Conditioning the Immune System

[Armada]

(Please move to the "speculation" forum if too speculationy.)

I became quite fascinated by the hygiene hypothesis a long while ago. It made a strange amount of sense, in that I'd lived in squalor in one form or another for much of my life (my childhood, being homeless, working at pretty filthy jobs) and have never had allergies or gotten sick too often.

 

The way I see it (as an admitted layman), the immune system is like a muscle: something that weakens and atrophies without adequate challenge and stimulation. Some of the most illness-prone people I know (other than the obviously unhealthy) are germ-phobes and hand sanitizer addicts.

 

More than just keeping the immune system up to snuff, I have, for the last couple years, made it a part of my lifestyle to challenge and "exercise" my immune system, within reason. Namely, eating lots of raw food and purposely leaving food unrefrigerated, letting it sit well past its expiration date or otherwise allowing it to push the threshold of spoiling. As long as it tastes fine (I'm no masochist) and doesn't make me sick, I've no qualms with the "ick factor" that might bother other people.

 

I have definitely learned from experience and trial and error, having had some close calls with food poisoning (nothing too serious), as well as doing adequate research: I know there's a worthy distinction to be made between ingesting reasonable and increasing amounts of bacteria (which is my goal, mostly) and the threat of toxic byproducts (eg. botulism) and parasites, neither of which I believe are a prudent way to challenge my immune system. My point being, I realize there's some inherent risk in what I'm doing, and have taken what I believe are appropriate precautions.

 

Anyhow, it's worked out great for me. I literally haven't been sick in years, and essentially don't have to worry about food poisoning. Which is good because I'm kind of lazy and absent-minded sometimes. A couple days ago I ate a burger I'd accidently left out for at least 9 hours. Tasted a little funky, honestly, but I felt fine.

 

Now, I definitely wouldn't recommend just anybody doing this willynilly. It's been a long and incremental process for me, and could be dangerous for people with weak immune systems (ironically, the people I feel could use it the most).

 

Anyhow, although I realize this isn't necessarily hard science the way I've been doing it (I don't have a hemocytometer to count the things swimming around in my food or anything like that) and could conceivably be seen as mere "speculation" (I believe there's enough evidence out there call this mostly factual, personally), I am above all interested in other people who know more than me opinions on the concept of training one's immune system. Especially in a hyper-sanitary culture that is rife with allergies, autoimmune disorders and, arguably, fragile (in the face of common pathogens to which we are otherwise mostly unexposed) immune systems.

 

Specifically, 1: Is it plausible, to you, that the immune system can be conditioned, "exercised" and strengthened? (Kinda my main premise here).

And 2: Do you think it is valuable, prudent or important in any way to do so, and/or to encourage others to do so as well, within reason?

 

Sorry for the long post, tried to make it easy to read at least. All comments, questions, suggestions, etc. are appreciated in advance. Thank you.

Edited July 7, 2012 by Armada

[JorgeLobo]

The hygiene hypothesis is just that - an hypothesis and one with very little direct data in support. Classic supporting data consist of asthma rates of city dwellers vs. those of folks from farm bckground.

 

For your report, I think you need to examine more closely assumptions in your investigation. First, just how do you propose consumption of food left out and beyond its expiration date offers a significantly greater immune challenge? I think you anticipate substantially greater bacterial numbers and you apparenty claimthis as factual. What information that convinced you this is fact?

 

Even if it is true - what are the data that convince you that incresed numbers consumed would substantially provoke immune response over the immune stimuli we encounter every day?

 

Also, on what basis are you sure increased consumption of bacteria provokes immune response enough that general health or immunity is improved?

 

 

Lastly, this is not science. A single set of subjetive observations by someone probably looking more to prove their hypothesis than test it.

[Jebus]

The immune system is not a, "muscle," it is a system, hence the term, "immune SYSTEM!" It is rather complex and there are several variables that contribute to your immunity: skin, diet, gut bacteria, etc. If someone is deficient in say, vitamin D, or C, their immune system would not function as well as someone who does get adequate nutrients. Most people (in developed countries) get enough of those nutrients.

 

Just because you havent been sick in years does not mean your immune system is stronger than someone else. What is your profession? Do you work at home? Alone?

 

I've herd teachers say, "my husband always eats food without washing his hands, but I stay clean and I get sick far more often then he does." Well, if the husband works a job that doesn't involve constant contact with several people everyday (manual labour), and since the wife is a teacher, who is in contact with several people every day, then she has a higher risk of contacting a virus.

