Mystery Rays from Outer Space

This year, I read some 200-odd scientific papers (or at least skimmed them). I posted 130 articles here on Mystery Rays; of those, just under 100 were full-length paper discussions, so I probably cited, I don’t know, between 150 and 200 papers here (though not all were from 2008, of course). I aim for about 2 posts a week, so I ended up reasonably close, I guess, in spite of slowing down during heavy teaching and grant-writing periods.

(As well as the full-length posts, I included 16 short quotes that struck my fancy. The remaining 16 included a few updates on XPlasMap, and bits and pieces of baseball, pictures of my kids, and other stuff.)

Some scientific high- and low-lights of 2008, in my highly biased opinion:

Highlight: Encouraging, though not overwhelming, new on the malaria vaccine front. ¹ Malaria vaccines have been extensively researched for decades, and this seems to be the best candidate so far. Unfortunately, it’s still not a very good vaccine, with efficacy levels that are in the 60% range — far lower than would be acceptable for most diseases. However, even providing limited resistance to malaria will make a huge impact on population health. As well, seeing even that much effectiveness is encouraging to other vaccine development.

Lowlight: I think the spillover from the 2007 failure of the HIV STEP vaccine trial has continued to be disappointing. A clinical trial can “fail” in that it doesn’t offer clinical success, but still give enough research data to move the field forward. I may be wrong, but it seems to me that the papers following up the STEP trial haven’t managed to build on the failed trial very effectively. (Not the fault of the researchers, but apparently the information simply wasn’t in the trial data.) It’s clear that new approaches are needed, but the STEP trial (so far) hasn’t clearly pointed what those new directions might be.

Personal disappointment (and I’m sure this will aggravate lots of people) is the lack of useful mathematical/computer models that are applicable to immunology. I’ve seen a number of attempts to model immune systems, but so far I haven’t been convinced they actually show anything meaningful, let alone useful.

I’m fascinated and intrigued by modeling of bioloigcal processes, and I think there’s a huge potential there, but to date I can’t say I’ve seen much exciting stuff in the field. (I’m very open to having my mind changed; please let me know if there’s something I should look at again.)

Interesting progress: I think the concepts of anti-tumor immunity continue to progress, slowly but surely, and there are glimmers of clinical utility on the horizon. That said, those same glimmers have been on the horizon for about the past ten years, and I’m not certain that they’re getting all that much closer.

More interesting progress: Organ transplanation is finally starting to take some advantage of regulatory T cells, inducing controlled tolerance in a planned, reproducible manner.² This has been the holy grail of transplanation biology for decades, and to me, at least, it seems to be almost within grasp now.

In a few days I’ll post my list of my favourite papers of 2008.

1. Abdulla, S., Oberholzer, R., Juma, O., Kubhoja, S., Machera, F., Membi, C., Omari, S., Urassa, A., Mshinda, H., Jumanne, A., Salim, N., Shomari, M., Aebi, T., Schellenberg, D. M., Carter, T., Villafana, T., Demoitie, M. A., Dubois, M. C., Leach, A., Lievens, M., Vekemans, J., Cohen, J., Ballou, W. R., and Tanner, M. (2008). Safety and immunogenicity of RTS,S/AS02D malaria vaccine in infants. N. Engl. J. Med. 359, 2533-2544. doi:10.1056/NEJMoa0807773

   Bejon, P., Lusingu, J., Olotu, A., Leach, A., Lievens, M., Vekemans, J., Mshamu, S., Lang, T., Gould, J., Dubois, M. C., Demoitie, M. A., Stallaert, J. F., Vansadia, P., Carter, T., Njuguna, P., Awuondo, K. O., Malabeja, A., Abdul, O., Gesase, S., Mturi, N., Drakeley, C. J., Savarese, B., Villafana, T., Ballou, W. R., Cohen, J., Riley, E. M., Lemnge, M. M., Marsh, K., and von Seidlein, L. (2008). Efficacy of RTS,S/AS01E vaccine against malaria in children 5 to 17 months of age. N. Engl. J. Med. 359, 2521-2532. doi:10.1056/NEJMoa0807381[↩]

2. Kawai, T. et al., 2008. HLA-Mismatched Renal Transplantation without Maintenance Immunosuppression. N Engl J Med, 358(4), p.353-361 [↩]

Polarized CD8 T cell responding to a HSV-infected neuron

Just because something is called a “cytotoxic T lymphocyte” doesn’t mean it’s actually, you know, cytotoxic. And just because something is called a “lytic granule” doesn’t mean it’s actually lytic.

