Mystery Rays from Outer Space

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

June 22nd, 2010

Dual-specificity T cells and autoimmunity

Painting of TcR interacting with artrificial membranes by Raghuveer Parthasarathy
TcR interacting with artificial membrane1

Why does autoimmune disease (sometimes) follow viral infection?2

It’s a pretty well-known phenomenon, but a definite answer isn’t yet known — and of course there may not be a single answer, there may be multiple causes. We know that many autoimmune diseases seem to be triggered by some sort of infection or inflammation. A classic example is Guillan-Barre syndrome, which is a little more common (though still very rare) in people who have received certain influenza vaccines, but there are plenty of other examples.3 It’s not believed that the infection actually “causes” the disease, but rather that someone who already has a genetic predisposition to the autoimmune disease needs to have some kind of environmental trigger to have the disease actually kick in; and, very rarely, a viral or other infection will provide that trigger.

(The genetic predisposition is clear because, among other points, identical twins are much more likely to both get autoimmune disease than are fraternal twins; whereas the need for an environmental trigger is clear because even if your identical twin gets an autoimmune disease, you’re usually less than 50% likely to get it yourself. Note that I’m lumping together hundreds of different diseases into the “autoimmune” package, and the specific odds and so on differ for each one.)

OK, so if you have a genetic predisposition to autoimmunity — and let’s get more specific, the paper I’m looking at deals with multiple sclerosis (MS) — there’s a small chance that a viral infection will trigger that disease. One of the most popular models for this is “molecular mimicry”. Simplified: This is the notion that a viral protein looks, to a T cell, a little bit like a self protein. The viral protein appears in the context of infection, with its concomitant inflammation and tissue damage and so on, and the T cell is activated to it. The T cell wouldn’t be activated by the self protein because it hasn’t been seen in the context of inflammation before, but once over the activation hurdle the T cell is now able to attack the self protein, and this is autoimmunity.

T cell receptor (top) interacting with MHC

Molecular mimicry is an attractive model, but there’s not a lot of direct evidence for it.  Another possibility has been proposed for a while: Dual TcRs. Normally, T cells can only recognize a single target. This is by “design”;4 if the T cell can see two targets, it could get activated by one, and then attack the other, even if the second target was never present during inflammation. This sort of dual target recognition is obviously dangerous, and there are safeguards that mostly prevent it; but some T cells do sneak through with at least the theoretical potential for dual recognition. So what could happen here is that one TcR could be directed against the pathogen, and activate the T cell; then the other TcR, recognizing self, could run amok because it’s now on an activated T cell.

T cells with dual specificity do exist, at a fairly significant frequency (1-8%; at least one source claims as high as 33%, which seems much too high to me), but whether they actually do anything in autoimmunity is up in the air. This idea has been around for a while, but I don’t think there’s been much evidence for it happening naturally. In at least one case, where it was tested in an artificial system, dual TcRs did not seem to be responsible for an automimmune disease. 5

The most recent paper offers evidence that (in quite an artificial system) dual-specificity T cells are responsible for multiple sclerosis: 6

Our results demonstrate the importance of dual TCR–expressing T cells in autoimmunity and suggest a mechanism by which a ubiquitous viral infection could trigger autoimmunity in a subset of infected people, as suggested by the etiology of multiple sclerosis.

It’s an interesting and solid paper as far as it goes, but we’re left with the issue of this being a highly artificial system — mice with manipulated TcRs and manipulated autoimmune disease. Is this a real issue in natural autoimmunity and natural infections? This paper doesn’t really address that, but it does support the notion that it’s something to look more closely at.  (And again, different autoimmune diseases, or even different people with the same disease, may have altogether different triggers.  Maybe some people have molecular mimicry as the trigger while others have dual TcRs and other have who knows what.)