 

Eating expired food will not give your immunity a boost, neither will eating yogurt btw. I know you didn't mention the latter but I thought I'd throw it in anyway.

 

The only real way we can strengthen our immune systems (as far as we know) is by getting vaccinated.

[JorgeLobo]

Well said, Jebus. I think Armada's post reflects the flawed conventional wisdom of immunity/disease and science in general. For this, we can thank ignorant news media pimping shallow and unspported concepts like the "hygiene hypothesis" as facts and failed educational system that breeds gullible unquestioning acceptance of such silliness.

 

 

 

Armada, can you tell us why you think the hygiene hypothesis has substance?

Edited July 8, 2012 by JorgeLobo

[JorgeLobo]

Here's a recent report again claiming some expression of the hygiene hypothesis. As with many of such studies, it reports an association - here, kids with dogs had fewer infections and related conditions. It interprets this as indicative of greater immunity (not demonstrated) and presumes this might be due to dogs bring in more bacteria (also not demonstrated). The work is typical MD rresearch - observe a phenomena and fit it into current concepts and it is limited in just that. The interpretation was obvious before the study and they could have included some measure of actual immunity and even bacterial type and numbers but they did not. Still, iIt goes the asthma studies one better in looking at conditions that are more directly and rationally associated with the concept.

 

http://children.webmd.com/news/20120709/many-babies-healthier-in-homes-with-dogs

[ecoli]

here are some papers which demonstrate direct evidence of the hygiene hypothesis

 

IBD:

http://stm.sciencemag.org/content/2/60/60ra88.abstract

http://www.ncbi.nlm.nih.gov/pubmed/15825065

 

Asthma/Allergies:

http://gut.bmj.com/content/57/5/561.full

 

 

The matter is obviously far from settled (and my hunch is that too much is attributed to microbe-immune interactions, simply because its a hot field right now) but, in general its always better to source primary research than things like half-digested press releases from WebMD. Often the research and researchers quotes are taken out of context.

 

But to the OP: 'strengthening' the immune system by eating recognized probiotics (yogurt, sauerkrauts, etc) is a good idea and, at worst, just isn't harmless. Eating spoiled meat is almost assuredly NOT a good idea. Though there are safe ways of purposefully fermenting meat products.

[JorgeLobo]

None of thse reports provides "direct evidence" of the hygiene hypothesis. They report coincidences and allude to relationships of specific conditions. The hypothesis is much more than that.

 

 

What's missing in this matter is a careful expeirment to address the hypothesis rather than citation of isolated tangential reports. If we were to test the hypothesis, what would be the experimental design?

 

 

Much of the "probiotic" story is overblown commercial hype.

[ecoli]

None of thse reports provides "direct evidence" of the hygiene hypothesis. They report coincidences and allude to relationships of specific conditions. The hypothesis is much more than that.

 

I have to disagree in part. While the mechanistic details aren't all worked out yet, reporting on associations between immune-related disorders and microbes is perfectly reasonable as evidence.

 

What's missing in this matter is a careful expeirment to address the hypothesis rather than citation of isolated tangential reports. If we were to test the hypothesis, what would be the experimental design?

 

I think you're being overly demanding. The hygiene hypothesis is a general framework of thinking about immune related disorders as arising from a lack of key microbe-host interactions. Only with recently sequencing technology has it become feasible to even study the hypothesis in a meaningful way.

 

I do agree with your skepticism about overdrawing conclusions, but your asking for general proof for a hypothesis that doesn't really make general claims! The only serious claims made by scientists is that some microbes may be factors in the prevention of some immune-related disorders. Therefore, scientists have been evaluation and testing this claims in human and animal studies one at a time. I'm not sure if there's a single experiment that could support or refute the many claims that the hygiene hypothesis is making, because the mechanistic details are probably very different depending on the disorder and microbe factor.

 

I mean, this is kinda like demanding 1 experiment to prove that genetic polymorphisms mutations cause cancer. Well, this claim is certainly true to a limit, but SNPs are only risk factors and difficult to predict outcomes from and usually only provides a clue about mechanism. Reasonable claims about the hygiene hypothesis are similar to this: microbes have been evolving with mammalian hosts for millions of years, so its not unreasonable to assume that they've evolved stable and even beneficial relationships with our immune systems: perturb these relationships and you might get diseases. Is this really so different than what we already know about the causes of other diseases?