I’ve posted earlier on the range of functions that CD8 T cells — the so-called “cytotoxic T lymphocytes”, or CTL — actually have. CD8 T cells can certainly deliver cytotoxic signals to their target cells; but it’s become increasingly obvious that this isn’t all they can do. For example, it’s recently been shown that in HIV infections, CD8 T cells that show more than one function (“multifunctional” or “polyfunctional” T cells) are correlated with better control of the virus, whereas T cells that only show one or two functions don’t seem to control HIV. (The diagram to the right is from a seminar by Mario Roederer, and it shows the average functions — for example, the ability to secrete cytokines such as interferon, IL-2, MIP1b, and TNF — in long-term non-progressors, who control HIV relatively well, vs. those who progress and don’t control the virus.)

In fact, Robert Hendricks’ group just showed that T cell functions are even more complex than that, and they did it in the context of a fascinating problem — control of herpes simplex virus latency and reactivation.¹

The movie below shows sort of the traditional view of CD8 cell functions. ² Here we see a CD8 T cell 9in blue) and a target cell (filled with a green dye). At about 10 minutes (the film is speeded up, don’t worry!) the T cell makes tight contact with the target. Within five minutes, the target loses its dye; this is probably because the T cell is punching holes in the target cell’s membrane, so that internal contents can leak out. This is the caused by the T cell protein “perforin”. But T cells are capable of killing their targets in several ways, and we see a second mode of killing kicking in over the next 45 minutes or so. The target cell starts to bubble up, showing dense internal structures; this is probably the target entering a programmed cell death (apoptosis) pathway, and this is caused by a number of T cell proteins, especially “granzyme B”.

So, perforin and granzyme B are both killer proteins. They’re part of the “lytic granules” found in activated CD8 T cells. What Hendricks’ group has found is that perforin and granzyme B can also protect against herpes simplex infections without actually killing the target cell.

Herpes simplex virus first infects the skin or mucous membranes, then rapidly jumps into the neurons that innervate that patch of tissue and track up the axons to the ganglion. For the familiar and ubiquitous herpes simplex type 1, this is usually the trigeminal ganglion. In the neuron bodies of the ganglion, the virus (supposedly! — this is the traditional view) shuts itself down, reducing its protein levels to an undetectable level, and enters a latent state, where the viral genome hangs out but it’s otherwise pretty much a passive blob. Intermittently, the virus can reactivate from latency (especially after local immunity is reduced, for example due to “stress”), and then it tracks back down the axon to the original site of infection, and sheds into the environment once again. For HSV-1 the reactivations are usually seen the common and fairly harmless cold sores.

That traditional view has been changing. For example, we now know that the virus reactivates far more often than was believed;³ the reactivations come in such short bursts that unless you monitor very closely (swabbing 4 times a day, in the study in question) you’ll miss most of them. And they’re not associated with any lesions, usually.

Another change in the traditional view is that, at least for some, and perhaps most or even all of the infected neurons, the virus doesn’t really shut down protein expression to zero. Levels are drastically reduced, but T cells are incredibly sensitive, and it is now clear that T cells do in fact detect HSV-infected neurons in the ganglia. I posted about this research HERE, noting the evidence that infected neurons are often surrounded by HSV-specific T cells.

So if cytotoxic T lymphocytes are constantly detecting target infected neurons, they should be killing the neurons, right? That’s what “cytotoxic” implies. But clearly that’s not the case. Most of you, sitting reading this now (if anyone has in fact made it this far) have lots of “latent” herpes simplex in your trigeminal ganglia — the vast majority of people are infected. And yet your trigeminal ganglia are not slowly disintegrating under the assault of lytic T cells. The virus will still be there when you’re 70 years old, and your ganglia will still be intact (at least, as far as this is concerned; I make no further promises or guarantees).

