Clemens A Dahinden, Institute of Immunology and Allergology Inselspital, Bern, Switzerland

The term anaphylatoxin stems from the observation, originally made by Friedberger in 1910, that injection of complement-activated serum in small experimental animals, such as guinea pigs, results in an anaphylactoid reaction similar to the symptoms of an acute hypersensitivity shock which occurs after exposure of sensitized animals to the antigen. This acute, potentially lethal, reaction was found to be due to small bioactive fragments, termed anaphyla-toxins to describe the functional behavior of these humoral factors. Some of the effects of systemic administration of anaphylatoxins are due to the release of bioactive cell-derived mediators as in hypersensitivity reactions, but the lethal effect is rather related to the potent spasmogenic activity of the anaphylatoxins causing respiratory failure due to acute bronchiolar constriction. It is unlikely that in humans anaphylatoxins have such dramatic effects, although they certainly contribute to the pathogenesis of, for example, septic shock and the acute respiratory distress syndrome (ARDS) in synergy with other proinflammatory factors, such as lipopolysac-charide (LPS) and tumor necrosis factor (TNF). Indeed, high levels of C3a can be detected in vivo under these clinical conditions.

Mainly based on their activity on the isolated guinea pig ileum, the anaphylatoxins C3a, C4a and C5a have been isolated from complement-activated serum and their amino acid sequence was determined many years ago. A large number of more recent func tional studies, and the characterization of anaphylatoxin receptors, however, clearly established that the anaphylatoxins are typical chemotactic cell agonists. They act in a very similar fashion to other chemotactic agonists, such as the bacterial leader sequence analogue N-formyl-met-leu-phe, the cell-derived lipid mediators leukotriene B4 and platelet-activating factor, and the very large group of cell-derived chemotactic cytokines, the chemokines. All these agonists act on cells mainly of hematopoietic origin, by interaction with specific, pertussis toxin-sensitive, Grcoupled seven-transmembrane (serpentine) receptors, and they activate the cells by utilizing very similar signal transduction pathways leading to similar cellular functions. Based on sequence homologies and the similarity in function, the receptors for all chemotactic agonists, including the receptors for anaphylatoxins, constitute a subfamily of the rho-dopsin receptor superfamily. It is important to note that, despite this redundancy, the anaphylatoxins are the only well-characterized endogenous humoral inflammatory mediators among this large group of chemotactic leukocyte agonists.

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