 

Much of the "probiotic" story is overblown commercial hype.

agreed, but that's what you get if your exposure to probiotics info (and science in general) is from sites like webMD. The actual science is making much more reasonable, carefully researched, and well-supported claims.

[JorgeLobo]

These are merely associations - not "direct" evidence. That much is clear.

 

Overly demanding only if one wants to in fact test the hypothesis and advance it beyond that context to a theory. Biology has few if any proofs - it does have hypotheses such as this one and established theories such as evolution. The objective of science is to know and understand and is therefore not satsfied with casual hypotheses supported only by tangential observatins. Science asks itself how to directly test the hypothesis.

[ecoli]

These are merely associations - not "direct" evidence. That much is clear.

Which is often how interesting research starts. The BRCA mutations are 'merely associated" with breast cancer risk, yet its common medical practice to undergo prophylaxis for people with suspected-harmful BRCA variants. So while much of the mechanism is worked out now, but certainly not for all variants. If researchers had scoffed at this mere 'association' millions of people would not currently understand their risk for developing cancer.

 

Overly demanding only if one wants to in fact test the hypothesis and advance it beyond that context to a theory. Biology has few if any proofs - it does have hypotheses such as this one and established theories such as evolution. The objective of science is to know and understand and is therefore not satsfied with casual hypotheses supported only by tangential observatins. Science asks itself how to directly test the hypothesis.

You seem to be conflating a philosophy or method of knowing (ie - "Science") with something teleological and thinking. People use science to find things out about the universe but science isn't really a proper noun. I agree that researchers shouldn't be satisfied with conjecture and that hypotheses should be tested and retested until the molecular details of any biological system is teased out. I've never claimed otherwise.

 

However, it seems like your saying that correlation & association isn't evidence. Well with that you're wrong. Its true that correlation doesn't imply causation, but its also true that you can't have causation without correlation. So finding robust associations is often 'good enough' for early stages of medical practice and is a frequent starting point for experimental validation (provided you know your stats).

 

What kind of evidence would be good enough for you? Because whether or not you agree with the hygiene hypothesis, many scientists certainly do and certainly the NIH does because research related to heterodox immune-microbe interactions IS getting funded.

[JorgeLobo]

Agree - one makes observations, proposes an hypothesis and tests this hypothesis. This is the nature of science. This is obvious and should be the next step for this hypothesis.

 

This is science.- simply that - not philosophy conflated or otherwise. I said simply that this needs to be tested and asked for folks to consider an experimental design to do just that as the tangential reports do not. You apparently can't think of appropriate experimental protocol. Let's see if others can.

 

To facilitate, I'll offer the hypothesis as proposed in 1988 and currently pursued in the literature.

 

The hygiene hypothesis, as originally proposed in the 80's, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. It was expanded to include exposure to microbial antigens.

 

With the freedom of an earyl-life propsective study protcol, what parameters would be followed in the popualtion to test this hypothesis?

Edited July 11, 2012 by JorgeLobo

[ecoli]

Agree - one makes observations, proposes an hypothesis and tests this hypothesis. This is the nature of science. This is obvious and should be the next step for this hypothesis.

 

This is science.- simply that - not philosophy conflated or otherwise. I said simply that this needs to be tested and asked for folks to consider an experimental design to do just that as the tangential reports do not. You apparently can't think of appropriate experimental protocol. Let's see if others can.

 

To facilitate, I'll offer the hypothesis as proposed in 1988 and currently pursued in the literature.

 

The hygiene hypothesis, as originally proposed in the 80's, postulated an inverse relation between the incidence of infectious diseases in early life and the subsequent development of allergies and asthma. It was expanded to include exposure to microbial antigens.

 

With the freedom of an earyl-life propsective study protcol, what parameters would be followed in the popualtion to test this hypothesis?

 

Nice... I'd want to take regular blood serum samples, microbiome samples and as much patient meta-data as possible to control for confounders. Are there antigen panels you could run from blood samples?

 

This is science.- simply that - not philosophy conflated or otherwise. I said simply that this needs to be tested and asked for folks to consider an experimental design to do just that as the tangential reports do not. You apparently can't think of appropriate experimental protocol. Let's see if others can.

I could definitely design an experiment if I put thought into it. You made the claim that ex post association isn't enough (though there are legit ways to deal with this, statistically) so the burden is really on you to propose an alternative.

[CharonY]

Nice... I'd want to take regular blood serum samples, microbiome samples and as much patient meta-data as possible to control for confounders. Are there antigen panels you could run from blood samples?

