Are We Too Clean For Our Own Good?

Nietzsche once said, `That which does not kill us makes us stronger`. Nowadays, people would vehemently disagree with this philosophy, cite horror-story articles about fatal cat diseases and contaminated foods, while squirting hand sanitizer by the bucketful. However, this was the thinking of previous generations, where a little dirt never did any harm, children played with mercury like playdough (ignorant of it`s poisonous properties) and if there was a little mould on top of the jam, you scraped it off. It`s certainly the philosophy behind the hygiene hypothesis.

The hypothesis postulates that the industrialized age`s increased use of vaccines, antibiotics and general hygiene standards prevents the body`s natural development of the immune system, causing an immunological imbalance1. The body then reacts inappropriately in response to harmless antigens. The main suggested mechanism behind this hinges on T-helper (Th) cells.

Th cells differentiate into two ¬subtypes, known as Th1 and Th2 cells, which produce different cytokines (cell-signaling proteins). Th1 cytokines are produced in response to intra-cellular antigens, such as bacterial and viral antigens, as well as causing certain organ-specific autoimmune diseases such as Type-I diabetes and inflammatory bowel disease (IBD). Th2 are produced in response to extra-cellular antigens and are responsible for allergic reactions, including asthma. When an allergen (with foreign, but not necessarily harmful antigens) enters the body, Th2 cells stimulate production of B-cells that differentiate into plasma cells (humoral response). They then produce IgE, an antibody that binds to receptor molecules on mast cells (in body tissues) and basophils (in blood) that trigger the release of histamines and leukotrienes, that cause symptoms of allergy, such as airway constriction in asthma. An excessive Th2 response causes Type-I hypersensitivity, leading to atopy, a predisposition to allergic reactions. Therefore, the hygiene hypothesis postulates that a lack of exposure to bacteria and viruses early in life (i.e. under-stimulation of the Th1 response) polarizes the immune system towards a more dominant Th2 response later in life (i.e. a tendency towards an antibody-driven response).

The hygiene hypothesis has been controversial. When first coined by David P. Strachan in 1989¬1, it was met with skepticism: childhood infections were known to contribute to the risk and severity of asthma, so how could they protect against it? But with allergies and other auto-immune diseases, particularly asthma, becoming more common2, some evidence has arisen to support the hypothesis. The inverse relationship between hayfever prevalence and family size was originally noticed by Strachan3. A 2011 study reported that the whey protein fraction in milk might be responsible for the `protective` effect, with children who drink raw milk (in comparison to those that drink supermarket milk) having a 41% lower risk of developing asthma4.

There has also been a recent study demonstrating a potential mechanism for the hygiene hypothesis at work in mice, published recently this year in Science4. One group of mice was kept in a perfectly sterile environment and given antibiotics, while the other was left to normal microbial contact. The `sterile` mice developed inflammation in the lungs and bowel, the rodent equivalent of human asthma and IBD. The inflammation was caused by increased levels of iNKT, a specialized white blood cell and, crucially, iNKT levels and inflammation did not decrease when the mice were exposed to microbes later in life. It is clear from this, that the higher numbers of iNKT could be similar to overactive Th2 immune responses. This marked an exciting step forward in immunology, but also raised two problems. Does the same mechanism actually apply to humans? And if so, what specific microbes have a `protective` effect?

Firstly, mice are very different to humans. Allergies have a genetic component5: in laboratory mice, there is very little variation, whereas amongst humans there is great genetic diversity. Extrinsic conditions can also be easily controlled in a lab: not so for humans. Overall it is highly unlikely that the level of `hygiene` imposed experimentally would ever be replicated for humans and therefore the proposed mechanism must be taken with a pinch of salt.

Secondly, there is much evidence to support that allergies are not caused by particular microbes, but that the immune response is shaped by the sum total of it`s immunological experience6. It is the cumulative pressure of constant exposure to pathogens, in diet, in the air, from runny-nosed siblings in the general humdrum of life during the formative years, that develops the immune system. Indeed, efforts to try and pin down a particular childhood infection that protects against allergies have failed, despite accounting for family size and older siblings6.

Importantly, there is epidemiological evidence against the hygiene hypothesis itself, with Th1-mediated auto-immune diseases such as Type-I diabetes, multiple sclerosis and IBD rising at the same time as Type-2 mediated allergies. The common factor between them was the lack of immuno-regulation: it was not an imbalance of Th1 and Th2 immune responses, but the overactivity of both types that caused chronic inflammatory diseases. Enter the `Old Friends` hypothesis 7, a variant of the hygiene hypothesis, which brings evolution onto the main stage: by suggesting there are microbes that evolved to provide the `background hum` and so help us produce an effective immunoregulatory network. These `old friends` that stimulate the activity of T regulator cells were once universal, but due to the significant changes in domestic life, with the lack of farm animals, better healthcare and vaccines, we have been deprived of their benefits. The hypothesis has proven so successful, there are multiple studies and trials using helminths, parasitic worms that work as `old friends`, as a form of treatment for the auto-immune diseases mentioned previously89.

If these clinical trials validate the `old friends` hypothesis, then we may indeed be too clean for our own good. Medicine would then need to find ways to selectively re-introduce these benign microbes. Or, as Douglas Adams so presciently put it in the `The Hitchhiker`s Guide to the Galaxy`, `So doctors will be back in business, recreating the diseases they had abolished, in popular easy-to-use forms`.