For anyone else with a 6-year-old kid: You will need Figure 3 from the Dromaeosaurid article1 in today’s issue of Science.
This is not a drill.
Problem: Neurons are very sensitive to all kinds of chemicals, and need protection from some of the crap that circulates through our blood vessels.
Solution: A blood-brain barrier acts as a firewall between the circulation and the brain.
Problem: Viruses infect cells.
Solution: Cytotoxic T lymphocytes constantly survey cells and destroy those that are infected.
Problem: Overenthusiastic CTL in the brain cause inflammatory diseases like multiple sclerosis.
Solution: Keep them out of the brain as well.
Problem: Viruses infect the brain too.
Solution: D’OH!
Part of the solution is described in a recent paper1 (and I will admit up front that one motivation for talking about this paper is that it gives me an excuse to use the gorgeous image at left,2 which I ran across on Wellcome Images a while ago).
It’s clear that in fact some CTL can enter the brain, but they’re much less abundant there than in other tissues. Galea et al asked if in fact all CTL were allowed to enter the brain, at a low rate, or whether in fact the CTL that were in the brain were a specific subset. An obvious specific subset that you’d want to allow in the brain, would be those that specifically recognize antigens in there. That way, you won’t have to worry about non-specific activation and damage, but you’d still let in those cells that might be able to attack local problems. Galea et al showed that indeed, CTL specific for antigens within the brain, did preferentially enter the brain.3
But there’s a chicken/egg problem. The CTL look for antigens in the brain, and if they find them, they enter the brain, at which point they can look for antigens in the brain, so that they can enter the brain, where they can look … How do the CTL know that on the other side of that blood-brain barrier, there’s something they’re interested in?
On the blood side of the blood-brain barrier, endothelial cells lining the blood vessel walls express MHC class I (which is, of course, what CTL recognize). (The figure to the right shows a blood vessel with MHC class I in green, and the basement membrane marker 1-laminin in red.) Blocking this luminal MHC class I reduced the CTL’s ability to enter the brain. “An integral requirement of MHC-dependent CD8 T cell traffic into the brain is the presentation of processed exogenous antigen by MHC class I on the luminal surface of cerebral endothelium.” So, presumably, what’s happening is that the endothelial cells are transmitting the signal across the blood-brain barrier that they form: they take up antigen on the brain side of the blood-brain barrier, process the antigen internally (through some form of cross-presentation), and then push it out on the other side in combination with MHC class I.
So what’s the significance?
This has profound therapeutic consequences for neurological diseases mediated by CD8 T cell entry into the CNS such as MS, human T cell lymphotropic virus–associated myelopathy, and various paraneoplastic CNS syndromes, as well as encephalitis and brain tumors. Our description of an antigen-specific pathway for CD8 T cells across the blood-brain barrier means that therapies aimed at blocking/augmenting the MHC-dependent migration of antigen-specific CD8 T cells, as opposed to the whole T cell repertoire, are possible.
In other words, where there are brain problems caused by overactive CTL, it may be possible to prevent them from ever entering the brain, perhaps by blocking their MHC class I ligands in the brain blood vessels.
Tara, over at Aetiology, blogged about the new measles outbreaks and death in Britain, following the drop in MMR vaccine use because of the fraudulant lies of Andrew Wakefield. (If you’re not familiar with the whole sordid story, Wakefield is the guy who claimed a link between MMR and autism. The link has been roundly debunked, and Wakefield has turned out to have had commercial links in the anti-vaccine industry.)
Anyway, the story immediately reminded me of a previous go-round of antivaccine lunacy. In the mid-1970s, pertussis (whooping cough) incidence had dropped spectacularly, as a result of vaccination. With unfamiliarity came contempt; people forgot what whooping cough was like, and anti-vaccine loons crawled out from under their rocks and started peddling spurious links between vaccine reactions and various problems. Parents fell prey to the alarmists, and stopped vaccinating their children. Unsurprisingly, whooping cough re-emerged as a killer. In England, for example, whooping cough incidence had dropped from 200-400 cases per 100,000, prevaccine, to … well, I can’t read it off the graph because it’s too low, but something much less than that.
Then in 1974:
Persistent television and press coverage interrupted a successful vaccination programme. A prominent public-health academic, Dr Gordon Stewart, claimed that the protective effect of the vaccine was marginal and did not outweigh its danger.1
Unsurprisingly, pertussis rates promptly climbed back up, with the classic epidemic spikes that parents in 1950s had been grimly familiar with.
There’s nothing like seeing your neighbours’ children suffocating to death on their own phlegm to change your mind about vaccination. As whooping cough swept across the country again, vaccine rates also shot back up. And once again, pertussis has dropped to background rates. (But not to zero. Tara has previously noted the recent increases in pertussis frequency, linked to reductions in vaccination.)
And now, history is repeating itself: antivaccine loons are responsible for another child’s death: Last year a 13-year-old boy, from a travelling community in the North-West, became the first person to die of measles since 1992.
