Molecular Mimicry and Disease

Everyone knows that bacteria/viruses/pathogens make you sick.

Everyone knows your immune system fights back against these guys so you get better.

But did you know that pathogens can (accidentally) make your immune system mutiny? Turn your own immune system against you?

They can! Through ‘molecular mimicry‘!

Lets say you woke up this morning, your throats super sore, huge tonsils– crap. Strep throat. Strep is usually caused by group A streptococcus bacteria. Normally your immune cells trot about, exchanging information, tips on where the little buggers are hiding, which epitopes are working the best, etc.

B cells, the guys who make antibodies, microevolve (hmm… microevolution is taken… ‘picoevolve’?) to make even better antibodies to the Strep. This picoevolution is called affinity maturation.

Mutation– The B-cells cells that react the best to Strep proliferate and change, just a little bit, through somatic hypermutation. Teeny-tiny changes in an antibody leads to lots of lots of antibodies that recognize the bacteria in teeny-tiny different ways. A theme in variations.

Natural Selection– So you now have lots and lots of B-cells that make an antibody that recognizes Strep. But maybe B-cell 6, 49, and 572 produce antibodies that are awesome at kicking that bacterias butt, while all the others are ‘just okay’. Well the 6, 49, and 572 B-cells are competing for survival signals with the just okay’ B-cells. The ones that react the best get the signal to survive, and they proliferate more and change just a tiny bit more. The ones that are ‘just okay’ die off.

This is a really cool process, but it has draw backs.

You might accidentally generate an antibody that works great against Strep… but also works great against your friggin brain!!! AHHH. Antibodies that stick to ‘self’ cells can lead to activation of the complement system (your self cells explode), or tell other immune cells to eat your self cells, or the antibodies might actually mimic a chemical signal and activate receptors on your cells in a weird way!!

To go back to the Strep example, a complication of strep throat is rheumatic fever. RH is caused by these self-reacting antibodies attacking your joints/heart/etc. One group has identified an antibody that mimics gangliosides, leading to too active CaM Kinase II, and basal ganglia death in your brain: Sydenham chorea.

The Strep isnt doing this on purpose. There is no benefit to staph for giving you jerky face movements.

Your immune system isnt doing this on purpose. There are many, many check-points in the immune system developmental process to make sure nothing that reacts to self can get through.

But more and more diseases are being linked to molecular mimicry– this same group found that antibodies that react to a different portion of Staph mimic epinephrine (!!!) and bind to epinephrine receptors on your heart, leading to a kind of heart disease.

Other people have been trying to connect molecular mimicry to lupus, multiple sclerosis, type I diabetes– any disease where your immune system is destroying the very things its supposed to protect. Kinda scary to think that the cold you got when you were 5 could make you have arthritis when youre 50…

Comments

  1. #1 Jérôme ^
    September 2, 2008

    It looks like the “Natural Selection” phase is actually more of a “Artificial selection” phase, the breeder not being a shepherd for once but rather the immune system itself. (Well, at least this falls somewhere in the middle).

  2. #2 Yoo
    September 2, 2008

    Sounds really nasty, although not too surprising in retrospect.

  3. #3 Beth
    September 2, 2008

    Its speculation at this point, but it seems logical that this is the sort of thing that caused the problems for the pork plant workers in Austin, MN. They were blowing pig brains out of skulls with pressurized air and then they started having problems with their immune systems attacking their own nervous tissue.

  4. #4 John Kwok
    September 2, 2008

    Abbie,

    This has some fascinating implications for coevolution at the molecular level. Thanks for posting this.

    John

  5. #5 Blake Stacey
    September 2, 2008

    OK, the post title poking into the text from the sidebar is kind of making it hard to read. . . .

  6. #6 Tatarize
    September 2, 2008

    >>It looks like the “Natural Selection” phase is actually more of a “Artificial selection” phase, the breeder not being a shepherd for once but rather the immune system itself. (Well, at least this falls somewhere in the middle).

    That’s natural selection. Darwin didn’t kick off breeding programs or artificial selection, his insight was that the same processes used there by humans must also exist in nature as the best critters give rise to the best critters. It would be nice to figure out the fail signals in the immune system and tell crap like RH that it fails at fighting diseases. Some good artificial selection of our immune system might actually cure some of those diseases.

  7. #7 Monado
    September 2, 2008

    I know of two cases in my limited circle of friends & family where adults developed insulin-dependent diabetes about a year to 18 months after having a flu-like illness. Both were physically active, normal-weight individuals who ate healthy diets. I know that anecdotes are not data; but it makes me wonder if the virus triggered an auto-immune response.

  8. #8 Cayte
    September 2, 2008

    In Louisa Alcott’s autobiographical novel, her sister died of “wasting sickness” a few years after a recovery from scarlet fever.