So what Hendricks’ group has shown is that, yes, CD8 T cells do recognize HSV-infected neurons (this was already known). And the T cells suppress the virus, preventing it from reactivating; this was already known too. What’s new is that they showed that the T cells need perforin and granzyme B to prevent the reactivation, even though the neurons are not killed! They went on to show that granzyme B (which is a protease, that’s how it causes apoptosis) chops up a critical viral protein, blocking the virus from further protein production. So lytic substances can protect without actually lysing — a new function for CD8 T cells.

It’s not clear to me exactly how this works. For one thing, they also showed that a little later in infection there are other factors that suppress the virus (multifunctional!), and suggested that interferon might play this role. Still, it’s a very cool finding, and reminds us that viruses and immunity are both more complex than we know, and put together are complex cubed.

Note that this does not mean that perforin and granzyme B are not cytotoxic proteins! That’s very clearly their major function.⁴ What Hendricks’ work does show is that cytotoxicity is not their ONLY function.

1. J. E. Knickelbein, K. M. Khanna, M. B. Yee, C. J. Baty, P. R. Kinchington, R. L. Hendricks (2008). Noncytotoxic Lytic Granule-Mediated CD8+ T Cell Inhibition of HSV-1 Reactivation from Neuronal Latency Science, 322 (5899), 268-271 DOI: 10.1126/science.1164164[↩]
2. And I don’t remember where I got this from. Can anyone remind me of the author?[↩]
3. Karen E. Mark, Anna Wald, Amalia S. Magaret, Stacy Selke, Laura Olin, Meei?Li Huang, Lawrence Corey (2008). Rapidly Cleared Episodes of Herpes Simplex Virus Reactivation in Immunocompetent Adults The Journal of Infectious Diseases, 198 (8), 1141-1149 DOI: 10.1086/591913[↩]
4. for example, see S MIGUELES, C OSBORNE, C ROYCE, A COMPTON, R JOSHI, K WEEKS, J ROOD, A BERKLEY, J SACHA, N COGLIANOSHUTTA (2008). Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell Elimination Associated with Immune Control Immunity DOI: 10.1016/j.immuni.2008.10.010 [↩]

Dendritic cells in the skin (Langerhans cells) form a dense network of “sentinels” that act as first line of defense of the immune system.1

What happens when a pathogen invades us? Well, lots of things happen, of course. Early on, there are innate immune responses; generic pathogen-like aspects of the pathogen trigger a relatively stereotyped immune response. Parts of this innate immune response then connect the pathogen features to the adaptive immune response (T cells and B cells), and in a few days there should be a much larger and more focused (pathogen-specific) immune response.

This link between the innate and the adaptive immune response is most often made by dendritic cells (DC). DC hang out in tissues all over the body, forming a net that constantly filters stuff in the tissues (see the image to the left). Almost all the time (one hopes) these DC don’t run into any pathogen signatures; and in that case, they just continue to hang out and filter some more. When a DC does run into something that’s associated with a pathogen (such as, say, lipopolysaccharide, LPS, a part of some bacterial cell walls) then the DC changes and enters a new program designed to efficiently interact with T cells.

There’s been no obvious reason to suspect that antigen presentation is connected to movement of the dendritic cell. But a paper in today’s issue of Science² shows that in fact the two are tightly linked, because the same protein helps regulate both of them. This protein is the invariant chain (also known as Ii), and it’s been known for years that it’s important in antigen presentation; the details of that are well worked out. The new, and really surprising, finding is that Ii also helps control movement of dendritic cells (and probably other cells, such as B cells, that also have Ii), by interacting with myosin II. The authors show that Ii acts as a brake on DC movement, and this brake is released when (as a part of its normal antigen presentation function) Ii is partially destroyed.

The use of common regulators for Ag processing and cell motility provides a way for DCs to coordinate these two functions in time and space. In immature DCs that patrol peripheral tissues, the periodic low motility phases induced by Ii may enable DCs to efficiently couple Ag uptake and processing to cell migration, facilitating the sampling of the microenvironment.  ²

The concept makes sense; the DC would want to look more closely for antigens in an area they’d just arrived in, rather than in somewhere they’ve already sampled for a while. One interesting implication, I think, is that antigen presentation, like the movement that they show, may be episodic, happening in bursts rather than in a continuous conveyer belt. We already knew that the conveyer belt was jerky on a larger scale, but I think this suggests that it’s on and off on a much finer scale than has been previously shown (as far as I know). I have some interesting data on a different type of antigen presentation that would fit with this model, so I’ve been wondering for a while about looking for jerkiness in antigen presentation anyway, and maybe this reinforces that notion.