 

This is tricky as high-dimensional data tends to exhibit patterns that appear to be statistically significant yet in truth are not related. Stronger support are studies from different angles that support the hypothesis (and none or only few that contradict it). To my knowledge and a brief scan through recent articles indicate that the hygiene hypothesis holds up well (i.e. the postulated inverse relationship was found more than a few times).

 

 

Also, a recent paper showed that reduced exposure to germs resulted in an expansion of natural T killer cells, which are involved in colitis and asthma. (forgot the reference but should be from Blumberg and Kaspar). While the latter was done in mouse models, it provides a mechanistic explanation.

[ecoli]

This is tricky as high-dimensional data tends to exhibit patterns that appear to be statistically significant yet in truth are not related.

 

This can be handled with good stats, though it often isn't (like correcting for spurious correlations when making multiple comparisons, autocorrelation analysis, etc.

 

To my knowledge and a brief scan through recent articles indicate that the hygiene hypothesis holds up well (i.e. the postulated inverse relationship was found more than a few times).

 

 

Also, a recent paper showed that reduced exposure to germs resulted in an expansion of natural T killer cells, which are involved in colitis and asthma. (forgot the reference but should be from Blumberg and Kaspar). While the latter was done in mouse models, it provides a mechanistic explanation.

Thanks for the references!

 

Also, there have been multiple studies showing immune system reponses changing to engineered or changed microbiota in germ-free mice and in recolonized humans. Often with the accompanying relief of IBD symptoms. In mice,SFB has been shown to induce TH17 responses upregulating immune defenses and decreasing pathogen susceptibility (all with prospective, molecular techniques)

 

Seems to me to survive the spirit of Koch's postulates, minus the requirement for culture based isolation, which isn't really necessary with genomic techniques.

[CharonY]

Stat only will not correct for that. A critical point is the number of correlations tested vs the number of true associations. Multiple hypothesis corrections do work, but still deliver false positives. A critical relationship is the type I error in relationship to the ratio of the number of true associations relative to false associations, in other words, the positive predictive value.

 

If we assume that for a given data set only 5% of all tested relationships are true (which is a lot) and were tested to be statistically significant with an corrected alpha of 5%, then the chance of for a statistically significant hit to be true (i.e. the PPV) is 50%.

[ecoli]

Stat only will not correct for that. A critical point is the number of correlations tested vs the number of true associations. Multiple hypothesis corrections do work, but still deliver false positives. A critical relationship is the type I error in relationship to the ratio of the number of true associations relative to false associations, in other words, the positive predictive value.

 

If we assume that for a given data set only 5% of all tested relationships are true (which is a lot) and were tested to be statistically significant with an corrected alpha of 5%, then the chance of for a statistically significant hit to be true (i.e. the PPV) is 50%.

You can do a little better than this by adjusting your alpha.If you think of the statistical test as a Bernoulli trial, with a random, binary outcome. If the null hyp is false for all trials, this gives you a distribution of outcomes at a probability equal to the statistical power. Therefore the probability of not making any type I errors is [math] .95^{N} [/math] where N = the number of trials.

 

So for multiple trials, to retain the same confidence, you adjust your alpha to 1- .95^(1/N). Which is very stringent for multiple comparisons and doesn't seem to be done much in practice.

 

edit: I just noted a small error with what you said. PPV isn't the ratio of true associations to false associations (that's the specificity). PPV is the ratio of true associations to the number of assocations tested as positive (so true + false positives). This may have not been what you said.

[CharonY]

I think I phrased it incorrectly and slightly confusing. However, the ratio that I meant is not the PPV (the sentence would not make sense if it was), but the ratio between true associations and no associations, or in the standard notation TP/TN.

Just to make it clearer [latex]PPV=\frac{(1-\beta )\times R}{((1-\beta)\times R)+ \alpha } [/latex]

 

With R being the ratio of true associations to the rest (no association), a value that is generally unknown.

 

Regarding corrections such as Bonferroni or the mentioned Dunn-Sidak, these more stringent approaches have the disadvantage that they increase tthe false negatives. And in the case of Dunn-Sidak, the hypotheses have to be independent (which is not easily determined in epi-studies).

 

But note that we only adjust our threshold to maintain the error level (say, 5%). As you can see that the PPV will still depend on largely on R relative to alpha (which was my main point).