  9. #9 marc buhler
    September 3, 2008

    Abby,

    The reason that vertebrates have done so well in the 500m years they have been evolving is because the critical sites used by antibodies and T-cell receptors are *not* encoded in the genome, and thus cannot be usurped by microbes.

    Every T-cell or B-cell uses genetic editing to create the binding site unique to that cell (and the daughter cells it can produce, somatic hypermutated in some B-cells, of course). This is kind of like the “rachet set” at a workbench – where diferent handles, adaptors and sockets make many, many different “tools” from the parts available.

    The binding site, which can be called an “idiotype” can itself be a template for an “opposite” antibody – called an “antiidiotype”, which can then be a template for an “anti-anti-idiotype” that is essentially the same as the initial antibody (to a degree…).

    Antibody binding sites, since they are *not* encoded in the genome, are not passed along between generations, but there *might* be a role for templates of idiotypes of antibodies passed from mother to infant in breast feeding.

  10. #10 Militant Agnostic
    September 3, 2008

    Guillame Barre syndrome follows an infection – would that be the same mechanism?

    This looks like another example of Unintelligent Design

  11. #11 clinteas
    September 3, 2008

    @ No 4:

    //This has some fascinating implications for coevolution at the molecular level//

    co-what? and what would those implications be?

  12. #12 Bill
    September 3, 2008

    Sort of off topic but this looks very interesting, would like to hear some comments on it.

    Virus is passed from parent to child in the DNA

    http://news.yahoo.com/s/nm/virus_dna_dc;_ylt=ArAmTjYdMTONTKHi.w5IbpADW7oF

  13. #13 Jared
    September 3, 2008

    This is pretty neat stuff, and doesn’t HIV-1 do something similar? I think several other bacteria do this, too.

  14. #14 John Kwok
    September 3, 2008

    Dear clinteas,

    Am thinking of a coevolutionary arms race of the kind envisioned in the Red Queen Hypothesis, which was proposed independently back in the early 1970s by vertebrate paleontologist Leigh Van Valen and ecologist Michael Rosenzweig. Think of it as some kind of molecular arms race between predators and prey.

    John

  15. #15 The Chimp's Raging Id
    September 3, 2008

    That’s fascinating! Thanks, Abbie.

  16. #16 Dustin
    September 3, 2008

    Am thinking of a coevolutionary arms race of the kind envisioned in the Red Queen Hypothesis, which was proposed independently back in the early 1970s by vertebrate paleontologist Leigh Van Valen and ecologist Michael Rosenzweig. Think of it as some kind of molecular arms race between predators and prey.

    What selective advantage does the bacteria gain by provoking an auto-immune response which will not affect the host until years after the infection has been eliminated? And how does avoiding such an auto-immune response impart a selective advantage to humans when, typically, the impact of such a response isn’t usually debilitating until late in life, when they aren’t reproducing anyway?

    Also, I’m not really in the mood for plausibility arguments. Since the list of publications on auto-immune reactions to infections is extensive, you can point me to a paper which has data supporting your “implications”.

  17. #17 Steven
    September 3, 2008

    Hi Abbie,

    Thanks for the little refresher read. I did an Immunology module for my degree last sememster. I think we called this antigen mimicry but I think it is more or less the same thing. Some examples below.

    Pathogen, Mimicked Molecule

    Virues

    Vaccinia, IL-1 receptor
    EBV, IL-10
    CMV, Beta Microglobulin

    Bacteria

    Group A streptococci, Human myocardial myosin
    Klebsiella, HLA B 27
    Mycoplasma, Blood group I antigen

    Fungi

    Candida, Complement receptor 3

  18. #18 fusilier
    September 4, 2008

    Mostly off topic for this thread – but did you see this?

    http://www.newscientist.com/article/dn14658-universal-childhood-virus-is-inherited-in-dna.html?DCMP=ILC-hmts&nsref=news8_head_dn14658

    Roseola – “soft measles” for those of us who are old enough to remember – seems to be an ERV which is still causing symptoms.

    fusilier
    James 2:24

  19. #19 John Kwok
    September 4, 2008

    Dustin:

    Am not by training a molecular biologist, but I knew that there’s been work in molecular biology exploring the consequences of the Red Queen Hypothesis:

    “A worm’s eye view of the immune system: consequences for evolution of human autoimmune disease

    David W. Dunne and Anne Cooke

    Nature Reviews Immunology 5, 420-426 (May 2005)

    doi:10.1038/nri1601

    Back to article | Previous Box
    The Red Queen hypothesis was originally proposed by Leigh Van Valen59 as an explanation for the evolution of sex. During gamete formation, at meiosis, there is the possibility of reassortment and exchange of genetic information between chromosomes, so together with mutation, this contributes to the development of genetically diverse individuals. Such genetic diversity enables the host organism to combat infection. As the host organism evolves in this way, so too does the infectious agent. It is, in essence, a description of the events that occur during the co-evolution of a host and its parasite, in which each is attempting to evade the defences of the other. It is known as the Red Queen hypothesis because it is taken from Lewis Carroll’s Through the Looking Glass (1872), when the Red Queen tells Alice, “[I]t takes all the running you can do, to keep in the same place.”

