Evolution of anaphylatoxins, their diversity and novel roles in innate immunity: Insights from the study of ﬁsh complement J.O. Sunyer * , H. Boshra, J. Li Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 413 Rosenthal, 3800 Spruce St., Philadelphia, PA 19104, USA Abstract Anaphylatoxins are small molecules (9 kDa) that are generated as a result of the activation of the complement system. These molecules play an important role in inﬂammation, and they are responsible for the activation of various innate and adaptive immune processes. The study of these important inﬂammatory molecules has been restricted to mammalian species so far. Recent studies have shown that teleost ﬁsh, unlike any other known animal species, contain multiple forms of the C3a anaphylatoxin, all of which are functionally active and play a prominent role in inducing superoxide production in ﬁsh leukocytes. The C5a anaphylatoxin has also been characterized in these animals, and like in mammals, it plays an important role in leukocyte chemotaxis and in triggering the respiratory burst of leukocytes. Interestingly, it has been shown that rainbow trout anaphylatoxins play an unexpected role in enhancing phagocytosis of particles. C5a and C3a receptors have recently been cloned and characterized in rainbow trout, suggesting that the duplication of these receptors from a common ancestor occurred before the emergence of teleosts. The studies derived from these molecules in teleost ﬁsh indicate that the basic structure and function of anaphylatoxins and their receptors, have been conserved for more than 300 million years. # 2005 Elsevier B.V. All rights reserved. Keywords: Complement; C3a; C5a; Anaphylatoxin; Teleost; Evolution; Fish 1. Introduction Activation of the complement system by microbes results in the activation of the C3 and C5 components of complement, leading to the generation of C3a and C5a anaphylatoxins. These molecules are considered to be endogenous danger signals that induce the inﬂammatory response, and trigger the activation of several key innate immune processes (Gasque, 2004; Sunyer and Lambris, 1999). In addition, C3a and C5a are also known to inﬂuence the generation of adaptive immune responses (Tempero et al., 1997; Ulrich et al., 2000). Anaphylatoxins exert their effects through the C3a and C5a receptors (C3aR and C5aR), which are both members of the large rhodopsin family of seven-transmembrane G-protein-coupled receptors (Ember and Hugli, 1997; Gasque, 2004). While anaphylatoxins have been extensively studied in mammals, very little is known about their presence and function in invertebrates or non-mammalian www.elsevier.com/locate/vetimm Veterinary Immunology and Immunopathology 108 (2005) 77–89 * Corresponding author. Tel.: +1 215 573 8592; fax: +1 215 898 7887. E-mail address: sunyer@vet.upenn.edu (J.O. Sunyer). 0165-2427/$ – see front matter # 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.vetimm.2005.07.009