Thursday, March 29, 2007

The Hygiene Hypothesis

The Hygiene Hypothesis: Probably the one idea in Immunology that annoys me the most. It bugs me, drives me nuts, nevertheless it has held and persevered for nearly twenty years. So there must be something to it, and I must shelve my prejudices and look into it.

Let me get my complaints out of the way first, so that you can treat my point of view with the necessary skepticism. On the other hand, maybe I am good person to look into this idea since I am the ultimate skeptic and totally disinclined to believe. Hopefully not too prejudiced, but I’ll leave you to be the judge of that. My biggest peeve with the Hygiene Hypothesis is irrational, it is the name- it is pejorative. There is no nice way to think of it. It is meant to explain the increased incidence of allergic diseases in countries with a “Western” lifestyle, and postulates that decreasing family size and improved hygiene in these countries has led to the increased prevalence of allergic disease. Why? How? Let me try and explain.

At the core of the ideas that eventually constitute the Hygiene Hypothesis and attendant years of research is a set of apparently contradictory observations, best exemplified by this one: farmers have a much lower incidence of hay fever than the rest of the population. Intuitively perhaps, this seems odd. Farmers and people who live on farms are exposed to pollen and other things that give rise to hay fever far more than people who live in cities, so if the tendency to get hay fever was evenly distributed in the population, there should be a similar percentage of farmers who get it as, say, bus drivers. This is not the case, however and the whys and hows have been hotly debated these many years.

There is a really important immunological idea that needs explaining at this point, it is the phenomenon of Th1 and Th2 T cells (which expand as Type 1 helper T cells and type 2 helper T cells, but that is not really necessary to know). Th1 and Th2 T cells as a concept have been around for donkey’s years, and anyone who has ever worked in immunology has brushed up against it. It describes two different subsets of T cells (ha, you would never have figured that one out) and it is a separation into subsets based on function. Specifically, that function is the production of certain small molecules called cytokines.

Cytokines are the e-mail messages of the immune system. Whenever a cell is activated, and this applies to nearly all immune cells, it sends out the message that it is activated by dumping cytokines into its milieu. The particular cytokine- or set of cytokines since immune cells can often produce a whole bunch of cytokines at the same time- dumped out depends on the way in which the cell has become activated. So, if you read about something horribly unjust on the news, you’re activated to be indignant and send indignant activist e-mail to your friends. Inflammatory even. On the other hand, if you’re really annoyed with a colleague’s carping or unprofessional behaviour, you send insistent annoyed e-mail to friends or family. You are irritated in fact. And then a friend sends you seven increasingly frantic messages about the date that didn’t call back and you see a need and send out an instant, powerful, soothing message. A dampening, or regulatory message. These messages have effects on other people, some intended and others unanticipated. These messages also affect people who are near and those who are far; those who are directly involved or hapless bystanders. Cytokines send out messages that initiate war upon an enemy infection, or those that irritate one’s own body to the point of itching or sneezing, or messages of cessation and calm. As required, and as far as blood can circulate. Sometimes they are just sparks, and other things form the flame, of fever for example, but that’s for another day. You get the picture.

Th cells are really good cytokine producers. Th1 cells make so-called Th1 cytokines, which are generally more of the sound-the-charge type. Th2 cells make, well, Th2 cytokines that belong more to the irritant family. The view has been long held that Th1 cytokines are needed to fight infections, and when they go out of control, they cause autoimmune diseases, such as Crohn’s disease. Th2 cytokines on the other hand are thought to be the ones that cause allergic types of reactions, but they are very necessary to clear parasitic infections, like worms living in your gut. Of course the longer something is studied the more ambiguous it becomes and that is not the whole story. Anyway, the key thing is that Th1 cytokines can block the production of Th2 cytokines and vice versa, which is why I have been discussing them as opposites. Depending on the order or amount (or both) in which they are made, either Th1 or Th2 cytokines end up dominating an immune response.

Back to the Hygiene Hypothesis. The idea builds up as follows:
Th2 cytokines are among the primary causes (actually effectors) of allergic disease,
Th1 cytokines suppress the production of Th2 cytokines,
Various microbes in the air, soil, water and environment cause the production of Th1 cytokines
Clean environments contain less microbial “challenges”, therefore less Th1 cytokines are made
Ergo, the Th2 cytokines run amok and you have a higher incidence of allergic disease.