    BTW, the authors have overlooked citing ecologist Michael Rosenzweig who independently derived the Red Queen – without coining it as such like Van Valen – referring to it as a zero sum game for evolution.

    I suggest you check the literature yourself in the future.

    John

  20. #20 Dustin
    September 4, 2008

    I didn’t ask for plausibility arguments. And I certainly didn’t ask about someone’s highly contentious paper asserting that parasitic worms may cause auto-immune responses in populations which haven’t been exposed to those worms for some time. Why? The data hasn’t come in supporting it yet, some people say they have data which undermines it (citation searches are your friends, Kwok), and even if that wasn’t the case, worms aren’t strep.

    Make the following statement true, clown:
    (Mathematical Model)∨(GTFO)∨(Statistical Data)∨(STFU)

  21. #21 Dustin
    September 4, 2008

    Disjunctions show up in previews but not in posts?! SCANDALOUS!

  22. #22 John Kwok
    September 4, 2008

    Dear Dustin:

    I think it’s ridiculous that you can expect me as a former paleobiologist to comment on immunological literature when that isn’t my background. As for the Red Queen Hypothesis itself, it has been the subject of much research since the early 1970s (It even appeared as part of an episode in the NOVA “Evolution” miniseries.).

    I have noted elsewhere that I didn’t understand everything I had heard during the Rockefeller University evolution symposium talks that I attended last spring (One of the session chairpersons, who is also, like me, trained only in organismic biology, found much of the content almost incomprehensible.).

    So if you’re interested in scoring “points” against me, then I’m not interested. Find the relevant literature yourself.

    John

  23. #23 Dustin
    September 4, 2008

    I think it’s ridiculous that you can expect me as a former paleobiologist to comment on immunological literature when that isn’t my background

    THEN. DON’T. FUCKING. DO. IT.

  24. #24 windy
    September 4, 2008

    The only way that I can see to make this about “coevolution at the molecular level” is if the pathogen is selected for immunological resemblance to the host’s proteins (to better “hide” from the immune system?), and the host is then selected for proteins that are dissimilar to the pathogen, and so on. It seems a bit implausible (for example, if it were true we would expect epinephrine to be replaced by a different molecule now that staph is “catching up” with it.) Probably John just wanted to say something relevant-sounding, for once.

  25. #25 John Kwok
    September 5, 2008

    Windy:

    You need to think out of the box maybe? I’m not going to comment further, except to make the following observation, simply because I am not familiar with the molecular biological literature.

    The best example of coevolution at the molecular level which I am acquainted with is the pharmaceutical arms race between humanity and the Plasmodium malarial parasite, which, as you may recall, leading Intelligent Design advocate Michael Behe has noted is a superb example of Intelligent Design. Of course it isn’t, but rather, that of both the Red Queen Hypothesis (in the version articulated by Mike Rosenzweig as an evolutionary zero sum game) and coevolution. It is a coevolutionary arms race in the sense that humans have developed drugs to kill the parasite, but through selective pressures, drug-resistant strains of Plasmodium have evolved, and so, in response, humanity has to develop more effective drugs.

    Why don’t you spend more time reading the appropriate literature for once instead of trying to act like a jerk.

    John

  26. #26 windy
    September 5, 2008

    It is a coevolutionary arms race in the sense that humans have developed drugs to kill the parasite, but through selective pressures, drug-resistant strains of Plasmodium have evolved, and so, in response, humanity has to develop more effective drugs.

    But this wasn’t about malaria. You still haven’t explained where you think an arms race is taking place in the specific case of the autoimmune response provoked by the strep and staph bacteria. If you want to make cryptic remarks about science, that’s fine, but you should be prepared to back them up rather than asking everyone to “read the literature” and try to figure out what you meant.

  27. #27 John Kwok
    September 5, 2008

    Dear Windy:

    Again I am not familiar with the immunological literature, so I really don’t think I can comment further. But to me, a cursory reading of this still seems like it could be coevolution.

