Similarities in mechanisms of ligand engagement by IgSF pathogen receptors and immunoglobulins, coupled with the evolution of the immunoglobulin fold prior to the existence of the vertebrate adaptive immune system, suggest the possibility that primitive members of the JAM/CTX and nectin families evolved to become soluble adaptive immune mediators in modern vertebrates. One attractive hypothesis is that soluble forms of pathogen receptors served as precursors to molecules of the adaptive immune system. Soluble receptors would neutralize viral [18] . Expression of a soluble pathogen receptor followed by duplication within the primitive genome and acquisition of mutations that permitted recognition of additional pathogens could confer a strong selective advantage. Upon introduction of RAGs into the vertebrate genome, such a gene family would have been primed to express molecules akin to present-day immunoglobulins. Alternatively, membrane-anchored forms of IgSF molecules that arose in primitive invertebrates may have been maintained in the genome due to their cell-adhesion functions, followed by the serendipitous introduction of mechanisms for the secretion and generation of diversity. In this scenario, pathogens may have contributed to the evolution of the modern adaptive immune system at much later evolutionary times. Is there evidence that favors either of these potential evolutionary mechanisms? In addition to similarities in their ligandbinding strategies, many of the closest structural homologs of JAM-A are immunoglobulins, which raises the possibility that immunoglobulins are more closely related to JAM-A than to other IgSF molecules. A search for structural homologs of the JAM-A D1 domain using the Dali algorithm [19] provides support for this hypothesis. The closest structural homologs of the JAM-A D1 domain are immunoglobulin domains, with the highest Dali Z-score of 14.6 for an IgAk variable domain (PDB code 2FBJ) ( Table 2) . Other IgSF proteins with similarity to JAM-A D1 have significantly lower Z-scores. The Z-scores correlate well with root mean square deviations for superpositions of JAM-A D1 with immunoglobulins, which also are lower (i.e., more similar) than the corresponding values for superpositions of JAM-A D1 with other IgSF proteins. This homology search can be extended to CAR, neural cell adhesion molecule, and nectin-like molecule 1, which result in Z-scores that are generally higher for the superposition of their D1 domains with immunoglobulins than with other cell adhesion molecules. In urochordates (Ciona) and cephalochordates (Branchiostoma), evolutionarily close relatives of the vertebrates, there are homologs of JAM/CTX and nectin IgSF molecules with features of membrane receptors. Ciona encodes only a single JAM/CTX-like molecule and two nectin-like molecules [20] . In humans, these molecules are all part of a single linkage group involved in immune function [17, 20] . Taken together, these results suggest that relatively few JAM/CTX and nectin family IgSF molecules were maintained in invertebrates, and the expansion and duplication resulting in the evolution of immunoglobulins may have occurred after the introduction of these molecules into the vertebrate genome.