The incidence of type 1 diabetes rose in some countries from about the middle of the 20th century, and was recognised as a worldwide phenomenon by the 1980s. The increase has been most apparent in early childhood, is log-linear in many populations, and is almost certainly due to the influence of an environmental factor or factors. It appears largely restricted to those with HLA markers of genetic susceptibility, and there is some evidence that diabetes now develops earlier than previously in those with a given level of genetic susceptibility. Many authorities have sought to explain the rise of childhood diabetes in terms of new environmental agents. The hygiene hypothesis, in contrast, argues that type 1 diabetes and a range of other disease conditions associated with inappropriate immune responses have developed because of the loss of immune stimuli to which our ancestors were exposed throughout evolutionary history. Loss of these co-evolutionary 'Old Friends' is hypothesised to allow potentially harmful patterns of immune response to develop and persist into later life, and might explain the parallel rise of asthma, allergy and other diseases associated with a failure of immune regulation.
Early childhood was a dangerous period of life in traditional societies, and between one-third and one-quarter of all neonates failed to survive their fifth birthday. Most of these deaths were due to infectious diseases, which thus constituted an intense evolutionary pressure. Although breast-feeding allows the transfer of passive immunity from mother to child over the first few months of life, those most likely to reach their firth birthday were those who could develop a sufficiently versatile immune repertoire in the shortest possible interval of time. Those who were preadapted to meet this challenge were most likely to survive and reproduce.
Nineteenth-century physicians noted that hay fever was a disease of city-dwellers rather than of those who lived in the country. The term hygiene hypothesis was coined by Strachan in the 1980s on the basis of similar epidemiological observations, including the higher prevalence of atopic disorders in affluent than in traditional societies, and a worldwide increase in atopy associated with the adoption of a western lifestyle.
These observations acquired the status of a biological hypothesis when linked to evidence that childhood atopic disorders are preceded by dysfunctional patterns of immune response, characterised by persistence of neonatal patterns into later life. This suggested that the developing immune system has evolved to encounter ubiquitous stimuli in the traditional environment, and that this interaction is needed to achieve a mature and balanced repertoire of responses. This hypothesis may partly explain the parallel rise in the incidence of a range of immune-mediated disorders, and might offer the potential of safe and effective immune intervention in neonatal life to prevent their development.
The term 'hygiene' has unfortunate connotations, particularly as applied to personal or domestic cleanliness. The hypothesis is really founded upon the coevolution of our immune repertoire with a wide range of microbial or parasitic organisms, and Graham Rook has proposed the term 'Old Friends' hypothesis to emphasise this Darwinian component. In his words, 'mammalian evolutionary history has led to a situation where the establishment of appropriate levels of immunoregulation is driven by the presence of organisms that are harmless or must be tolerated, and so act as signals for regulatory rather than aggressive responses'.
Two epidemiological transitions
It has been suggested that there have been two major changes in our living environment in our recent evolutionary history. The first was settlement into stationary agricultural communities in the course of the neolithic revolution, some 10,000 years ago. This resulted in greatly increased opportunities for faecal–oral transmission of commensal organisms, bacteria and parasites, and for transmission of infections between domestic animals and humans. The second evolutionary transition, encountered scarcely more than 100 years ago, saw the sudden depletion of these immune stimuli from our environment.
The past century has seen an apparent increase in a number of immune-mediated conditions, ranging from asthma and allergy to inflammatory bowel disease and multiple sclerosis and type 1 diabetes, and loss of the 'Old Friends', when superimposed upon a background of genetic susceptibility, has been invoked as a possible contributor to all these conditions. Helminth parasites have even been used in apparently successful experimental treatment of inflammatory bowel disease.
Efficient immune function implies the ability to mount an effective response against specific antigens in the context of danger signals, to prevent this response from spreading to other targets, and to terminate such responses promptly when no longer needed. Defective immune regulation can result in the development and persistence of 'friendly fire' directed against self tissues.