  1. By Raghuveer Parthasarath, then in the Groves lab[]
  2. Also, why are so many of my keyboard keys sticking together? An altogether easier question quickly answered by pointing to my kids “helping” me with my work while holding popsicles[]
  3. For a review:
    Fujinami, R. (2001). Can Virus Infections Trigger Autoimmune Disease? Journal of Autoimmunity, 16 (3), 229-234 DOI: 10.1006/jaut.2000.0484[]
  4. I.e. evolution.[]
  5. McGargill MA, Mayerova D, Stefanski HE, Koehn B, Parke EA, Jameson SC, Panoskaltsis-Mortari A, & Hogquist KA (2002). A spontaneous CD8 T cell-dependent autoimmune disease to an antigen expressed under the human keratin 14 promoter. Journal of immunology (Baltimore, Md. : 1950), 169 (4), 2141-7 PMID: 12165543 []
  6. Ji, Q., Perchellet, A., & Goverman, J. (2010). Viral infection triggers central nervous system autoimmunity via activation of CD8+ T cells expressing dual TCRs Nature Immunology, 11 (7), 628-634 DOI: 10.1038/ni.1888[]
June 17th, 2010

Dendritic cells that don’t prime

Langerhans cells in the skin
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

There’s a lot of interest in using dendritic cells as vaccines these days.  A paper in PLoS One2 offers a cautionary note.

Dendritic cells (DC) are the main cell type that drive T cells from their normal naive state to an active state.  In the naive state, a T cell can recognize its target, but doesn’t do anything about it; in the active state, the T cell does something, ranging from spreading inflammation to killing infected cells, and so on.  The DC is needed to bridge these states.  DC do many things, but at the simplest level they connect  the presence of an antigen (a T cell target, in this case) with the presence of something dangerous or abnormal — a pathogen, or tissue damage.

There are some conditions where we’d like an immune response, where DC don’t detect one or the other of their components (i.e. antigen or danger).  For example, there may be a situation that we know is dangerous, but where there’s  little evidence of “danger” for the DC.  A vaccine, for example, doesn’t want to deliver a huge amount of tissue damage, but we’d still like to get a strong response to an antigen.  For a natural situation, cancers are often ignored by the immune system even though there may be lots of cancer antigens, and one reason (of many) for this ignorance is that the DC may not perceive a lot of danger in the context of the cancer.

So why not take the DC out of the system, alarm them with some danger information in the test tube, load them up with antigen, and then return them to the body? That’s called a dendritic cell vaccine, and there’s fairly intense interest in the approach.

There’s been some success using this approach, but perhaps less than you’d expect from the biology as we understand it.

Several clinical trials conducted over the past decade have demonstrated that DC vaccines can prime and boost antigen-specific CD8+ T cells in humans. However, their clinical efficacy remains to be definitively demonstrated [6], [19], [20], [21]. The lack of success has been variously attributed to several factors: administration of relatively low cell numbers of DCs, suboptimal route of administration, improper antigen dose, poor choice of antigenic targets, unsuitable maturation state of DCs, and inappropriate frequency of injections. However, understanding exactly which of these concerns represent true problems may be difficult because little is known regarding the fate and function of ex vivo generated DCs after they have been injected 2

Dendritic cell

Yewdall et al asked what happens to DC after they’re given this course and returned to the patient (mice, in this case).  Their surprising conclusion is that the DC don’t work to prime T cells directly.  Instead, they have to hand off their antigens to other cells in the body that have never left:

Contrary to previous assumptions, we show that DC vaccines have an insignificant role in directly priming CD8+ T cells, but instead function primarily as vehicles for transferring antigens to endogenous antigen presenting cells, which are responsible for the subsequent activation of T cells. … This reliance on endogenous immune cells may explain the limited success of current DC vaccines to treat cancer and offers new insight into how these therapies can be improved. Future approaches should focus on creating DC vaccines that are more effective at directly priming T cells, or abrogating the tumor induced suppression of endogenous DCs. 2

As always in science, a single paper needs to be confirmed by others, so we won’t get too distressed until we see if other groups replicate this, and if it’s a universal truth or something specific to the particular system these authors were looking at.  (And, of course, this doesn’t trump actual evidence of efficacy for DC vaccines.) My own suspicion is that the work is accurate but limited, and there’s something about this particular system which prevented the transferred DC from being good primers; but as I say, I’d like to see some followup from another group.

