Invertebrate immune systems--not homogeneous, not simple, not well understood

Abstract

The approximate 30 extant invertebrate phyla have diversified along separate evolutionary trajectories for hundreds of millions of years. Although recent work understandably has emphasized the commonalities of innate defenses, there is also ample evidence, as from completed genome studies, to suggest that even members of the same invertebrate order have taken significantly different approaches to internal defense. These data suggest that novel immune capabilities will be found among the different phyla. Many invertebrates have intimate associations with symbionts that may play more of a role in internal defense than generally appreciated. Some invertebrates that are either long lived or have colonial body plans may diversify components of their defense systems via somatic mutation. Somatic diversification following pathogen exposure, as seen in plants, has been investigated little in invertebrates. Recent molecular studies of sponges, cnidarians, shrimp, mollusks, sea urchins, tunicates, and lancelets have found surprisingly diversified immune molecules, and a model is presented that supports the adaptive value of diversified non-self recognition molecules in invertebrates. Interactions between invertebrates and viruses also remain poorly understood. As we are in the midst of alarming losses of coral reefs, increased pathogen challenge to invertebrate aquaculture, and rampant invertebrate-transmitted parasites of humans and domestic animals, we need a better understanding of invertebrate immunology.

Fig. 1. An illustration of the conditions under which diversification without subsequent selection is likely to have a positive effect

The abscissa is the inverse off-rate and the ordinate is the effectiveness of the response. Suppose that τ₀ is the current value of the inverse off-rate. The three panels show the different behaviors that can occur in the neighborhood of τ₀. The top panel shows the case of a negative second derivative. Note that this condition diminishes the advantage of increasing τ and exacerbates the disadvantage of decreasing τ. Thus, the expected value in the presence of diversification, f_T, is less than the current value of the effectiveness f(τ₀). The middle panel shows the case where the second derivative is zero, where potential advantage is exactly balanced by potential disadvantage, so that f_T = f(τ₀). Finally, the bottom panel shows the case of particular interest: positive second derivative, which enhances the advantage of increasing τ and moderates the disadvantage of decreasing τ. Under these circumstances, the expected value under random diversification is greater than the present value, so that diversification becomes a good bet, even without selection.

Fig. 2. A general model indicating hypothetical interactions between the major component of the invertebrate defense system, a multipurpose hemocyte, and self, non-self (pathogen), and virally infected self cells

This model emphasizes the recognition phase of the interaction and does not consider the signaling pathways or effector mechanisms employed by the hemocyte in actually killing a pathogen. Note that the version presented involves a system of dual recognition, featuring both detection of a specific self signal, which is found on self cells, and non-self signals, which are on pathogens or virally infected self cells. Pathogens are assumed to be capable of generating diversified antigens. Receipt of a self signal conveys an inhibitory signal to the hemocyte and downregulates a response, analogous to natural killer (NK) cells, although no strict homology with NK self receptors is implied. In addition to a self receptor, two different kinds of non-self receptors are illustrated, both of which convey stimulatory signals to hemocytes. The response of the hemocyte might depend on the integration of both inhibitory and stimulatory signals. Non-self receptors of the first category are the conventional pattern-recognition receptors such as the surface-associated peptidoglycan-recognition protein receptors of Drosophila (24). These would interact with a repetitive pattern on a bacterium, fungus, or possibly a virus. Also shown is a hemocyte-associated multipurpose receptor that interacts with a set of diversified humoral non-self recognition molecules. These humoral factors might be diversified by processes such as somatic mutation and gene conversion. Once these recognition molecules have bound a pathogen-associated antigen, they are either modified or undergo a conformational change that allows them to interact with the multipurpose hemocyte receptor. Note that some of these diversified recognition molecules might react with components on self cells, creating the possibility of autoreactivity. This tendency could be overridden by simultaneous receipt of the self signal by the self receptor. Note also that the pathogen may bear a mimicked self signal that enables it to escape detection. Another pathogen strategy not shown here is the production of factors that directly harm or interfere with defense cells or molecules. Self cells infected with a virus might either undergo downregulation of self signals or upregulation of membrane-associated viral antigens, tipping the balance in favor of destruction of the infected cell. Depending on the invertebrate involved, symbionts may also play a role in producing anti-microbial peptides or other biologically active compounds that inhibit pathogen growth.