Cellular and humoral immune responses

While some leukocytes in protochordate invertebrates (close relatives of the vertebrates) have been termed 'lymphocyte-like cells', evidence that these are homologs of vertebrate lymphocytes remains tenuous: these animals lack the rearranging genes and clonal expansion that characterize the vertebrate lymphoid receptors for antigen.

Among both primitive (acoelomate) taxa, such as the sponges and the corals, and more derived (coelomate, with blood circulatory systems) taxa such as the tunicates (sea squirts, phylum Chordata), many species live permanently fixed to solid substrata where competition for living space is severe, and the risk of being overgrown by neighbors is constant. Here, the ability to preserve one's genome (and pass it on through reproduction) is dependent on aggression toward neighbours. Such responses arc effected by cellular and molecular components of the interacting individuals. The kinetics of rejection (establishment of a necrotic zone where contact has occurred) is reduced on second or later encounter. This heightened reactivity is directed specifically at the genotype of the individual that was previously encountered; rejection responses to third party encounters follow kinetics similar to those of first encounters. These responses thus resemble vertebrate graft rejection responses in that they involve leuko-cyte-mediated alloaggression with specific memory! The fine discrimination of cell surface markers implied by these phenomena is also essential for correct tissue differentiation in all Metazoa. This ability to discern specific markers within a species should not be surprising, since even the earliest free-living eukaryotic amoebae must have been able to distinguish nutritive particles worthy of ingestion (food) from inorganic detritus, and potential mates from potential competitors/aggressors. Mating types, known for modern unicellular eukaryotes (e.g. yeast, Paramecium), are identified by means of specific carbohydrate markers (epitopes) on cell surfaces. Also, a diversity of cell surface markers and receptors able to distinguish these is essential for the maintenance of self-sterility and nonself-fertility in plants and animal gametes.

So-called alloaggressive responses occur also in nonsedentary (free-moving), noncolonial invertebrates. Leukocytes from different individual sipuncu-lid worms and echinoderms kill one another on encounter in vitro. And body wall allotransplants made between earthworms, between ribbon worms, between echinoderms, and between solitary tunicates meet fates like those described above for sponges, corals and colonial tunicates. It is surprising to find complex invertebrates in which alloaggression appears to be lacking. This is the case in molluscs (snails) and in insects, where nonself-recognition mechanisms remain poorly understood. Nevertheless, a fascinating variety of effector mechanisms in these animals is responsible for defense against microbial and parasitic infection.

The great variety of blood cells in invertebrates precludes meaningful treatment here. Suffice to say that cells containing respiratory pigments (usually hemoglobin) for the transport of oxygen occur in a small percentage of species. Other pigments, thought not to transport oxygen, occur in echinoderm (sea urchins) granular cells; their functions are unclear. In the majority of taxa, leukocytes (nonpigmented, free cells) are diverse. In primitive species lacking circulatory systems, amebocytes wander throughout the body, scavenging foreign and damaged material and, in some cases, contributing significantly to the nutrition of the organism. Most invertebrates have not only discrete nervous, excretory and musculoskeletal systems, but circulatory systems as well. In annelids (earthworms and their relatives) and echinoderms, more than one coelomic compartment contains free cells, and the role of scavenger may be met by distinct cell types in distinct locations. Among the more intriguing of the scavenging cells are the motile free urns of sipunculids and the vibratile cells of echinoderms. Common to all taxa, however, are phagocytic cells resembling vertebrate macrophages.

The fate of most foreign particles entering the body of a metazoan invertebrate is to be phago-cytosed or, if too large, encapsulated by leukocytes. Fixed phagocytes, analogous to the reticuloendothelial system, occur in crustacean gills and in the midgut glands of crustaceans and molluscs. All invertebrates, even those lacking body cavities - like sponges, anemones and flatworms - contain phagocytes, and in some species there are more than one phagocytic cell type. Like vertebrate macrophages, these cells orchestrate inflammatory responses, synthesize and use lysosomal enzymes, and possess cvto-cidal mechanisms dependent on superoxide and its metabolites.

In addition to phagocytosis, both encapsulation and nodule formation occur in invertebrates. Encapsulation is the net result of frustrated phagocytosis by many leukocytes. Metazoan endoparasites, unless they enter rare susceptible host individuals, elicit encapsulation, often with consequent death to the invader through toxic intermediates from an enzymatic cascade resulting in melanization. One recognition/effector mechanism, characterized in crustaceans, is the prophenoloxidase activating system that is present in many invertebrates and yields cytokines. A plasma protein binds microbial polysaccharides (LPS or [31-3 glucans) and induces activation of a prophenoloxidase-activating enzyme that cleaves the proenzyme prophenoloxidase yielding phenoloxidase. This oxidizes phenols to quinones that polymerize and form melanin, all exhibiting antimicrobial properties. Encapsulation may also involve sclerotization, an essential reaction in cuticle development. Nodule formation occurs in insects when large numbers of bacteria enter. In addition to phagocytosis, encapsulation and nodulation, these cells can exhibit cytotoxic responses against foreign pro- and eukaryotic cells.

The interaction of hemocytes with foreign materials can trigger clotting of plasma, limiting the spread of microbes in the body. In horseshoe crabs, hemolymph contains abundant proteins (hemocyanin, limulin/CRP and a2-M) and two types of hemocytes. The first - granulocytes - contain two types of secretory cytosolic granules that selectively store proteins participating in defense mechanisms. L-granules contain clotting factors, protease inhibitors (serpins and cystatin), anti-LPS factor and lectins with LPS-binding or bacterial-agglutinating activity. S-granules contain basic proteins with antimicrobial or agglutinating activity. Except coagulogen, all the clotting factors are serine proteases activated by limited proteolysis. LPS from gram-negative bacteria and (l-3)-p-d-glucans from fungi activate factors C and G respectively, triggering the clotting cascade. In synergy with other aforementioned factors, this comprises an effective host defense against pathogens. Hemocytes of the American horseshoe crab (Limulus polyphemus) have provided commerce with a sensitive probe for endotoxin.

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