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The "Old Friends mechanism" (the Darwinian reformulation of the hygiene hypothesis) suggests that in rich western countries there is a general failure of regulation of the immune system, that can manifest itself as a variety of chronic inflammatory disorders. Exactly which disorder, if any, depends on the genetics and personal history of the individual.
The book described below gathered together many experts in different fields, to discuss the potential role of failing immunoregulation in the aetiology of chronic inflammatory diseases of different organ systems.
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The image to the left is the cover illustration (designed by Anne) from :-

The Hygiene Hypothesis and Darwinian Medicine
Series: Progress in Inflammation Research
Rook, Graham A.W. (Ed.)
2009, XII, 308 p. 24 illus., Hardcover
ISBN: 978-3-7643-8902-4
Birkhäuser, Basel

This book can now be accessed online

The text that follows is my preface to the book.
The hygiene hypothesis hit the headlines in 1989 when David Strachan observed that hay fever is less common in children with older siblings, suggesting that multiple childhood cross-infections from dirty older brothers might protect from allergic disorders. The implication was that elimination of these infections by modern hygiene might be responsible for the increased prevalence of allergies in developed countries. However the notion that mankind’s changing lifestyle is contributing to the increased incidences of various chronic inflammatory disorders was not new. In 1873 Blackley had observed that farmers rarely had hay fever, and in 1966 Leibowitz and colleagues noted that, in Israel, the incidence of multiple sclerosis correlated with the level of sanitation. Similarly, inflammatory bowel disease, which was almost non-existent before the 20th Century, was already known to be increasing in Northern, urban, educated white-collar populations. Meanwhile animal models studied in the 1970’s had shown that different manipulations of the microbial flora of the gut could either increase or decrease susceptibility to autoimmune arthritis.
The findings in Strachan’s 1989 paper were initially considered narrowly in relation to allergic disorders, and this led research in two unhelpful directions. First, there was emphasis on the notion that protection was provided by the burden of recognizable symptomatic childhood infections: subsequent epidemiological surveys have consistently failed to support this hypothesis. Secondly it was thought that the role of these infections might be to drive Th1 cells able to inhibit development of the Th2 cells that mediate allergic disorders: this view ignored the simultaneous increases in Th1- and Th17-mediated disorders, and the increasing evidence for the importance of helminths and of orofecally transmitted organisms. The latter were often subclinical, so had been identified by antibody studies rather than by documenting manifest clinical infections.
Therefore by the late 1990’s several authors were suggesting an inclusive hypothesis that could account for the simultaneous rises in allergies, autoimmunity and inflammatory bowel diseases in rich developed countries, while at the same time incorporating all the different epidemiological clues, in addition to the protective effects of older siblings. These clues included orofecal transmission, living on a farm, economic deprivation, keeping a dog, and having helminth infections.
This reworking of the hygiene hypothesis has three components. First, it suggests that the increases in chronic inflammatory disorders are partly due to an imbalance between effector cells and regulatory cells, rather than an imbalance between Th1 and Th2. Secondly the new synthesis suggests that the most relevant organisms will turn out to be those with very long associations with the mammalian immune system, often as commensals, environmental “pseudocommensals”, subclinical infections or asymptomatic carrier states. (This long association is necessary for the development of evolved dependence and has led us to use the term “Old Friends” hypothesis). Thirdly, it suggests that the most relevant lifestyle changes are those that deprive us of contact with these particular organisms (less contact with animals, soil, and faeces), rather than the details of modern hygiene technology.
This book seeks to summarise the mass of data from epidemiological studies, laboratory experiments, animal models and clinical trials that lead to this view of the hygiene hypothesis. It also seeks to establish the broader significance of the hypothesis, and its boundaries. We first present a Darwinian view of the role of microorganisms in setting up the correct balances within the immune system. Then we consider the history of human interactions with microorganisms in order to analyse how microbial exposures have changed from Paleolithic to modern times. This is followed by chapters on the mechanisms involved in the priming of immunoregulatory circuits by microorganisms, including sections devoted specifically to gut microbiota and skin flora. There are then chapters considering the evidence for and against the importance of the hygiene hypothesis as a mechanism contributing to increases in allergies, multiple sclerosis, inflammatory bowel disease, Type 1 diabetes, depression, atherosclerosis, cancer and neurodegenerative disorders. Finally, there is an important chapter describing other aspects of the modern western lifestyle that might provide alternatives to the hygiene hypothesis, or might be interacting with, and exacerbating, the effects of our changing microbial environment.

This book is therefore unusually interdisciplinary, with implications for those working in essentially all areas of medicine. The year 2009 is the 150th anniversary of the publication of On the Origin of Species (24 November 1859) and the 200th anniversary of Darwin's birth (12 February 1809). We hope that this book will provoke debate and research on the hygiene hypothesis, which should now be seen as a crucial and expanding aspect of Darwinian Medicine.