Jaws and AIS

Abstract

In considering the ongm of the anticIpatory (adaptive) immune system (AIS), we have developed several theses. We propose that the AIS emerged not in a big bang, but gradually, in a piecemeal fashion. Different components of the AIS emerged at different times. For example, rudimental antigen processing systems existed before the protostome-deuterostome split; lymphocytes may have appeared before the divergence of gnathostomes from the agnathans; the RAG-based diversification mechanism emerged close to the origin of gnathostomes; and so on. Whether living agnathans possess Mhc, Tcr, and /g genes in some form remains an open, but answerable question. Non-vertebrates have not evolved the AIS because this option is not included in their developmental program. (Jawed) vertebrates evolved the AIS not because they are plagued by parasites more than non-vertebrates, but because their developmental program and their body plan allowed it. There is no single factor (such as the appearance of jaws) responsible for the emergence of the AIS. The system is the result of a set of particular circumstances and of a particular pattern of embryonic development. The vertebrate developmental pattern is contingent on specific changes in the genome, both in the regulatory and structural genes. The trigger for the changes may have been a w~olesale genomic amplification leading to the formation of new regulatory circuits. The amplification provided genes (e.g., those of the Mhc proper), cells (e.g., donaHy-selected lymphocytes), tissues (e.g., neural crest), and organs (e.g., the thymus) necessary for the fuH realization of the AIS. Although the impetus for the emergence of the AIS was endogenous, the evolution of the AIS was driven by selection exerted by parasites. The selection-driving factors included increase in body and tissue complexity, increase in the efficiency of the circulatory systems, lengthening of lifespan, and reduction in fecundity. None of these factors are unique to vertebrates, but together they make vertebrates more vulnerable to parasites. The time interval required for the agnathan-gnathostome transition remains undetermined; it may have been as long as > 160 million years. The various mechanisms by which organisms resist assaults from parasites can be classified into two broad categories -those effected by the anticipatory (adaptive) immune system (AIS) and those comprising the nonanticipatory (nonadaptive) immune system (NAIS; see Klein and Horejsi 1997). The fonner rely on the interplay of three receptor sets which together anticipate all ligands (antigenic detenninants) that parasites can present to the host, except those present in the host itself (i.e., the system discriminates between self and nonselt). The latter involve a variety of unrelated receptors, each specific for a particular ligand usually shared by many different parasites (Klein 1999). The three receptor sets of the AIS are the major histocompatibility complex (l\I1hc) molecules, the T-cell receptors (Tcr), and the B-cell receptors (Bcr) or immunoglobulins (Ig). Each of the l\I1hc receptors is broadly specific for a set of peptides which have certain physico-chemical characteristics in common. The specificity of these receptors is genn line-detennined and it varies from one allele to another among individuals of a population. The specificity of the Tcr and Bcr is determined in part in the genn line by large sets of separate gene segments and in part by somatic mechanisms involving shuffling of the segments and mutations. The Tcr are specific for the Mhc receptors and the peptides bound to them, whereas the Bcr recognize antigens independently of the Mhc molecules. Both the Tcr and Bcr are expressed clonally, each T or B lymphocyte expressing a receptor of a single specificity. An encounter with the matching ligand leads to the activation of the lymphocyte, expansion of the done, and the generation of memory cells which can be rapidly expanded upon a re-encounter with the same antigen. There is now a general agreement that invertebrates (nonchordates) lack the AIS and rely exclusively on the NAIS for protection against parasites. This conclusion is based primarily on the failure to find any evidence for the presence of AIS receptors (Mhc, Tcr, Bcr) in any of the invertebrate taxa examined. Indeed, in the one nonchordate animal whose genome has been sequenced in its entirety, the nematode Caenorhabditis elegans, there is no sign of the three sets of AIS receptor genes (The C. elegans Sequencing Consortium 1998). Less certain is the time of AIS emergence within the chordates (Fig. 1). Some recent developments in the molecular biology of the AIS have been widely interpreted as favoring the notion that the AIS may be restricted to the jawed vertebrates, the Gnathostomata, and hence that it may have arisen during the transition from the jaw less vertebrates, the Agnatha, to Gnathostomata (henceforth the A-G transition). This view, too, is in the main based on the failure of several laboratories to clone agnathan Mhc, Tcr, and /g genes. Here we take a critical look at the evidence for the absence of the AIS in agnathans, examine what it may take to pinpoint the origin of the AIS more precisely, and speculate on the evolutionary incentives that may have been behind the emergence of the AIS.