By the way, the paper has some cute movies of dendritic cells in little runways, chugging down the lines like little trains, including the DC’s occasional stops and reversals like a train that’s passed the passenger loading area and has to back up.

1. Tolerogenic dendritic cells and regulatory T cells: A two-way relationship. (2007) Karsten Mahnke, Theron S. Johnson, Sabine Ring and Alexander H. Enk.  J of Derm Sci 46:159-167 doi:10.1016/j.jdermsci.2007.03.002 [↩]
2. Gabrielle Faure-André, Pablo Vargas, Maria-Isabel Yuseff, Mélina Heuzé, Jheimmy Diaz, Danielle Lankar, Veronica Steri, Jeremy Manry, Stéphanie Hugues, Fulvia Vascotto, Jérôme Boulanger, Graça Raposo, Maria-Rosa Bono, Mario Rosemblatt, Matthieu Piel, Ana-Maria Lennon-Duménil (2008). Regulation of Dendritic Cell Migration by CD74, the MHC Class II-Associated Invariant Chain Science, 322 (5908), 1705-1710 DOI: 10.1126/science.1159894[↩][↩]

After the “suppressor T cell” debacle of the 1980s, there was an embarrassed pause for a few years before people dipped their toes back into the suppressor T cell water; but the underlying phenomenon itself is a very strong and important one, and by the late 1990s and early 2000s researchers were again studying the cells, renaming them “regulatory T cells” (TRegs) in the process. Since the phenomenon is so strong, the field quickly exploded (from two papers mentioning TRegs in 2000, to 780 this year). We now know where TRegs are made and, mostly, how they’re made; we know what they look like and which cells they talk with; we know of various ways to make them in the lab; we know diseases where they’re overactive, and diseases where they’re underactive.  I’ve talked about these things quite a bit here.  

We didn’t know, though, how they actually work. Do they act directly on their target T cells, or via intermediaries? Do they have to contact their targets, or can they act at a distance? What molecules deliver their “regulatory” signals, and what molecules receive the signal? Well, we still don’t really know the answers to most of those questions, but a paper last month¹ brought the answers a lot closer with evidence that CTLA4 is essential for TRegs to have their regulatory effect.

TRegs in normal skin

This isn’t a new idea; it was first put forward in one of the very early TReg papers, way back in 2000². The difference is that the earlier papers couldn’t cleanly distinguish TReg-specific effects of CTLA4 from its myriad other effects. CTLA4 is a very broad-acting molecule with lots of immunosuppressive (or if you prefer, immunoregulatory) activities. In the present paper, Wing et al managed to eliminate CTLA4 specifically from TReg cells, leaving its other activities intact. These TReg-specific knockouts still developed the horrible, fatal autoimmune diseases characteristic of TReg deficiencies.

So CTLA4 is essential for TReg function. This is especially interesting because there’s a lot of clinical interest in CTLA4; for example, blocking CTLA4 has been effective in generating (or regenerating) immunity to cancers, at least in experimental models. The rationale for this has been because signaling through CTLA4 on “conventional” (that is, effector, as opposed to regulatory) T cells reduces or blocks their activity;³ but now this is directly linked to TReg activity as well.

The link between TRegs, CTLA4, and tumor immunity was really emphasized in the Wing et al paper. In one experiment, they demonstrated that mice with normal TRegs were not able to reject a tumor (“All recipients of FIC splenocytes died of tumor progression within a month“), whereas mice with the knockout TRegs (that is, TRegs lacking CTLA4) were able to control it (“In contrast, recipients of CKO splenocytes halted the tumor growth, with the majority surviving the 6-week observation period, during which 60% of them completely rejected the tumor“).

