Implications of the immune response

I started writing this post before I read ERV dissecting some "the immune system is perfect" BS. Go read hers, then come back if you want more.

Now that I've gone through the basics of a typical immune response, I think it's necessary to point out some of its many flaws. In many of the immunology courses I've taken, the mammalian immune system is presented almost as the pinnacle of evolution, but it is far from perfect. In fact, in many ways, we might be better off if it had never evolved at all.

First up - Autoimmunity. T-cells and B-cells generate random receptors that can in principal see any molecular shape, and that includes shapes that our own body produces. Intrinsically, T and B cells (collectively called lymphocytes) have no way of knowing if their receptor sees some virulent strain of E. coli or they myelin sheath of your own neurons. To counteract this problem, we have evolved elaborate mechanisms to promote immune tolerance of our own tissues. Developing lymphocytes are programed to self-destruct if their receptor binds something early on (before they are likely to have seen a real pathogen), and they get turned off if they bind something in the absence of a danger signal (usually provided by a pattern recognition receptor). There are also regulatory cells flying around the blood stream, tamping down runaway signals and trying to keep them quiescent.

But these mechanisms often break down, and we have diseases like multiple sclerosis, type-1 diabetes, rheumatoid arthritis, Crohn's disease, Lupus, etc. In addition, there are so-called hyper-inflammatory disorders in which the immune system over-reacts to harmless molecules, yielding the wonderful trifecta of allergies, asthma, and IBD.

"But surely," you say, "those are rare side-effects of a system that, on balance, is protective." I'm not so sure. The second obvious flaw with our immune system is that it doesn't actually protect us from the virulence of pathogens. This statement seems deeply counterintuitive (especially coming from an immunologist), but hear me out. How many of you readers have never gotten sick? I feel pretty confident saying that no one raised their hand. "But without an immune system, that pathogen would have killed me," you say, and this is sort of true. Certainly, people with compromised immune systems are at a much higher risk for death from fairly routine infections, but the real question is, if no one had an immune system, what would be the outcome?

To understand this point, I think it helps to look at this from the pathogens' perspective. What is the goal of a rhinovirus (that might cause a cold), or Plasmodium falciparum (which causes malaria), or Bacillus anthracis (better known as anthrax)? The goal is not (necessarily) to kill you. The goal is to maximize replication and transmission. And depending on the mode of transmission, there are different levels of virulence (ability to make you sick) that are more beneficial.

Transmission of a cold virus occurs by person-to-person contact. You'll infect far more people if you're just sick enough to still go to work or go to buy groceries. If that rhinovirus made you as sick as malaria, you'd never infect anyone. Plasmodium falciparum, on the other hand, has mosquito vectors that carry it around, and you're actually less of a threat to the mosquitos if you're incapacitated. It doesn't want to kill you, because then the parasite will die as well. People do die from malaria, but that's an unintended side effect, and in any case those people have probably already fed many mosquitos and passed the disease on. B. anthracis doesn't care if you die, but that's because its method of transmission doesn't depend on its host living. It just wants to replicate as much and as quickly as possible, devouring whatever nutrients it can get its hands on. If and when the host dies, Bacillus can form spores, which are extraordinarily hearty. They can withstand all kinds of extremes (even autoclaves - the industrial sterilizers used in labs and hospitals won't kill Bacillus spores)**, and can lay dormant for decades or even centuries millions of years!, just waiting for a new hapless host to wander along.

This whole idea is called virulence theory, and if you think about it, the best way to guess how virulent a pathogen will be is to look at its method of transmission. Of course, there are exceptions, but the exceptions aren't particularly successful pathogens. Several hemoragic fever viruses (think Ebola) spring up now and again and wipe out whole villages, but then they die off because they incapacitated and then killed their entire host supply too rapidly to make it to a neighboring village. But what does all this have to do with the immune system?

Pathogens have evolved to expect an immune system, and they've gauged their virulence accordingly. That's why an AIDS patient can die from a normally harmless bacterial infection - those bacteria expect push-back from an immune system that isn't there. But if we had never evolved immune systems, the pathogens wouldn't have evolved all of those ways around it, and we would all expend far less energy and arrive at the same outcome. This is a classic example of an Red Queen evolution - an arms race between competitors. And you can see it everywhere in life, from cheetahs and antelopes to hundred-foot tall redwood trees. And my larger point is not really that the immune system is useless - clearly it was beneficial enough to our ancestors to be worth the price of energy expenditure and potential autoimmunity. The larger point is that when I write (as I often do) about the ways that pathogens get around our high and mighty immune system, remember that these evasion strategies are the rule, not the exception.

Immune response from start to finish series
Part 1: Invasion and detection: Innate immunity
Part 2: T-cells, B-cells and adaptive immunity
Part 3: Immune Memory
Implications of the immune response (current)


**Evidently, this is one of those things I heard at one point as an undergrad, and stupidly repeated here without double-checking. My bad - thanks for calling me out Tuco. I did find this cool paper though (free full text - check out the intro for the references):

Endospores are dormant forms of bacteria that are stable for great lengths of time and are resistant to inactivation from radiation and heat. Bacillus spores are so resistant and hardy that they have been revived from the abdominal cavity of an extinct bee entombed within Dominican amber 25 to 40 million years ago and isolated from a brine inclusion dated at 250 million years old.