I’ve put up a static page with a brief summary of the MHC class I antigen presentation pathway. I just put up the introductory slide I usually use in my talks and added a simple key. It’s a pretty superficial overview that omits a number of critical steps, but it might be useful as background for some of the stuff I talk about.
There’s a new paper just out on the sea urchin immune system, and since I’ve recently become a fan of sea urchin immune systems I’m not actually going to talk about that paper here. Instead, I’m going to rewrite a different blog post I made on the sea urchin immune system, pre-Mystery Rays. That way, when I do talk about the new one, I have my references set up in a row. Anyway, I think this is so cool it’s worth talking about twice.
Last fall the purple sea urchin (Strongylocentrotus purpuratus) genome sequence was published;1 it’s online at the Sea Urchin Genome Project. At the time one of the aspects of the urchin genome that was specially singled out was the immune system,2 but one of the most interesting things about the genome had already been published earlier that year:
An ancient evolutionary origin of the Rag1/2 gene locus.
Fugmann SD, Messier C, Novack LA, Cameron RA, Rast JP.
Proc Natl Acad Sci U S A. 2006 Mar 7;103(10):3728-33.
Sea urchins are the closest relatives of the chordates:
Based on similarities of embryonic organization, zoologists grouped echinoderms and Hemichordata (a phylum of marine worms) with chordates in the superclade Deuterostomia … Within the deuterostomes, the chordates (vertebrate and invertebrate) form one large assemblage, and the echinoderms and their sister group the hemichordates the other, all members of which are more closely related to one another than they are to any other animals.3
But echinoderms split off before the discovery of the adaptive immune system, which apparently appeared, full-fledged4, in sharks. Lampreys and hagfish, which of course have common ancestors with sharks, more or less lack adaptive responses, whereas sharks and all their descendants unto us do have adaptive responses.5
The key molecular development that makes this system work is the RAG1/RAG2 gene pair. The RAG genes rearrange DNA — given appropriate sequence cues, these genes (and their supporting cast) can grab and shuffle and splice DNA. That means you can get vastly more complexity out of your genome. (If you start with 10 upstream halves of a gene, and 10 downstream halves, you can get 100 possible genes by randomly rearranging the DNA. The adaptive immune molecules are more complicated than that, and in fact you can get something like 1013 different antibodies, and 1015 possible different T-cell receptors, by rearranging the DNA. It’s that huge number of possible sequences that allow the adaptive response to target variable regions of pathogens; it’s the fact that the DNA is permanently altered that allows persistent memory.)
Lampreys and hagfish don’t have RAG1/RAG2. However, some invertebrates do have things that look kind of RAG-ish.6 They’re transposable elements, which makes sense, since transposable elements would like to be able to cut and re-attach DNA so that they can transpose. But there’s nothing that looks like sharks’, and our, RAG1/RAG2. (Lampreys and hagfish haven’t had their genomes done yet, so it’s possible something has been missed in them, but it would have to be a fairly distant relative of RAG1/2.) The presumption has been that, around the time sharks split off from the lamprey ancestors, the transposable element entered their genome and mutated to become RAG1/RAG2, and the rest is history. And so echinoderms shouldn’t have RAGs. “The Rag1/2 gene cluster is predicted to be missing in this phylum by evolutionary scenarios in which the locus was assembled as a consequence of horizontal gene transfer close to the time of the emergence of jawed vertebrate adaptive immunity.” 7
You see where this is going, though. Sea urchins do have a RAG1/RAG2 gene cluster! Fugmann et al identified a set of genes that are pretty clearly RAG-ish:
We thus conclude that SpRag1L and SpRag2L represent homologs of vertebrate Rag1 and Rag2. In combination with the apparent absence of V(D)J recombination in echinoderms, this finding strongly suggests that linked Rag1- and Rag2-like genes were already present and functioning in a different capacity in the common ancestor of living deuterostomes, and that their specific role in the adaptive immune system was acquired much later in an early jawed vertebrate.
In other words, instead of arising in sharks, the RAG1/RAG2 pair may have arisen well before that, in their common ancestor with sea urchins. In that case, lampreys may have lost the genes, rather than sharks gaining it. (The other possibility is that RAG1/RAG2 moved into sharks and urchins independently, perhaps from a common ancestor of the RAG-related transposon.) (The figure at right is Fugmann et al’s Figure 3, comparing SpRag1L and SpRag2L to various vertebrate RAGs.)
Sea urchins don’t appear to have an adaptive immune response, but this still simplifies the history of adaptive immunity. I’ve always been a little puzzled by the shark thing. It’s not just RAG1/2 that leads to an adaptive immune system: there are a host of other changes — molecular signals indicating where its safe to rearrange DNA, for example — that are essential for a functional adaptive response, and it seemed pretty remarkable that they’d all arise together, in a relatively short period. But this observation, along with other recent findings (lymphocyte-like cells in lampreys, for example) shows that many of the changes arose over a much, much longer period, and sharks were just the first to put together a set of unrelated changes to pull an adaptive immune system out of their molecular hats.