  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. Yewdall, A., Drutman, S., Jinwala, F., Bahjat, K., & Bhardwaj, N. (2010). CD8+ T Cell Priming by Dendritic Cell Vaccines Requires Antigen Transfer to Endogenous Antigen Presenting Cells PLoS ONE, 5 (6) DOI: 10.1371/journal.pone.0011144[][][]
June 9th, 2010

I aten’t dead

Yeah, when I said the blog might have some hiccups as I transition from Michigan State to the CDC, I wasn’t really expecting them to be this large.

Part of the problem is that I’m doing a ton of influenza reading, and I’m reluctant to talk much about influenza here. Maybe that doesn’t make much sense, but I don’t want this to be in any way an “official” blog. I also worry a little about inadvertently talking about unpublished and premature stuff. Still, I’ll probably have some flu stuff here as I get a better grasp on the field.

I usually don’t like to give brief pointer-type posts, but I think that’s what I’m going to try for a little while — short posts pointing to recent papers that have caught my eye, without the background and context I usually try to include, but that I don’t have time (or mental energy) for right now.

Besides catching up on the flu field and preparing to drive down to Atlanta next week to start at the CDC, some other things that are keeping me busy at the moment:

  • Finding landing spots for my students. I think we now have found labs and projects for all of them. One will move to the CDC with me and take up a flu project, while remaining an MSU student.  This has all taken a certain amount of paperwork and planning
  • Playing catch with my kids in the back yard
  • Trying to rearrange my grants. I don’t know if it is possible but I have proposed a new consortium and principal investigator to take over some of them
  • Planning the future of my ongoing research projects.  Some will stay at MSU; one will probably move to a group of collaborators
  • Arranging a temporary place to stay in Atlanta; looking for a permanent house in the Atlanta area
  • Taking my kids to their baseball games (Monday/Wednesday – William; Tuesday/Thursday: Matthew; Friday – makeup games for both). I’m an  “assistant coach”, which means I tie shoelaces, rig up catcher’s gear, and act as 3rd base coach when I’m not doing the more important shoelace-tying jobs
  • Preparing our house here for sale.  Anyone want a lovely home in the East Lansing area? Crayon stains on the carpets will be removed, unless buyer likes the dramatic effect
  • Co-ordinating plans with our movers. This is arranged through the government and takes a certain amount of paperwork
  • Writing part of a book chapter on influenza
  • Working on papers with co-authors. I play a minor role in 3 or 4 papers in press and submitted
  • Preparing 3 of my own papers. Two are very close (waiting for replicates on data for the final figures); one could be done but needs to wait for one of the others to be in press before I submit it
  • Throwing a goodbye party for our friends here.  Going to goodbye parties thrown by our friends here
  • Preliminary exams. I’m on a bunch of students’ thesis committees, and one or two have arranged their qualifying exams to catch me before I go
  • Taking my kids to Lansing Lugnuts (our local Single-A baseball team) games
  • All the government paperwork involved in starting in the CDC.  There is a lot, and none of it is Mac-compatible, whereas I have no Windows computers available. Hmm.
  • Going to our kids’ school for their end-of-year plays, performances, and parties. (Rainforest party this afternoon in Matthew’s class!)

There’s a lot more, but you get the idea.  My kids get off school this Friday, and I plan to spend the next week mostly hanging out with them, so I want to get as much paperwork and so on out of the way this week.

Anyway, I hope I’ll be able to get back into some posts, even if they’re relatively terse, soon.