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A fun* post. One thing, though:

[E]ven autoclaves - the industrial sterilizers used in labs and hospitals won't kill Bacillus spores

Steam sterilization (i.e., autoclaving) will in fact kill Bacillus spores. Ampules of Bacillus spores are often used to verify sterilization.

*As much "fun" as disease, plague, and pestilence can be, I guess.

There is a tiny problem with the links to the
3 parter introductory course in immunology.

The links are to the following pages.

you need to add in /2010/11 before the part of the links I've listed.

By who Cares (not verified) on 06 Nov 2010 #permalink

As an 'amateur' immunologist, I find that this piece describing the flaws of the immune system in the context of evolution to be more about opinion, or a viewpoint, about the purpose of the immune system strictly in the context of pathogen eradication, than it's 'holistic' purpose, may I say; which, through my observations, is about maintaining homeostatic balance.
With the great multitude of biological functions which occur at any given nanosecond in any given species, things will and can go wrong, not limited to somatic hypermutations, protein folding, etc. I think that one problematic view of the immune system is that it is an entity in itself, that just sits back and waits for a perturbation to occur, become engaged, then return to senescence. When in fact, that is not how it works at all.
The immune system is under a consistent barrage of insults. Not only from 'rare' instances of rhinoviruses, influenza, HIV, tuberculosis, but from would be pathogens that at most times are symbionts on our skin and laden throughout our guts. What I mean by rare is that these are not typical insults that our immune system has to deal with on a daily basis.
We've evolved intimately with microbes. In fact, in order to have a healthy immune system, not only does it need to 'learn' but it absolutely requires a deep symbiotic relationship with microbes. Perhaps you were being sarcastic when you said we'd be better off having not evolved an immune system, but the development of the immune system is intrinsically dependent on our symbionts. I think that the added energy expense has of course, been highly beneficial for our evolution, as we receive a great deal of benefits from the symbionts that well out number our own cells, just sitting in our guts.
A pathogen doesn't care whether or not they're exploiting our immune systems. It's natural selection. And thanks to those pathogens, whatever a pathogen may really be, they've helped select species that can achieve homeostatic balance in their presence.
Evolution fine tunes the immune system, performed by so-called 'pathogens', and autoimmunity. It's a continuing process, as it always has been. It's still a work in progress, and so you want to place blame on something that is far from being finished? Or, could we actually place the blame on our inadequacies in trying to stop evolution?
Lest I certainly agree, it is far from perfect, but let me ask you this: what defines a successful immune system? Is it complete eradication of a pathogen, or is it the ability to maintain homeostasis during a perturbation? What about all those retroviral-like retrotransposons in our DNA?
Furthermore, the immune system does more to rid your body of endogenous junk every second, macrophages picking up dead cellular debris, extracellular DNA, etc, than fending off potential 'pathogens'. For this purpose, there's the threat that it would 'clean' out things that it shouldn't, like myelin sheaths, etc.,and hence, autoimmunity.
The immune system is a peculiar beast. And at times it seems autonomous from the individual it is supposed to protect, but it's functions go well beyond it's ability to protect from pathogens, but more in its abilities to maintain homeostasis, such as in instances of sterile immunity.
I do like your articles and it's nice to see someone sharing immunology related material here; I just like to share my view of the immune system in a broader context.

@JeffF - YES! mostly.

This post is intended to be a bit tongue-in cheek. In order for an immune system to be selected for, the enormous energy expenditure must have imparted a selective advantage. The larger point is that at the same time the immune system evolved, the pathogens evolved almost immediately to exploit other weaknesses, so the net result is an immune system that does not protect us against real pathogens, but costs a lot of energy.

This sort of arms race happens all the time in evolution, and this post is rather like arguing that trees would be better off if they'd never grown taller (this example I first heard in Dawkin's The Greatest Show on Earth). The end result is that you have redwoods growing hundreds of feet, spending tons of energy and in the end not being any better off. Of course, the truth is that at each step, the tree that grew just a little bit taller had a competitive advantage and so on ad infinitum.

I could quibble with a few specific details of what you wrote above, but the overall idea is absolutely correct. I really just want to knock the immune system off the high pedestal that a lot of immunologists put it on - it does some amazing things, but it's an incredibly imperfect, grossly overstated and often poorly constructed system. But in that way, it's no different from any other biological system. That said, there's beauty in the way it's cobbled together, and that's why I'm spending my life studying it :-)

Hi Kevin -

I am curious if you've seen any work by either Pittman or Bilbo that implicate a neonatal innate immune response and subsequent persistent modifications to neuroimmune function, HPA-Axis metabolism, and ultimately, behaviors?

There are lots, but here is one that ought to especially peak your interest, Neonatal programming of the rat neuroimmune response: stimulus specific changes elicited by bacterial and viral mimetics

which seemed to find not only persistent neuroimmune effects from an early life immune challenge, but ones that are bacterial or viral mimic specific; suggesting a training of specific TLRs. (!) There is a surpising (to me) amount of work in this area recently.

- pD

I hadn't seen that. It's an interesting observation, but this paper seems sorely lacking in mechanism. That said, there's no reason why early inflammatory events, especially during development, wouldn't impact future inflammatory events. It's pretty cool that it's specifc, but not that surprising considering the inflammatory out-put of LPS and polyI:C is quite different.