What with visiting speakers and new faculty recruitment, I’ve been out late every night this week; what with committee meetings1 and trying to squeeze in experiments, I’ve been up early every morning; and what with teaching starting up again, seminars from visiting speakers and recruitees, and faculty meetings, I’ve had little time for other stuff. So this is going to be a short post. 2
A while ago I talked about lamprey immune systems. The key points are that lampreys …
- have an immune system
- that works pretty well
- and in concept looks a lot like our immune system, with lymphocytes and specific receptors
- but the receptors are utterly unlike our T cell receptors and antibodies
- using instead of the immunoglobulin domain structure, a leucine-rich repeat (LRR) structure;
- and, instead of using RAG-based recombination, uses a gene conversion system to generate diversity.
There’s a temptation, even for those who intellectually know better, to assume that “primitive” animals have “worse” systems; so because lampreys are more like the common ancestor of vertebrates, their immune system must be “worse”. (Hagfish and lampreys, which may have diverged some some 500 million years ago — see the figure to the right;3 click for a larger version — have very similar immune systems, so this system must be at least that old.) In some ways the mammalian immune response does seem to have some advantages — faster memory response, for example. Still, lamprey immune systems have served them well for 500 million years, which is more than we can say about ours; and in some other ways lampreys do better than we do. They have if anything a greater diversity to their receptors, for example, potentially generating more than 1014 different receptors — compare to our roughly 108 T cell receptors.
Max Cooper, who has done much of the work on lamprey immunity,4 has just published a paper showing off some other unusual properties of lamprey immune receptors. 5 Since there’s no system for making lamprey monoclonal antibodies that’s analogous to the mouse monoclonal antibody systems, he used a molecular cloning approach to express monoclonal variable lymphocyte receptor (VLR) -B cDNAs from immunized lampreys.
What did they get?
They got soluble “antibodies”, capable of the highly specific recognition that’s seen in conventional monoclonal antibodies. The VLR-B antibodies are extraordinarily stable, maintaining binding at pH 1.5 and maintaining structure at pH 11, as well as after incubation at 56 oC for a couple days or at room temperature for weeks. 6 Although the individual LRR subunits have relatively low binding affinity, they are secreted as multimers of eight to ten subunits (see the diagram to the left), and as a result the VLR-B binding ability can be at least as good as mouse monoclonals: “Equal concentrations of VLR4 and EA2-1, starting at 0.5 mg/ml, were serially diluted in 10-fold increments and scored for the degree of spore agglutination. Spore agglutination by VLR4 was detected at a concentration 1,000-fold more dilute (5 pg/ml) than the mouse monoclonal antibody (5 ng/ml).”
Finally, as opposed to mouse monoclonals, these are single proteins; conventional mouse monoclonals have two components, a heavy and a light chain. That makes VLR-B easier to work with in some ways: “The single peptide composition of VLR-B antibodies makes them more amenable to molecular engineering, including manipulation of the antigen binding site by mutagenesis and fusions to the coding sequences of other peptides, such as enzymes, toxins, and epitope tags to extend their functional capabilities.” 7
These things clearly have potential to be useful in all kinds of things — a nice example of basic research giving rise to clinically and commercially useful tools.
- Proof, if proof were needed, that deans are evil: 7:30 AM meeting with the dean[↩]
- Also, I just realized I really, really need to get some flowers for my wife today, don’t I.[↩]
- From: Modern look for ancient lamprey. Philippe Janvier. Nature 443, 921-924(26 October 2006 [↩]
- It was his talk at the Autumn Immunology Conference in Chicago a couple of years ago that made me realize how fascinating the subject is[↩]
- Herrin, B.R., Alder, M.N., Roux, K.H., Sina, C., Ehrhardt, G.R., Boydston, J.A., Turnbough, C.L., Cooper, M.D. (2008). Structure and specificity of lamprey monoclonal antibodies. Proceedings of the National Academy of Sciences, 105(6), 2040-2045. DOI: 10.1073/pnas.0711619105[↩]
- Conventional antibodies are pretty stable, but not up to this level.[↩]
- I think it’s camels that make single-chain antibodies, and there’s been interest in developing monoclonal systems based on camel antibodies for the same reason.[↩]