Mystery Rays from Outer Space

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

July 27th, 2008

Reduced immunity in the elderly

TRegs (Red with green nuclei) in skin

It’s a well-known, but poorly-understood, observation that the elderly are more susceptible to disease; their immune system isn’t as effective. Not only are older people (and animals) at more risk of disease like influenza, they are also at risk of having a reactivation of some of the many chronic infections we pick up during our lives. And, of course, cancer is more common as one ages, as well.

There are lots of reasons why this might be the case, and likely most of them are factors. A recent paper supports a new and exciting possibility, offering evidence that part of the reason is an overactive immune response: An increase in regulatory T cell activity and numbers is partially responsible for the dampened defense against pathogens.1

Regulatory T cells are a critical component of the immune response; immune responses to pathogens are by their nature destructive, and TRegs are an important way of limiting the destruction. People and animals lacking TRegs have terrible (and usually rapidly fatal) autoimmune disease.

The development and regulation of TRegs themselves is still not all that well understood, but it’s generally accepted that there are at least two sources of TRegs: “Central” TRegs, that develop in the thymus as purpose-built regulatory cells, and “peripheral” TRegs, that are converted T cells that were originally from other lineages, like ninjas converting to zen Buddhism. Perhaps somewhere along this process there’s a small imbalance that, eventually, tilts the balance toward a gradual slow accumulation of TRegs.

In any case, TRegs do seem to be relatively more abundant in older animals. However, it wasn’t clear whether these accumulated cells are actually functional — after all, it’s known that many of the immune lineages in older animals have reduced function, perhaps the TRegs are also less effective, and you need more of them for that reason.

LeishmaniaLages et al demonstrated that this is not the case — in fact, TRegs in old mice are if anything more effective than those from young mice, in terms of suppressing immune responses.  Even more interestingly — and this may translate into the clinic at some point — these TRegs are a part of the problem; reducing TRegs reduced disease, in at least some diseases. They used a model of Leishmania infection2 which is more severe in old mice than in young. Depleting the number of TRegs in older mice, though, made them much more resistant to disease — probably as resistant as the young mice.3

This is probably not universal, but it’s an exciting possibility. Perhaps things like shingles (reactivation of latent varicella-zoster virus) are actually manifestations of overactive TRegs, rather than an underactive effector response. Since we are much better at destruction of a response than creating one, this offers a much easier handle for treatment. I look forward to seeing followup on this.

By the way, my wife instructs me that we will be going on vacation for the first half of August, so I likely won’t be updating this blog as regularly for a bit. I aten’t dead.

  1. Functional Regulatory T Cells Accumulate in Aged Hosts and Promote Chronic Infectious Disease Reactivation. Celine S. Lages, Isabelle Suffia, Paula A. Velilla, Bin Huang, Gregg Warshaw, David A. Hildeman, Yasmin Belkaid and Claire Chougnet.  The Journal of Immunology, 2008, 181: 1835-1848.[]
  2. Leishmania is a trypanosome parasite, transmitted by sand flies, that causes a variety of unpleasant diseases in people, as well as other species.[]
  3. I don’t think there’s a direct comparison of young vs. old depleted of TRegs, which is why I say “probably”[]
November 9th, 2007


Ephemeroptera (Mayfly)

One of the questions in antigen processing is what happens to peptides between the time they’re generated, and the time the they bind to MHC class I.

(The reason we care about peptides and MHC is that antiviral lymphocytes react with a complex of peptides and MHC class I, so this is a central point for antiviral immunity. Peptides are formed as a byproduct of normal protein degradation; an outline of the process, should you care, can be found here.)

In general, the peptides we’re interested in are produced by proteasomes. A protein (say, 500 amino acids long) enters the proteasome, the protein is chopped up, and peptides (between 3 and 30 amino acids long) come out. Almost all of those peptides are further chopped up, to produce amino acids – recycling and replenishing the amino acid pool for new protein synthesis. A small fraction of the peptides (perhaps between 0.01% and 1%), though, escape destruction and manage to bind to MHC class I. We would like to know more about that fraction of peptides, because they drive the lymphocyte attack on virus-infected cells. Why are they not destroyed — is it pure chance, or is there something special about the peptides that are not destroyed? How do they reach the MHC — is it chance again, just random diffusion, or is there some kind of specialized shuttle system that ferries the peptides to the proper subcellular location? Is there any active process modifying the peptides, to make them more (or less) suitable for binding MHC? And so on.

The problem is that it’s really hard to look at those peptides. Ideally, we’d like to grab samples of peptides at every point in the process: Exiting the proteasome, in transit, being degraded and processed, and so on. Then we could analyze what they’re like at each step, and develop a time course of modifications, interactions, and so on. But we can’t do that (yet), because it’s really difficult to measure peptides within a living cell.

A couple of years ago Jacques Neefjes (who always turns out cool papers) put some numbers on just how difficult is is.1

Blogging on Peer-Reviewed ResearchThere were a whole bunch of really cool things about this paper, but just focusing on one: Neefjes’ group came up with a way of measuring the rate of peptide destruction in living cells. They added a fluorescent tag to peptides in such a way that it would only fluoresce when the peptide was degraded; injected the tagged peptides into single cells; and measured (again in single cells) the rate at which the fluorescence appeared.

The injected peptides were destroyed with a half-life of 7 seconds. That is, a single cell can destroy hundreds of thousands, or millions, of peptides within a few seconds. (Most of this destruction, by the way, is performed by aminopeptidases, which are very abundant in cytosol.)

That’s not a long time, and it doesn’t give any individual peptide much chance to find its potential MHC binding partner. “A peptide will thus diffuse through the entire cell in 6 s and has to find TAP within this short period for translocation into the ER lumen.”

Why so fast? Why is the cell so worried about letting peptides hang about? Well, we presume this is because peptides are potentially very toxic. These peptides are generated, pretty much randomly, from active proteins. The peptides will therefore include short chunks of active protein domains, separated from any regulatory context; they could conceivably have biological activities by themselves. Also, you’d get hydrophobic chunks that could cluster into degradation-resistant clumps, if you let them accumulate, and it’s believed that such degradation-resistant complexes are themselves toxic. So you need to get rid of peptides fast, before they accumulate to form dangerous side-effects.

As a result, we antigen processing guys have to pretty much guess and use roundabout, indirect methods to measure peptides. Keeps us off the streets, I guess.

  1. Reits, E., Griekspoor, A., Neijssen, J., Groothuis, T., Jalink, K., van Veelen, P., Janssen, H., Calafat, J., Drijfhout, J. W., and Neefjes, J. (2003). Peptide diffusion, protection, and degradation in nuclear and cytoplasmic compartments before antigen presentation by MHC class I. Immunity 18, 97-108 .[]