Lightning storm NOAA We usually expect that our immune system will protect us against disease. But it’s not unusual for diseases (especially viral diseases) to cause their damage through the immune system. One of the popular concepts for this is the “cytokine storm” idea — cytokines being the soluble proteins produced by immune responses that drive inflammation, and a “cytokine storm” being a massive release of these inflammatory mediators, leading to immune-mediated damage to blood vessels, leakage from the vascular system, shock, and eventually death. This is a death caused by a hyperreactive immune system.

It’s important to point out that cytokine storms are far from the only cause of immune-mediated disease, even in the context of infection; and in fact, cytokine storms are probably pretty rare. For example, although it’s often stated as fact that avian influenza and the 1918 flu cause death through cytokine storms, especially in the wake of a paper by Chan et al,1 I think the evidence for this is pretty weak — and for avian flu in particular, it’s been shown that cytokines are probably not the culprits at all. 2

However, I don’t question that in some cases — for example, Dengue virus,3 some poxviruses,4 and other viruses– cytokine storms are the underlying problem. It would seem, then, that one way to protect against this would be to inhibit the T cell response, right? — thereby reducing cytokine production. Well, not necessarily so.

Traditionally, innate and adaptive immune responses are taught separately. I do this too, but at least I always preface the split with the explanation that this is an artificial division. The immune response is a tightly integrated system,5 and the innate and adaptive immune systems talk back and forth, modulate each other, help each other and suppress one another.

Natural killer cells are traditionally considered as parts of the innate immune response. They are early responders, ramping up very fast, and then fading away around the time the adaptive immune response (in the form of T cells) kicks in (a few days after an infection, for example). Because of the time course, it’s been easy to understand how effectively NK cells can modulate the adaptive immune response — NK cells release cytokines that talk to T cells and help activate, attract, and guide the subsequent T cell response.

Blogging on Peer-Reviewed ResearchRecently we learned that the reverse is also true. 6 T cells also regulate the NK cell response — and without adult supervision, NK cells can trigger a lethal cytokine storm.

Nude mice — mice lacking any T cells — are very susceptible to some virus infections, as you’d expect; they have essentially no adaptive immune system. But Kim et al (looking at infection with mouse hepatitis virus) found that the mice do not die because the virus is out of control. On the contrary, there really was no more virus in the nude mice (which have no T cells, remember) than in wild-type mice with a fully functional immune system. Instead, the deaths are apparently because of a cytokine storm.

Nude mice do have highly active NK cells, and it further turned out that these uncontrolled NK cells explode with huge amounts of interferon when they’re stimulated. Interferon is generally a useful antiviral cytokine, but it is well known to be highly toxic when overproduced — and blocking interferon in these mice protected them from death when their NK cells were stimulated.

This is interesting for a couple of reasons. For one, it’s generally been assumed that mice without T cells are susceptible to virus infections because they can’t effectively control the virus. In fact, it may be that they die because they can’t control the immune response. Are NK cells contributers to cytokine storms even in normal people? Could this offer a tool to control some of these viral diseases? 7

The concept of an unleashed innate response in the absence of adaptive modulation may also lead to new diagnosis and treatment for individuals with congenital or acquired immune deficiency.

For another, while it’s been obvious that NK cells can regulate T cell responses, the reverse hasn’t been as obvious — the timing, for example, didn’t seem to fit. But now it’s clear that the conversation goes both ways:8

Because the innate immune response precedes the adaptive immune response to infection by several days, one would assume that adaptive immunity should not affect the early innate response, but the findings of Kim et al. show that even the earliest innate response requires adaptive regulation.

  1. Chan, M. C., Cheung, C. Y., Chui, W. H., Tsao, S. W., Nicholls, J. M., Chan, Y. O., Chan, R. W., Long, H. T., Poon, L. L., Guan, Y., and Peiris, J. S. (2005). Proinflammatory cytokine responses induced by influenza A (H5N1) viruses in primary human alveolar and bronchial epithelial cells. Respir Res 6, 135. []
  2. Salomon, R., Hoffmann, E., and Webster, R. G. (2007). Inhibition of the cytokine response does not protect against lethal H5N1 influenza infection. Proc Natl Acad Sci U S A 104, 12479-12481. []
  3. Pang, T., Cardosa, M. J., and Guzman, M. G. (2007). Of cascades and perfect storms: the immunopathogenesis of dengue haemorrhagic fever-dengue shock syndrome (DHF/DSS). Immunol Cell Biol 85, 43-45. []
  4. Stanford, M. M., McFadden, G., Karupiah, G., and Chaudhri, G. (2007). Immunopathogenesis of poxvirus infections: forecasting the impending storm. Immunol Cell Biol 85, 93-102. []
  5. For that matter, there’s no such thing as an “immune system” that exists in glorious isolation somewhere — the whole body is one integrated network. But our tiny little human brains have to start somewhere.[]
  6. Kim, K. D., Zhao, J., Auh, S., Yang, X., Du, P., Tang, H., and Fu, Y. X. (2007). Adaptive immune cells temper initial innate responses. Nat Med 13, 1248-1252. Also see the commentary on this paper: Palm, N. W., and Medzhitov, R. (2007). Not so fast: adaptive suppression of innate immunity. Nat Med 13, 1142-1144. []
  7. Kim, K. D., Zhao, J., Auh, S., Yang, X., Du, P., Tang, H., and Fu, Y. X. (2007). Adaptive immune cells temper initial innate responses. Nat Med 13, 1248-1252.[]
  8. Palm, N. W., and Medzhitov, R. (2007). Not so fast: adaptive suppression of innate immunity. Nat Med 13, 1142-1144. []