The Enemy WithinThe immune system is, by its nature, destructive. Its function is to eliminate problems. Because it’s so destructive, there are many layers of control that constantly check and limit the response. Equally, there are controls that try to ensure that the response doesn’t start until it’s needed.

How does the immune response know when it’s needed? It has to eliminate problems, which means it needs to detect problems. So, what’s a problem?

In general, the immune system perceives two conditions as “problems”. One is when microbes are detected, and another is when damage is detected. These conditions are both detected through specific sets of receptors, and both lead to similar cascades of events that culminate in the response we think of as classically “immune” – first an innate immune response, and then if appropriate, an adaptive immune response that’s triggered by the initial innate response.

I’ve talked before about these two forms of problem detection. To summarize and grossly oversimplify some of the history: Charlie Janeway predicted the first form, which we now call “Pathogen-associated molecular pattern” (PAMP) detection; Polly Matzinger predicted the latter form, which we can call “Danger-associated molecular pattern” (DAMP) detection. PAMPs include things that are unique to bacteria or viruses — cell wall components that are present in bacteria, but not in vertebrate cells, for example; or double-stranded RNA, which is found in lots of viruses but would be unusual in our own cells. “Danger” signals, on the other hand, are indications of cell death — internal components of a cell, for example, that have leaked out as the cell dies. 1 For a while, it looked as if PAMPs were the major signal leading to innate and then adaptive immunity, but more recently it’s become clear that DAMPs are also very important.

One example of DAMP recognition would be tumor recognition. We know that tumors are recognized by the immune system — by T cells and B cells, which are adaptive immunity. We know that adaptive immunity is very inefficient without an innate response to set up the proper conditions. We also know that tumors aren’t pathogens as such, and so you wouldn’t expect them to trigger PAMP receptors. So what’s triggering the immune response to the tumor? The answer seems to be DAMPs. As tumor cells die, which they tend to do much more exuberantly than normal cells, they release internal components that the immune response registers as evidence of danger. 2 It’s even been proposed that the massive tumor cell death caused by chemotherapy is the real reason chemo works: The cell death is detected by the immune system as evidence of massive danger, and it’s the resulting immune response that actually eliminates the tumor, not the chemo per se.


So, historically, DAMPs are DAMPs and PAMPs are PAMPs, and never the twain shall meet. After all, internal cell components are quite different from microbes, right?

Well, except for the internal cell components that actually are microbes. Mitochondria, of course, are actually exceedingly symbiotic bacteria that live inside our cells, right? And it turns out that, yes, some DAMPs actually are PAMPs, because some of the danger responses are actually triggered by mitochondrial components that are really bacterial in origin. A lovely paper from Carl Hauser’s lab3 shows that mitochondrial components, released from cells after damage, trigger innate immune responses through pathways that are more traditionally associated with pathogen-specific patterns.4

As I say, immune responses can be very destructive, and Hauser’s interest in this arises from the destructive aspect.  Trauma that produces lots of tissue damage can lead to severe inflammation that looks a lot like sepsis, even though there are no bacteria involved, so he has been looking for triggers for this sterile systemic inflammatory response syndrome (SIRS):

Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial ‘enemies within’ by cellular injury is a key link between trauma, inflammation and SIRS.3

I found it particularly interesting  that one of the mitochondrial DAMPs is formylated peptides. Formylation of peptides is typical of bacteria, not eukaryotes, so it’s a good way of detecting pathogens. Indeed, there are receptors for formyl peptides on neutrophils (FPR1), among other cells, and the mitochondrial DAMPs (including the formyl peptides) cause neutrophils to migrate toward the source (chemotaxis) — see the movie below:

Neutrophils migrate toward a pipette tip that is releasing mitochondrial DAMPs3

(Compare to this other movie I posted a while ago, which shows neutrophils in a mouse’s ear, being attracted to areas of tissue damage.)

H-2M3 structure
H-2M3 crystal structure5

In fact, formylated peptides have been long known to be a PAMP, but not just via the FPR1; they’re also presented by a mouse non-classical MHC class I molecule, H-2M3.  (I didn’t include a picture of H-2M3 in my Field Guide to the MHC earlier, so here’s a picture to the left. 5 Heavy chain in grey, beta2-microglobulin6 in red, peptide in green with the formylated end of the peptide — see how neatly it tucks into the peptide-binding groove there? in magenta.) And again, H-2M3 presents formylated peptides, not just from bacterial pathogens, but also from mitochondria. 7

Most people probably don’t think of MHC-family molecules as innate immune detectors, but many of the non-classical MHC molecules are true PAMP receptors (pattern recognition receptors, PRRs). It’s even been argued — based on H-2M3 itself, in fact — that this broad pattern-recognition ability is the original function of MHC molecules, and the role of MHC molecules in adaptive immunity is the latecomer:

F. M. Burnet asserted that it was their polymorphism that made MHC genes biologically significant. Certainly this is true for I-a8 function, but modern PRR-like I-b molecules9 suggest an alternate model for MHC origins. … Because most genes are monomorphic or minimally oligomorphic, and most class I-like genes not linked to the MHC are monomorphic, parsimony suggests the ancestral MHC locus was also monomorphic. This primitive MHC molecule, functioning as a PRR, would have been preadapted for the evolution of polymorphic class I-a molecules in the evolving adaptive immune system. 10

  1. In apoptosis, the programmed cell death that’s a normal part of tissue growth, internal cell components are carefully packaged up in such as way as to prevent this kind of response.[]
  2. Which, of course, it is.[]
  3. Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal, T., Junger, W., Brohi, K., Itagaki, K., & Hauser, C. (2010). Circulating mitochondrial DAMPs cause inflammatory responses to injury Nature, 464 (7285), 104-107 DOI: 10.1038/nature08780[][][]
  4. Thanks to Alex Ling, who wrote to me suggesting I talk about this paper.  I’d filed it in with the other 512 papers that I want to talk about here, some time, but her email made me take another look and appreciate how neat the work is.[]
  5. Wang, C. R., Castano, A. R., Peterson, P. A., Slaughter, C., Lindahl, K. F., and Deisenhofer, J. (1995). Nonclassical binding of formylated peptide in crystal structure of the MHC class Ib molecule H2-M3. Cell 82, 655-664.[][]
  6. Why doesn’t the beta symbol ? stick? No matter how often, or how, I enter the code, it changes to a ? in the published post.[]
  7. Loveland, B., Wang, C. R., Yonekawa, H., Hermel, E., and Lindahl, K. F. (1990). Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell 60, 971-980.
    Shawar, S. M., Vyas, J. M., Rodgers, J. R., Cook, R. G., and Rich, R. R. (1991). Specialized functions of major histocompatibility complex class I molecules. II. Hmt binds N-formylated peptides of mitochondrial and prokaryotic origin. J. Exp. Med. 174, 941-944.[]
  8. I-a are the classical MHC class I molecules that present peptides to cytotoxic T lymphocytes[]
  9. And, logically enough then, I-b are the non-classical MHC molecules that often present fairly conserved molecules.[]
  10. Doyle, C. K., Davis, B. K., Cook, R. G., Rich, R. R., and Rodgers, J. R. (2003). Hyperconservation of the N-formyl peptide binding site of M3: evidence that M3 is an old eutherian molecule with conserved recognition of a pathogen-associated molecular pattern. J. Immunol. 171, 836-844.[]