There is a lot of evidence in favour of the hypothesis and a fair amount against it. The interesting thing about the Hygiene Hypothesis is that most of the data for or against comes from epidemiological studies. Epidemiology is the statistical study of diseases in populations, and is by its nature observational while Immunology is the mechanistic study of disease and is primarily an experimental science. The reason for this strong reliance on epidemiological methods, in my opinion, is that it has been tremendously hard to show experimentally that normal every day environmental stimuli induce Th1 cytokines. Exceptions exist, such a group that has collected stable dust in Switzerland and is going to use that to determine if there is any immunologic response to it. (Stable dust! There’s also a study that compares the effects of cats and dogs as opposed to farm animals during pregnancy.) Most of the data come, however, from observations of large cohorts of people in different environments.

Some of these studies have come out with really cool results. One idea that seems to have a lot of validity is that persistent, heavy worm infections protect you from developing asthma, or more precisely atopic disease, which is more or less allergic skin irritations. This is graded however, and you need to have a really massive worm infection to get this protection. Heavy but not massive worm infections do not really protect, but they do not harm (as far as asthma is concerned anyway) and light worm infections, as might be found under hygienic conditions, actually mean you may get more asthma. Worms induce strong Th2 responses, so this may seem like we’re really on to something. Here’s the rub: the same societies that have a higher incidence of Th2-type allergic diseases also have a higher incidence of Th1-mediated autoimmune diseases like Crohn’s disease.

There is a lot more data for or against, but this example is clear and well-characterized, so I'll just stick to the case of the worms.

So Th1 and Th2 do not provide the entire explanation. Here’s one that I found a lot more satisfying. Take the case of massive worm infections; a person with a massive worm infection has usually mounted an intensely strong immune response to it (Th2, but that isn’t really material). The body has very effective mechanisms in place to ensure precisely that immune responses don’t run amok and eventually destroy everything in their paths. These mechanisms, dampening or regulatory mechanisms, kick in when there is a really strong immune response and turn it off irrespective of the nature or outcome of the immune response. So highly worm-infected people have probably turned down their immune response quite a bit, and since allergy is an immune response, it is turned down as well. Therefore people who have much less worm infections have revved up and ready immune systems and may therefore be more prone to develop allergies or autoimmune diseases. This mechanism feels very plausible to me. Does that mean I have been converted to the Hygiene Hypothesis? Not entirely, and these are my reasons.

Allergic diseases abound in less hygienic environments, South Asians and Africans do get asthma, eczema etc. Of course, the hygiene hypothesis doesn’t claim to explain all asthma incidence, merely increased incidence in certain societies.

The other objection is a technical one. Most of the epidemiological studies use “atopy” or skin irritation (oversimplified, but) as their readout since asthma may take a long time to come up as actual wheezing symptomatic asthma. And asthma patients are usually heavily medicated, so all observation are much more difficult to interpret. However, atopy is not asthma, and may not even be a prelude to asthma, so in a way, they are all using apples to measure orange growth. There are some studies that go much deeper though, but in general, with epidemiological data, one need many many numbers of people and much statistical significance before one can have confidence in the data. Time will tell.

This is linked to the one above: For every study that has a certain result, there is one that has the opposite. That worries me, because I wonder if we are not inventing a correlation when there isn’t one?

And one can go on, genetics, economics etc. I think the crux of the matter is that it is not as simple as the original Th1 vs. Th2 idea, nor is it an explanation of all relevant phenomena. However the Hygiene Hypothesis does seem to have some validity and one needs to wait and see. And change the name!

Papers read (All reviews I’m afraid):

Yazdanbaksh M., et al Allergy, Parasites and the Hygiene Hypothesis. 2002. Science. Volume 296. p 490.

Vercelli D., Mechanisms of the Hygiene Hypothesis-Molecular or Otherwise. 2006. Current Opinion in Immunology. Volume 18. p 733.

Liu AH., and Leung DYM., Renaissance of the Hygiene Hypothesis. 2006. Journal of Allergy and Clinical Immunology. Volume 117. p 1063.

Ramsey CD., and Celedon JC., The Hygiene Hypothesis and Asthma. 2005. Current Opinion in Pulmonary Medicine. Volume 11. p 14.


MinCat said...

loveliness i say! i can see how your theory might actually make a better case, even if it is similar to the HH. How about mine? People in developed countires have more time and moeny to worry about sneezing and sniffles than the majority of people in poor countries? activism activated :D

Veo Claramente said...

Not my theory really, a prevailing theory in the field.
asthma and autoimmune disease are real problems though :)