Allorecognition and Immunity
Allorecognition is the ability of an individual to discriminate its own cells and tissues from those of another individual, and is the process that controls the acceptance or rejection of transplanted tissues in the clinic. In mammals, transplants are rejected by the adaptive immune system, but the proteins that control the outcome are not found in organisms below the cartilaginous fish (e.g., sharks). In contrast, allorecognition is found throughout the metazoa, with examples in nearly every phylum. Why is this ability so widespread, and why has it been conserved through evolution? Are the origins of the mammalian adaptive immune system found somewhere in these more primitive allorecognition systems? The answer touches upon fundamental questions in multiple disciplines, including immunology, stem cell and developmental biology.
Botryllus undergoes a natural transplantation reaction when two individuals come into contact. Terminal projections of the vasculature, called ampullae, touch, and that interaction will result in one of two outcomes. Either the two ampullae will fuse, creating a vascular parabiosis (and hematopoietic chimera), or they will reject, an active inflammatory reaction that prevents further interactions. Fusion or rejection is rapid (the response takes 48 hours), and is controlled by a single, highly polymorphic locus called the fuhc with the following rules- two individuals that share one or both fuhc alleles are compatible and will fuse, while those sharing neither will reject. There are about 1000 alleles of the fuhc worldwide, thus Botryllus can detect a self-allele from hundreds of competing specificities, a remarkable level of discrimination reminiscent of vertebrate adaptive immunity. The fuhc locus contains multiple genes that play a role in this reaction, including receptors, ligands, and chaperones, and we are carrying out both in vivo molecular mechanistic studies as well as in vitro biochemical assays to dissect their roles in the reaction. We wish to understand how this remarkable specificity is established and maintained over time, and if there are any evolutionarily conserved aspects of allorecognition.