Molecule of the Month: Beware the IgEs of March!

“Things exist either because they have recently come into existence or because they have qualities that made them unlikely to be destroyed in the past.” Richard Dawkins.
Sometimes in human history, selective pressure creates genetic adaptations that, when environments, technology, and cultural factors change, may be less-than-beneficial—and harmful to health, in fact. The situation calls to mind the sickle-cell trait, which evolved in humans because it provides some protection against malaria. However, when people inherit the trait from both parents (homozygous), they develop sickle-cell disease, a serious blood disorder. And the benefit of the sickle-cell trait disappears in the absence of endemic malaria. This month's Molecule of the Month, like the sickle genes, is another example of what Geneticists call 'balancing selection'. A selective process by which multiple alleles (different versions of a gene) are actively maintained in the population at frequencies longer than expected from genetic drift alone. This usually happens when the heterozygotes for the alleles under consideration e.g. A1AT discussed below, have a higher adaptive value than the homozygote. In this way the genetic polymorphism is conserved.

The idea for this month's molecules came via a tweet from my good friend Professor Richard Pleass who is based at the Liverpool School of Tropical Medicine. Richard has a broad interest in all things immunological, which is why he was able to make some interesting connections between experiments in his lab on IgE (the immunoglobulin class that we associate mostly with the allergic response and protection from worms, see RHS) and the protease inhibitor alpha-1-antitrypsin (A1AT) (see below); which as its name suggests, acts to stop proteases like Trypsin, in its tracks. 

These proteases are also produced by our cells but also by parasitic worms to break down tissues as they migrate through your body. Proteases in particular, must be carefully regulated since they can, if not properly controlled, cause disease. The structure of A1AT (red) bound to elastase (blue) is shown on the left. The question we must now ask, is what is the relationship between A1AT, elastase and IgE. Oh, yes and where do the Vikings fit into this? Over to Richard.....Archaeological excavations of Viking toilet pits in Denmark have revealed that these populations suffered massive worm infestations.Their genes must have adapted to protect their vital organs from disease caused by these worms and these adapted genes have now become the inherited trait leading to lung disease in modern day smokers. Contrary to what you might believe, Vikings did not smoke tobacco (nor weed), which was only introduced into Europe in 1559 by Hernandez de Boncalo. Chronic obstructive pulmonary disease (COPD) and emphysema affect over 300 million people, or nearly 5% of the global population. The only inherited risk factor is alpha-1-antitrypsin (A1AT) deficiency, and this risk is compounded if individuals smoke tobacco. 

A1AT protects the lungs and liver from enzymes called proteases that are produced not only by cells of the immune system, but also by parasitic worms. In the absence of A1AT these proteases can break down lung tissue leading to COPD and emphysema. Deficiency of A1AT is genetically determined and is due to variants of A1AT that are surprisingly common, particularly in Scandinavia, where they evolved in Viking populations more than two thousand years ago. 

Why these disease-causing deviants of A1AT are so common in human populations today has long been a mystery. Vikings would have slept ‘cheek-by-jowl’ with their animals (for warmth), and would have eaten contaminated food, and come into contact with parasites that would have migrated to various organs, including the lungs and liver, where the proteases they released would cause disease.We could show that the deviant forms of A1AT bind an antibody called immunoglobulin E (IgE) that also protects people from worms. The binding of A1AT to IgE prevents the antibody molecule from being broken down by proteases, and would allow IgE to kill parasites more effectively. Thus these deviant forms of A1AT would have protected Viking populations, who neither smoked tobacco nor lived long lives, from worms. It is only in the last century that modern medicine has allowed human populations to be treated for disease causing worms. Consequently these deviant forms of A1AT, that once protected people from parasites, are now at liberty to cause emphysema and COPD.

You can read the original paper here

http://www.nature.com/articles/srep20509