    John

  28. #28 John Kwok
    September 5, 2008

    Windy:

    Based on this excerpt from the Wikipedia article which Abbie has linked, I’m going to take a stab:

    “Despite no obvious amino acid sequence similarity from pathogen to host factors, structural studies have revealed that mimicry can still occur at the host level. In some cases, pathogenic mimics can possess a structural architecture that differs markedly from that of the functional homologues. Therefore, proteins of dissimilar sequence may have a common structure which elicits an autoimmune response. It has been hypothesized that these virulent proteins display their mimicry through molecular surfaces that mimic host protein surfaces (protein fold or three-dimensional conformation), which have been obtained by convergent evolution. It has also been theorized that these similar protein folds have been obtained by horizontal gene transfer, most likely from a eukaryotic host. This further supports the theory that microbial organisms have evolved a mechanism of concealment similar to that of higher organisms such as the African praying mantis or chameleon who camouflage themselves so that they can mimic their background as not to be recognized by others.[11]”

    Where coevolution comes in is probably in the mechanism of concealment undertaken by these pathogens. So, strictly speaking, it is not a strict “arms race” kind of coevolution between pathogens and our cells.

    John

    P. S. I was using the malarial example as a valid, quite classic, example of a coevolutionary arms race. You should be sufficiently smart enough to realize that.

  29. #29 windy
    September 5, 2008

    P. S. I was using the malarial example as a valid, quite classic, example of a coevolutionary arms race. You should be sufficiently smart enough to realize that.

    Yes, I know it is an arms race, oh obnoxious one. But if you agree that molecular mimicry is not an arms race, it was rather pointless to use the malarial arms race as an example.

  30. #30 Dustin
    September 5, 2008

    Hey. You know what really shows that molecular mimicry is an evolutionary arms race? The Cold War. See, you’d know that if you’d read Connddoolleezzaa Rice’s papers. She was the provost of Stanford University, and is an accomplished Afro-American.

  31. #31 minimalist
    September 5, 2008

    Yes Dustin, but the crucial question here is, do you know her from somewhere?

  32. #32 windy
    September 6, 2008

    The crucial question is: does John know Kevin Bacon?

  33. #33 Dustin
    September 7, 2008

    Connddoolleezzaa Rice did graduate from the distinguished alma mater of one of my distinguished statistician friends.

  34. #34 Dustin
    September 7, 2008

    The crucial question is: does John know Kevin Bacon?

    Several of my former professors collaborated with Fred Richman, student of Alonzo Church, contemporary of Alan Turing. Alan Turing argued for formalism against Wittgenstein’s intuitionism while taking a seminar on the philosophy of mathematics from Wittgenstein. Wittgenstein was a childhood classmate of…. ADOLF HITLER! More notably, Wittgenstein once famously debated Karl Popper while weilding a fireplace poker.

    Back to Alan Turing. He once met G.H. Hardy. That’s impressive by itself, but Hardy was a student of Edmund Whittaker, who was a student of George Darwin, son of Charles Darwin.

    There are three different routes I can take through my mathematical genealogy back to one E.H. Moore. E.H. Moore’s advisor was one H.A. Newton, whose advisor was one Michel Chasles, whose advisor was none other than Simeon Denis Poisson. Poisson was taught by Lagrange himself, Lagrange by Euler, Euler by Johann Bernoulli, Jacob Bernoulli, who was taught by motherfucking Leibniz.

    My economics professor, a neoconservative fundamentalist lunatic, was a student of a student of John Maynard Keynes. This, once again by association, brings us back to G.H. Hardy, Bertrand Russell, Freeman Dyson, Ramanujan, G.E. Moore, and Wittgenstein.

    I’ve also had the opportunity to meet Peter Lax personally. Peter Lax, while being one of the modern age’s foremost mathematicians, was taught by a student of none other than Richard Courant. Do you know who Richard Courant’s advisor and mentor was? David freaking Hilbert, that’s who! Hilbert was, of course, the student of a student of Felix Klein (who has a group and a bottle named after him). Klein was a student of Rudolf Lipschitz (of analysis fame). Lipschitz was a student of none other than Dirichlet and Martin Ohm. Lipschitz was a student of Poisson, who we’ve already mentioned, but also of Jean-Baptiste Fourier, who usually needs no introduction.

    From the names above, I’ve also got Chandrasekhar, Eddington, Einstein, Bohr, Hawking, Dirac, Hans Reichenbach, Hilary Putnam, Quine, Carnap, Feynman, Gell-Mann, Weinberg… you get the point.

    You lose, Kwok.

  35. #35 Dustin
    September 7, 2008

    AAAAnd I’ve met George H.W. Bush.

  36. #36 Dustin
    September 7, 2008

    And my alma mater has Nobel Prizes up the yin-yang and a whole lotta famous astronauts.

  37. #37 Dustin
    September 7, 2008

    Which reminds me…

    I’ve met Buzz Aldrin, Neil Armstrong and John Glenn.
    My mom worked with the late Dr. Kaplana Chawla on something, once.

  38. #38 Dustin
    September 7, 2008

    Finally, I’ve insulted celebrated science fiction author Kevin J. Anderson, who lived a few miles from me, to his stupid face.

The site is currently under maintenance and will be back shortly. New comments have been disabled during this time, please check back soon.