There also is evidence of expansion of IgSF molecules in invertebrates. For example, like many immunoglobulins, chitin-binding protein (CBP) of Branchiostoma is a close structural homolog of JAM-A (Table 2 ). Variable region-containing (V) CBPs contain a V-type immunoglobulin domain with extensive sequence diversity in the N-terminal region [21, 22] . This diversity is thought to result from high haplotype variation, including variable copy number, polymorphisms, and potential for alternative splicing [23] . Another of the closest structural homologs of JAM-A is Down syndrome cell adhesion molecule (Dscam), an IgSF member of the more evolutionarily distant invertebrate Drosophila (Table 2) . Dscam is an immune mediator found in clusters of variable exons flanked by constant exons [24, 25] . Thousands of different Dscam molecules can be generated via alternative splicing, a mechanism that is highly conserved across insect orders [26] . Secreted isoforms of Dscam circulating in insect hemolymph contribute to phagocytic uptake of bacteria. While the structural similarities between JAM-A and VCBP or Dscam may not indicate a direct evolutionary relationship, it is clear that diversification and secretion of soluble forms of IgSF molecules can occur in invertebrates and raise the possibility that pathogens have had selective influence on the diversification and secretion of these molecules. Thus, IgSF proteins that served as precursors to soluble adaptive immune effectors may have diversified both prior to and following their introduction into the vertebrate genome. A more thorough examination of IgSF members in invertebrates may clarify mechanisms that led to the evolution of modern adaptive immune mediators and the role of JAM/CTX family molecules in this evolutionary process.