These observations . . . could be explained if allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally . . . Over the past century declining family size, improved household amenities and higher standards of personal cleanliness have reduced opportunities for cross-infection in young families. This may have resulted in more widespread clinical expression of atopic disease.

In the nearly 20 years since, this hypothesis hasn’t been proved or disproved. There are quite a few interesting correlations, and the underlying biology seems to make a lot of sense, but as least as far as I know there’s been no smoking-gun study that makes an undisputable link. A Nature Medicine paper² from a couple of weeks ago adds a little more support to the hypothesis, and this one also holds out a distant hope of some kind of intervention as well. It’s long been known that parasitic worms — now rare in the West, but until recently a normal part of the human condition — induce an immune response that is broadly similar to a lot of allergic responses.

Melendez et al show that one class of parasitic worms make a protein that inhibits the anti-parasitic immune response. The protein, ES-62, does this by binding the pathogen pattern receptor molecule TLR4, thereby blocking a signalling pathway that ultimately leads to mast cell activation. This is presumably a parasite immune evasion molecule, analogous in concept to the many viral proteins that block TLR pathways. (The reason I say this is “presumably” a immune evasion molecule is that the other possibility is that the response is driven by the host — that this is more analogous to the way rodents develop a regulatory T cell response to persistent viruses, reducing harmful inflammatory diseases but allowing long-term infection with the virus.)

As the authors say, this is an exciting observation for two reasons. First, while not a smoking gun (that’s a rhetorical question in the title, OK?), it offers a mechanistic explanation for at least part of the hygience hypothesis. Second, the protein offers a handle for therapy of allergic diseases:

Suppression of mast-cell function by ES-62 offers a new explanation for the reason why people harboring worms of at least the filarial nematode type show reduced incidence of allergy, in spite of their elevated serum IgE. … By inhibiting mast-cell effector function, ES-62 offers a new potential therapeutic approach for diseases such as asthma, a medical problem of enormous importance in the developed world. Although ES-62 per se is unlikely to be used for treatment, enough is known about its structure and function to allow one to envisage the development of small, presumably phosphorylcholine-based, derivatives as drugs.

1. Strachan, D. P. (1989). Hay fever, hygiene, and household size. BMJ 299, 1259-1260.
2. Melendez, A. J., Harnett, M. M., Pushparaj, P. N., Wong, W. S. F., Tay, H. K., McSharry, C. P., and Harnett, W. (2007). Inhibition of Fc[epsi]RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat Med 13, 1375-1381.