 

Validation studies are always needed and as it turns out, even with proper multiple-hypothesis correction, the issue of FP is not resolved, when the search space expands (a common problem in omics and epi-studies).

[Marcus Williams]

The immune system is not a, "muscle," it is a system, hence the term, "immune SYSTEM!" It is rather complex and there are several variables that contribute to your immunity: skin, diet, gut bacteria, etc. If someone is deficient in say, vitamin D, or C, their immune system would not function as well as someone who does get adequate nutrients. Most people (in developed countries) get enough of those nutrients.

 

Just because you havent been sick in years does not mean your immune system is stronger than someone else. What is your profession? Do you work at home? Alone?

 

I've herd teachers say, "my husband always eats food without washing his hands, but I stay clean and I get sick far more often then he does." Well, if the husband works a job that doesn't involve constant contact with several people everyday (manual labour), and since the wife is a teacher, who is in contact with several people every day, then she has a higher risk of contacting a virus.

 

Eating expired food will not give your immunity a boost, neither will eating yogurt btw. I know you didn't mention the latter but I thought I'd throw it in anyway.

 

The only real way we can strengthen our immune systems (as far as we know) is by getting vaccinated.

 

He is not claiming that the immune system is a "muscle" he is comparing the two and trying to speculate on how the immune system could possibly function the same way as the muscle.

 

Personally I know that from our current knowledge the only way to strengthen the immune system is to get vaccinated. Most likely by consuming undercooked or spoiled food there is a possibility of feeling the effects later (ex. parasite). I respect the train of thought though and it would be interesting if modern science found out that we actually could naturally build our immune system in almost the same way we condition our muscles. I think it is a great thought, not so on board with the test trial, but I think that this idea will prove to be another great leap for scientist if they choose to study it!

[Isaacson]

I'm not in general an advocate of the Hygiene Hypothesis nor of ignoring proper hygiene, But what those who so strongly advocate conventional hygiene practices fail to address is that these too have the same lack of statistically significant epidemiology trials to support them. Most evidence for practices such as hand-washing and food hygiene come from either laboratory culture of bacteria or from hospital settings (where indeed there is a massive amount of evidence in favour of good hygiene). They do not constitute proof that good hygiene will make any difference to the total number of infections you will contract in your lifetime. As many commentators have pointed out, there simply is no evidence one way or the other as to the long term effect of hygiene practices on normal healthy individuals. We must therefore accept that both conventional hygiene advice and the Hygiene Hypothesis/Immune conditioning are theories supported by a limited amount of evidence.

[Bill Angel]

Specifically, 1: Is it plausible, to you, that the immune system can be conditioned, "exercised" and strengthened? (Kinda my main premise here).

And 2: Do you think it is valuable, prudent or important in any way to do so, and/or to encourage others to do so as well, within reason?

 

There is another situation that might be relevant to this discussion. Many people, including myself, suffer from an affliction known as psoriasis. In patients with psoriasis, certain immune cells are activated and produce too much of a protein called tumor necrosis factor (also known as TNF) a protein produced by the body, usually in response to infections. Medications such as Enbrel and Humira are taken to supress the production of this Tumor Necrosis Factor. But in supressing the production of this TNF factor, the medications also suppress the person's immune system, making them more susceptible to infections.

 

Now here is the connection to the poster's question. After taking Enbrel for three years, the medication had noticibly lost its effectiveness in supressing the symptoms of psoriasis. It's as if my body's immune system had developed a counter-response to the medication, making it less effective. Since the medication's purpose was in effect to "attack" my immune system, my immune system was able to counter this attack and become resistent to the medication's effects. This result caused my dermatologist to switch me onto a different medication, Humira, which works in a slightly different manner in supressing the immune system than Enbrel and to which my body's immune system has not yet developed a counter response.

 

So my answer to the original question "Is it plausible, to you, that the immune system can be conditioned, 'exercised' and strengthened?" is YES, but in the medical situation I mentioned I wish that it wasn't the case, that it didn't happen the way that it does.

[CharonY]

I think it has been mentioned already somewhere but an important point regarding immune response is that it works within certain biological parameters which are determined by regulatory networks. An efficient defense happens within this

 

The strength of a response does not scale with the efficiency of the immune response. In biological context a strong immune system is one that effectively protects the individual from infections while not creating issues (as mentioned above) due to it.

Exposure to harmless microinfections (such as per the hygiene hypothesis, but which is essentially also the reasoning behind vaccinations) do not strengthen the response but allow the system to mount an efficient response against something they encountered already.