Obviously, you don’t want to eliminate TReg function willy-nilly even in cancer patients; remember that these mice died of autoimmune disease when they were a couple of months old. But if there’s a way of localizing CTLA4 blockade so that the tumor-specific TRegs alone are affected, this could be very interesting.

1. K. Wing, Y. Onishi, P. Prieto-Martin, T. Yamaguchi, M. Miyara, Z. Fehervari, T. Nomura, S. Sakaguchi (2008). CTLA-4 Control over Foxp3+ Regulatory T Cell Function Science, 322 (5899), 271-275 DOI: 10.1126/science.1160062

   Also see the commentary by Ethan Shevach:
   E. M. Shevach (2008). IMMUNOLOGY: Regulating Suppression Science, 322 (5899), 202-203 DOI: 10.1126/science.1164872[↩]

2. Cytotoxic T Lymphocyte–Associated Antigen 4 Plays an Essential Role in the Function of Cd25⁺Cd4⁺ Regulatory Cells That Control Intestinal Inflammation.  S. Read, V. Malmstrom, F. Powrie, J. Exp. Med. 192, 295 (2000).[↩]
3. For a review, see:
   Principles and use of anti-CTLA4 antibody in human cancer immunotherapy. Karl S Peggs, Sergio A Quezada, Alan J Korman and James P Allison Curr Opin Immunol. 2006 Apr;18(2):206-13. doi:10.1016/j.coi.2006.01.011[↩]

After the Dover trial of Intelligent Design,¹ there was a fair bit of talk about Judge John Jones, who made the decision that “Intelligent Design” is not science and should not be taught in school science classes.  It was clear from the decision itself that Judge Jones is a formidable man who reached his conclusion in an honest, rational way, but most of the talk about him (that I saw, anyway) didn’t really go much past that.²

The latest issue of PLoS Genetics has an interview with Judge Jones that is by far the most interesting and detailed I’ve seen.  Judge Jones explains the background of the case, the history of the legal battles between evolution and creationism, how the trial itself was supposed to work and how it did work, how he reached his decision, all kinds of stuff.  Jones does a great job of putting things in an understandable way, and the interviewer³ asks good questions.  Go read it now.  

… some of the school board witnesses were dreadful witnesses and hence the description “breathtaking inanity” and “mendacity.” In my view, they clearly lied under oath. They made a very poor account of themselves. They could not explain why they did what they did. They really didn’t even know what intelligent design was. It was quite clear to me that they viewed intelligent design as a method to get creationism into the public school classroom. They were unfortunate and troublesome witnesses. Simply remarkable, in that sense.
–Judge John E Jones III

1. Kitzmiller et al. v. Dover Area School District, 2004[↩]
2. I see that there are several books about the case, and I haven’t read any of them, but I imagine they talk about this too.[↩]
3. Jane Gitschier, Departments of Medicine and Pediatrics, Institute for Human Genetics, University of California San Francisco[↩]

Our bodies are crammed with millions of tiny time bombs: lymphocytes that could begin to attack our own bodies, causing lethal autoimmune disease. Traditionally, it was said that these self-reactive lymphocytes were rare, because they were eliminated during their development and were never allowed to reach maturity. But it’s been known for quite a few years now that that’s not entirely true. The vast majority of self-reactive T cells may, indeed, be destroyed in the thymus, but by no means all. (Something like a couple million T cells leave a happy, functioning thymus every day. If central tolerance is 99.999% perfect, then 10 self-reactive T cells will enter the system every single day — and it only takes a couple of T cells to initiate a lethal disease.)

Why don’t we all die as infants of autoimmune attack, if circulating self-reactive T cells are so (relatively) common? As with just about everything in our body, there are redundant systems. For autoimmunity, the next line of defense is the regulatory T cell (TReg).

TRegs were identified as a phenomenon long ago, in the 1960s and 1970s; but the concept abruptly fell out of favor in 1984 (for fascinating and rather embarrassing reasons I talked about here), and it wasn’t until the new millennium that immunologists really returned to the field (first firmly changing the name from “suppressor T cells” to “TRegs” to keep their feet out of the muck), and the field really exploded 5 or 6 years ago.

TRegs have proved more important and powerful than just about anybody would have believed ten years ago. Even very powerful immune responses can be controlled by TRegs; strong TReg responses can actually allow a complete “take” of an organ transplant, for example (I mentioned some examples here).