Th1 and Th2 responsesAccordingly, there are many immune cells whose sole function is to regulate the behaviour of immune effector cells. These include T helper (Th) cells, which are characterised by the presence of CD4+ receptors on their surface. These cells are the targets of HIV infection, and their depletion results in AIDS (acquired immune deficiency syndrome). Studies in the mouse have suggested the existence of two main sub-populations of Th cells, known as Th1 and Th2, and distinguished by their pattern of cytokine secretion. Th1 cells modulate cellular immune responses, whereas Th2 cells influence the responses of antibody-producing B cells. Unwanted or excessive Th2 responses are associated with asthma and allergy, and Th1 responses with autoimmunity. Although simplistic as described in these terms, this model has provided the useful concept of an immune balance, preventing unwanted immune deviation towards either end of the spectrum; in the past, only those with extreme genetic predisposition would break this barrier to develop, for example, asthma or type 1 diabetes. A failure of immune regulation associated with loss of the traditional educators of the immune system could thus result in a parallel increase in immune deviation at both ends of the Th1/Th2 spectrum (see figure), and increasing penetrance of genetic predisposition to such disorders.
The biological basis for the hygiene hypothesis derived from studies of neonatal T cells. Pregnancy has a Th2 orientation which is reflected in the newborn child. Early environmental stimulation balances this by generating a repertoire of Th1 responses, a process marked by changes in the pattern of cytokine secretion by T cells. It has been argued that when such environmental stimulation is reduced, and where genetic predisposition exists, a dysfunctional Th2 bias will persist in some children and predispose to atopic disorders.
The gut immune system is the major crossroad for many of these immune interactions, and this raises interesting possibilities in terms of intervention. No-one would wish a return to the conditions of the past, but harmless manipulation of the early environment of the gut (and gut-associated immune responses), for example by use of probiotics, is well within our means.
What are the candidate organisms?
Rook has propose the following criteria for candidate organisms that may have exerted an immunoregulatory influence upon our evolution: 1. Present and ubiquitous throughout human evolution. 2. Absent or declining in the modern environment. 3. Evidence of immunomodulatory properties in humans or in animal models of disease.
Intestinal microbiota Interactions between microbes and the developing gut immune system are abundantly documented, and the faecal flora of African children living in a traditional environment have much greater diversity than those of children in the West.
Helminths These have well-known immunomodulatory effects upon the intense Th2-driven immune responses they provoke in the host, and several studies have demonstrated an inverse association between the prevalence of atopic conditions and parasitic infestation.
A pinworm and its eggsHelminths were ubiquitous in human evolution, and it seems likely that 100% of our ancestors were affected at some time in their lives. To take one example, pinworms (E. vermicularis) affected almost all pre-school children until the recent past, and their decline in the European population closely reflects the rise of type 1 diabetes, asthma and other conditions. Correlation does not prove causation, but pinworm infestation effectively abolishes susceptibility to diabetes in colonies of NOD mice.
The hygiene hypothesis has appeal as a broad-ranging explanation of the rise of type 1 diabetes and other conditions ranging from asthma to multiple sclerosis and inflammatory bowel disease. It finds support from a range of theoretical and experimental considerations, and focuses attention on the ontogeny of the immune system as it first confronts the external world. The main weakness of the hypothesis is that it lacks specific testable components. This might be overcome by further investigation of the potential of the 'Old Friends' to produce therapeutically useful immunoregulation in humans.
^ Strachan DP. Hay fever, hygiene and household size. BMJ 1989;299:1259–60
^ Rook GAW. Hygiene hypothesis and autoimmune diseases. Clinic Rev Allerg Immunol 2012;42:5–15
^ Summers RW et al. Trichuris suis therapy in Crohn's disease. Gut 2005;54:87–90
^ Holt PG, James CA. The development of the immune system during pregnancy and early life. Allergy 2000;55:688–97
^ Gale EAM. A missing link in the hygiene hypothesis? Diabetologia 2002;45:588–94