Leeches are out in force in New England right now. Apparently, the slimy, defenseless creatures agree with humans that it has been a long, hard winter. The warm and moist weather we’re having has them going practically giddy. Instead of slithering along in the garden detritus keeping to the shadows, they are basking in full moonlight on the walk.
I have leeches on my mind because of a little computational inquiry we completed today after years of delay (thank you Becky Martin). It didn’t take long (perhaps about 15 minutes), but there it was — the answer to my query: Hirudin has few T cell epitopes. Remarkably few.
What is hirudin? It is a protein made by blood-sucking leeches and injected into the human blood stream so as to reduce clotting while the leech feeds. What are T cell epitopes? T cell epitopes are linear protein sequences, about 10 amino acids in length, that drive immune response, including the kind of antibody response in the blood that could bind to, and interfere with, hirudin.
Why do leeches have low potential immunogenicity, from the T cell epitope perspective? I suspect that the reason is to escape antibody response, but why and how did that happen? I tried to looked up human and leech co-evolution on Google tonight. I don’t know why I thought there might be information on line about the human evolutionary relationships with leeches (of the annelid variety), but, you never know. Somebody, somewhere could just be a leech fanatic and might have written a page for Wikipedia.
Indeed there is a page on leeches: https://en.wikipedia.org/wiki/Leech, but no mention of leech and human co-evolution. Come to think of it, leeches have actually evolved with blood – they have to inject hirudin into blood and can only effectively take their meal if the hirudin is not interfered with by neutralizing antibodies (like the ones that are generated by recombinant proteins and monoclonals such as Humira).
Linked to this page (below) is the EpiMatrix immunogenicity scale that Becky ran today, that shows hirudin as scoring ridiculously low, compared to other proteins. The scale is a straightforward count of T cell epitopes (presented by class II HLA that are common in humans to be specific; see our publications on line for more information on the calculation).
The finding that hirudin is almost devoid of T cell epitopes – a characteristic of a deimmunized protein -one that does not illicit an immune response when injected into blood.– is quite striking. It’s even lower on the scale than some other well-known non-immunogenic proteins. Such as albumin. And some other proteins.
We previously found this to be true of proteins that are abundant in extracellular space (in humans) and not of proteins that are intracellular or lower abundance. We published this observation in Clinical Immunology in 2007. Since then, we’ve paid attention to proteins that are high and low immunogenicity with sometimes surprising discoveries. Such as the fact that complement factor 3 (C3) has a particular section (C3d) that contains a high number of potential epitopes – that section binds to polysaccharide antigens, enhancing their immunogenicity (such as is seen with conjugated vaccines). (Knopf and De Groot, 2008).
And some proteins that are abundant in serum – such as IgG, are very low immunogenicity. This would also be consistent with our hypothesis. We also find that where these proteins have clusters of epitopes, the regions may actually have a critically important function. That’s how we discovered Tregitopes, which are highly conserved peptides in IgG that contain T cell epitopes now shown to suppress immune response (Treg epitopes, De Groot and Scott, 2008).
Getting back to deimmunization, it makes sense that hirudin would have few epitopes, since that would clearly benefit leeches. Hirudin without T cell epitopes would be incapable of inducing antibodies in its human host. Antibodies would interfere with the activity of hirudin, thereby limiting the period of time that a leech could feed. Thus ‘deimmunized hirudin” would be evolutionarily advantageous to the leech that injects this protein in human blood to survive.
But it’s curious that leeches would co-evolve in this way. Basically the human genetic profile would be having an influence on the evolution of the proteins of an anneid parasite that actually lives outside the human body. I’m not an evolutionary biologist, but I find the idea that something as large as a human could influence the genes of an organism as small as a leech quite amazing. There’s magic in that. It makes you wonder, also whether the magic goes both ways. Did leeches somehow teach humans to use them for medicinal purposes (an example of a meme) so as to improve their own survival?
In the meantime, I’m just going to ponder the idea that leeches make low immunogenicity proteins – “quality by design”. By the way, ticks also appear to do this, too.
Sometimes it’s a good idea to pay attention to the outliers. Like leeches basking in the moonlight on the garden path.