Integrating Innate Immunity into a Global “Systems” Context: The Complement Paradigm Shift - Systems Biology: Networks, Models, and Applications - page 179

their weak adaptive immune response and poor and undiversified
Ig repertoire. In an effort to characterize the phylogeny of C3 in inver-
tebrates and lower vertebrates, recent studies have documented the
existence of multiple C3 isoforms in two teleost fish species: the rain-
bow trout, Oncorhynchus mykiss , and the gilthead seabream, Sparus
aurata [69,70]. In all other animals studied so far, C3 was shown to exist
as a single gene product. However, the three trout C3 isoforms (C3-1,
C3-3, C3-4) are products of different genes and significantly differ in
their binding efficiencies to various C'-activating surfaces [69]. Such
findings have favored the hypothesis that teleost fish have developed
a unique approach to expand their innate immunity by duplicating
their C3 genes. Thus, the structural and functional C3 diversity
observed in fish may have important consequences for our under-
standing of the evolution of the C3 molecule, and other innate immune
processes.
The Search for Complement Receptors in Lower Vertebrates
Complement anaphylatoxins mediate their proinflammatory functions
by binding to G-protein-coupled transmembrane receptors that are
expressed mainly on blood-derived leukocytes. Their function has
been—thus far—characterized only in mammalian systems, since no
such receptors have been cloned or isolated in lower vertebrates.
Recently, evidence was produced suggesting that inflammatory path-
ways mediated by anaphylatoxic peptides are present both in teleost
fish and urochordates, an invertebrate species.
The presence of two C3-like genes in the invertebrate urochordate
Ciona intestinalis [71] was recently demonstrated . To define the func-
tions mediated by these innate immune molecules in urochordates, the
C3a moiety of Ciona C3-1 (CiC3-1a) was expressed in E. coli and shown
to stimulate the dose-dependent directional migration of granular
amebocytes (hemocytes), in a manner similar to mammalian C3a. The
chemotactic activity of this peptide was localized to the C-terminus,
and pretreatment of Ciona hemocytes with pertussis toxin abolished
the chemotactic response to C3a, suggesting that this effect is mediated
by a Gi-protein-coupled receptor. This is the first report documenting
the presence of a C3aR-like receptor in an invertebrate species [72].
Furthermore, recent studies have demonstrated the presence of a
functional C5aR receptor in a teleost species, the rainbow trout.
Recombinant trout C5a was able to induce the chemotactic response of
trout granulocytes isolated from a head kidney cell population in a
dose-dependent fashion, and C5aR receptor expression was localized
in granulocyte/macrophage cell suspensions of the head kidney as
well as in trout peripheral blood leukocytes [73].
Taken together, these results strongly indicate that the inflamma-
tory pathways mediated by C3a and C5a are also present in lower