Mystery Rays from Outer Space

Meddling with things mankind is not meant to understand. Also, pictures of my kids

December 1st, 2008

Three waves for the locals

Lung tonic (Wellcome Images)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.

Sneeze (Marshall Jennison??)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[][]
December 1st, 2008

I’m trying …

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.