Regulatory t cells infiltrate tumor tissue

As well as transplants, being able to turn on TRegs has potential for lots of other diseases. Autoimmunity, obviously, could be controlled this way; but also, less obviously, it’s possible that some virus diseases might benefit from a TReg response. HIV infection, for example, is exacerbated when T cells are activated, and monkeys with SIV are resistant to disease when their T cells are less reactive (see here and here); could a controlled TReg response reduce the harmful activation associated with HIV? It may seem counterintuitive to try to treat a viral disease by reducing immunity, but there is some precedent. Rodents infected with hantaviruses develop a TReg response and don’t have much disease (see here), while humans react with a more conventional immune response and have severe disease. And recently, it was shown that elite suppressors of HIV may have an exceptionally strong TReg response.¹

Conversely, there are lots of instances where we’d like to turn off TRegs, in a controlled way. Tumors are often associated with TRegs, which very likely prevent a cleansing immune response to the tumor (discussed here). And the well-known observation that the elderly often have poor immunity against various pathogens is at least partly because TRegs build up over time.

This is a very fast-moving field, and there are a several recent papers that show exciting advances. One is a huge basic step forward, and I’ll talk about that later. The others² are technical advances, developing new techniques (that are much less cumbersome and finicky than some of the previous approaches) to generate large numbers of TRegs in a controlled way. The obvious use for this is in transplants:

The ex vivo expansion protocol that we describe will very likely increase the success of clinical Treg-based immunotherapy, and will help to induce tolerance to selected antigens, while minimizing general immune suppression. This approach is of particular interest for recipients of HLA mismatched transplants.³

Controlled TRegs have been a holy grail of transplant biology for years, and it’s exciting to see that we may finally be entering an era when TRegs can be produced and used as tools.

1. Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation.
   Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF
   J Virol 2008 Sep 82(17):8307-15[↩]
2. Including, but not limited to:
   W. Tu, Y.-L. Lau, J. Zheng, Y. Liu, P.-L. Chan, H. Mao, K. Dionis, P. Schneider, D. B. Lewis (2008). Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells Blood, 112 (6), 2554-2562 DOI: 10.1182/blood-2008-04-152041

   In Vitro Expanded Human CD4+CD25+ Regulatory T Cells are Potent Suppressors of T-Cell-Mediated Xenogeneic Responses. Wu, Jingjing; Yi, Shounan; Ouyang, Li; Jimenez, Elvira; Simond, Denbigh; Wang, Wei; Wang, Yiping; Hawthorne, Wayne J.; O’Connell, Philip J. Transplantation Volume 85(12), 27 June 2008, pp 1841-1848.

   Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233

   and a review in Piotr Trzonkowski, Magdalena Szary?ska, Jolanta My?liwska, Andrzej My?liwski (2008). Ex vivo expansion of CD4+CD25+ T regulatory cells for immunosuppressive therapy
   Cytometry Part A, 9999A DOI: 10.1002/cyto.a.20659 [↩]

3. Jorieke H. Peters, Luuk B. Hilbrands, Hans J. P. M. Koenen, Irma Joosten (2008). Ex Vivo Generation of Human Alloantigen-Specific Regulatory T Cells from CD4posCD25high T Cells for Immunotherapy PLoS ONE, 3 (5) DOI: 10.1371/journal.pone.0002233[↩]

We spend a lot of time trying to understand immune responses against the most virulent pathogens. Perhaps it’s just as useful to look at the response to feeble, marginal pathogens. Serious pathogens are serious because immunity doesn’t control them well, so if we’re trying to understand effective immunity, why not look at minor infections, where the immune system really works?

Most of us have been infected with respiratory syncytial virus (RSV) as children, but most of us never knew it. It’s one of the myriad viruses that are lumped together as “the common cold”. An infant with a runny nos, a bit of a fever, not feeling quite right — maybe wheezing and not eating well — might have RSV; or she might have something else, too. (Even though the vast majority of infected kids have no real problems, because the virus infects essentially everyone, the small minority of problems add up to a large number — some 100,000 children are hospitalized for RSV-related diseases per year in the US alone.)

