activity in patients with thrombotic thrombocytopenic purpura

“…The presence of correlation between PMNE and Bb levels point to the initiation of alternative amplification loop extending complement activation. Complement activation attracts and activates neutrophils [31,32], and in turn may exacerbate NET release, initiating a positive feed-back loop. These observations are in line with the recent report on the association among circulating nucleosomes, activated neutrophils (as indicated by increased neutrophil elastase-α1-antitrypsin complexes), and presence of deep vein thrombosis [33].…”

Complement C3a, CpG Oligos, and DNA/C3a Complex Stimulate IFN-α Production in a Receptor for Advanced Glycation End Product-Dependent Manner

“…C1q deficiency causes a defect in the clearance of apoptotic cells (33), reduces B cell tolerance to intracellular Ags (34), and predisposes patients to autoimmune disease. Complement C3a is a small 7-kDa protein generated by C3-convertase during complement activation through the classical pathway, MB-lectin pathway, or alternative pathways (35). C3a is one of most potent mast cell chemoattractants and induces mast cell degranulation (36).…”

Deficiency of C5aR Prolongs Renal Allograft Survival

“…1 In addition to their role in innate immunity, several effector molecules including C3a and C5a have been shown to regulate adaptive immunity through activation of their receptors on immune cells. 2,3 The small fragments C3a, C4a, and C5a released by complement activation are anaphylatoxic peptides. Of these mediators, C5a has the highest specific biologic activity.…”

“…4 Expression of C5aR has been reported in many cell types including both myeloid and nonmyeloid cells. 2,4 It is well known that engagement of the receptor on several myeloid cells (e.g., neutrophils, monocytes/macrophages, and mast cells) leads to the induction of local inflammation through a process of cellular degranulation, increased vascular permeability, and leukocyte recruitment to the site of injury/infection, whereas engagement of the receptor on parenchymal cells (e.g., endothelial cells and epithelial) lead to cell activation and functional modulation. 4 Although C5a-induced inflammation plays an important role in the host defense, many studies have shown that C5a can also cause undesired inflammatory responses that contribute to the pathogenesis of several inflammatory diseases such as sepsis, asthma, and ischemia/reperfusion injury.…”