Written by Lauren Robertson, Science Writer.
Research from the University of Pittsburgh School of Medicine has revealed that some of the key components of our adaptive immune system evolved much earlier than we previously thought – more than 540 million years ago to be precise. The study, published in PNAS, suggests that a better understanding of the self-recognition process in invertebrates could help improve our understanding of transplant rejection in humans and guide the development of new immunotherapies.
Under the sea
Scientists have been peering beneath the depths of the ocean to study immunology for decades. A lot of work has gone into studying a marine creature called Hydractinia symbiolongicarpus – a tube-like organism belonging to the same group as jellyfish, corals and sea anemones. Hydractinia are adorned with tentacles that help catch prey and they tend to grow in colonies atop the shells of hermit crabs. So why are they of interest to researchers? Because they possess the ability for self-recognition – a staple of the human immune system.
“As colonies grow and compete for space on crab shells, they often bump into each other,” said senior author Matthew Nictora, assistant professor of surgery and immunology at the Thomas E. Starzl Transplantation Institute. “If two colonies recognize each other as self, they fuse together. But if they identify each other as non-self, the colonies fight by releasing harpoon-like structures from special cells.”
To understand whether this self-recognition process works in a similar way to that of humans, Nictora and his team took a closer look at the genes (and encoded proteins) involved.
Spotting a structure
The group had already identified a pair of genes involved in the organism’s unique fuse-or-flight system, but they predicted there must be something else at play.
“If you imagine that the genome of the animal is spread out in front of us, we had a flashlight on these two little points, but we didn’t know what else was there,” said Nicotra. “Now we’ve been able to sequence the whole genome and illuminate the whole region around these genes. It turns out that Alr1 and Alr2 are part of a huge family of genes.”
All in all, they sequenced 41 Alr (allorecognition) genes involved in a complex that controls self-recognition. They then looked more closely at the proteins encoded by these genes and compared them to other proteins found in vertebrates – specifically, the immunoglobulin superfamily (IgSF) that includes antibodies and lymphocyte receptors.
In previous years, this type of work might have been near-impossible. But thanks to the recent release of AlphaFold, the researchers were able to make more accurate predictions about the 3D structures of these proteins based on their gene sequences.
An insight into immunity
Although their amino acid sequences vary greatly, IgSF proteins are made up of highly conserved residues. Their structure typically consists of 3 regions, including one called the V-set (variable) domain. These V-set domains get rearranged in a mature B or T cell, producing a variable sequence that the immune system uses to recognise “foreign” objects like pathogens or other cells.
Intriguingly, the Alr proteins found in Hydractinia symbiolongicarpus appeared to have a very similar structure to that of the V-set domains – albeit they seemed a bit “strange.” In other words, they lacked most of the highly conserved residues seen in other animals, but still adopted a structure very similar to V-set domains.
This is the first time a study has found IgSF proteins in such a distantly related animal. Until now, it was believed that V-set domains arose in a branch of the animal kingdom that originated around 540 million years ago. The new findings suggest that they were around much further back in the evolutionary tree.
“We know lots about the immune systems of mammals and other vertebrates, but we’ve only scratched the surface of immunity in invertebrates,” said Nicotra. “We think that a better understanding of immune signalling in organisms like Hydractinia could ultimately point to alternative ways to manipulate those signalling pathways in patients with transplanted organs.”