Immunity to RSV is often considered to be inadequate,¹ but the fact is that most infections are rapidly eliminated without problems. The “inadequacy” label is probably for two reasons. One is that it’s hard to get long-lasting protective immunity; the immune response that cleared the virus doesn’t necessarily protect against a new infection in a year or two. (This is a common factor among many of the common cold complex, of course, though there are probably many different reasons for that.) The other reason is the lingering memory of the disastrous RSV vaccine that I’ve mentioned here previously. ² There seems to be something of a resurgence of interest in the basic pathogenesis of RSV, and a recent paper³ makes some interesting observations.

One of the general problems with understanding immunity to many viruses — especially human viruses — is access. It’s easy to measure immune responses in the blood, because blood is easy to access. It’s not so simple to look at the actual site of infection, whether it’s liver, lungs, gut, or whatever, and so blood is often used as a surrogate. But it’s an open question how closely the immunity in the blood tracks the immunity at the local site. (Again, this is especially true of humans. In mouse studies, you can sacrifice the mouse and remove the lungs. That’s not a real option for human viruses. It’s also an open question as to how well the mouse and human compare.)

In this study, Heidema et al. managed to look at the local lung immune response to RSV, as well as to influenza virus, and compared the local and blood immune parameters. They used tracheostomy patients so that it was relatively easy to access the lungs; easier than running a hose down your nose and washing the bronchi that way, anyway.

Encouragingly, they saw the same general patterns as with mouse experiments. The lung response wasn’t quite the same as the blood. In the lungs, there’s a 3-part response: First, the T cells that are already present in the lungs respond. These are memory cells. We know that memory cells live for a long time, and it was already known that most of the lymphocytes that hang around in the lungs normally are memory type cells:

… long after clearance of a respiratory infection, cells present in tracheal aspirate are of the effector/memory type. These cells reflect the effector/memory cells already present before the next exposure to a respiratory pathogen. ³

Second, both specific and non-specific T cells from the blood enter the lungs. (There’s no way for the circulating T cells to tell which virus is causing the inflammation in the lung, so all of the memory cells drop in to check it out.) The specific ones stick around for a while; the non-specific ones don’t. In mice this seems to be a one-way street, with the non-specific lymphocytes mostly dying off, but from the work here, it’s possible that in humans the non-specific lymphocytes can return to the blood and continue their surveillance.

In the third wave, newly expanded virus-specific T cells enter the lungs. These are the guys who ran into antigen in the draining lymph nodes, got stimulated, divided and became activated, and then went looking for trouble. Because there are a number of events that have to happen before these cells arrive (the antigen has to move from the lung to the draining lymph nodes; the lymphocytes have to respond and dive, and then have to enter the circulation and finally enter the lungs) it takes longer for these cells to appear, but once they’re in they stick around for a long time. In fact, they’re the cells that remain in the lungs to act as the first wave for the next infection.

The experiments are not perfect, given the usual problems of dealing with humans, but there’s a lot of information there, and it should be possible to build on this to figure out more about the local immune response to viruses.

1. “Unfortunately, RSV infection provides only limited immune protection to reinfection, mostly due to inadequate immunological memory”" — S BUENO, P GONZALEZ, R PACHECO, E LEIVA, K CAUTIVO, H TOBAR, J MORA, C PRADO, J ZUNIGA, J JIMENEZ (2008). Host immunity during RSV pathogenesis International Immunopharmacology, 8 (10), 1320-1329 DOI: 10.1016/j.intimp.2008.03.012[↩]
2. Actually, maybe I’ve never mentioned it, or if I have I can’t turn up the post. I should talk about it, because it’s a fascinating story.[↩]
3. Heidema J, Rossen JW, Lukens MV, Ketel MS, Scheltens E, Kranendonk ME, van Maren WW, van Loon AM, Otten HG, Kimpen JL, van Bleek GM (2008). Dynamics of human respiratory virus-specific CD8+ T cell responses in blood and airways during episodes of common cold. J Immunol., 181 (8), 5551-5559[↩][↩]

Something is screwed up with WordPress, or with DreamHost’s database, or something; I can save blog posts once and only once, after that the system hangs without saving. Once I get things working I’ll post a thing on RSV and local immunity.