Skewed Exposure to Environmental Antigens Complements Hygiene Hypothesis in Explaining the Rise of Allergy

3.1.1 Control of Fire and Shaping of the Immune System

Apparently, the modernization of humans started with the control of fire. The control of fire, however, was only the beginning of the human control of his surrounding environment. Doing so, man was able to cook his food and kill a lot of microbial organisms before ingestion. Consequently, the use of cooked food altered the contact of humans with their microbial environment and contributed to the shaping of their immune system.

Whereas some studies have revealed pieces of evidence suggesting that the first control of fire was achieved by the ancestral hominid Homo erectus about 790,000 years ago (Goren-Inbar et al. 2004), there is common agreement that widespread use of fire was implemented by H. sapiens around 125,000 years ago (James 1989). There is also ample evidence suggesting that the use of fire was adopted from the Neanderthal subspecies Homo sapiens neanderthalensis, which was particularly adapted to the colder climates of the Eurasian continent (Roebroeks and Villa 2011). The cultural transfer of fire control from H.s. neanderthalensis to H.s. sapiens (i.e. modern humans), touches upon the question of whether H.s.s. led to extinction of the Neanderthals some 40,000 years ago, or whether both subspecies had significantly interbred while co-habiting in a number of regions of the Eurasian continent (Fu et al. 2015). Interestingly, recent studies provided evidence for a genetic transfer of HLA-class I alleles from archaic humans (consisting of two sister groups, the Neanderthals and Denisovans) to modern humans in Europe, (East-)Asia and Oceania (Abi-Rached et al. 2011). These alleles, some of which encoding for unique or strong ligands for natural killer (NK) cells, appeared to be missing in the original African gene pool, but may have been introduced into Africans at a later stage (Roebroeks and Villa 2011). These data would be suggestive for the interbreeding hypothesis (Roebroeks and Villa 2011; Fu et al. 2015; Abi-Rached et al. 2011), and suggests that beside the use of fire also changes in immunological defense mechanisms took place when H. sapiens started to inhabit the colder regions of the northern hemisphere. It is still not known what happened among humans between 125,000 and 40,000 years ago.

3.1.2 The Invention of Clothing, Foot Wear and First Human Steps to Modernity

Much later, also other ‘inventions’ occurred that reduced the contact with infectious organisms. Examples hereof are the use of shoes (already around 40,000 years ago, as observed from a change in anatomy of the proximal pedal phalanges) (Trinkaus 2005) and man-made clothing (Fisher 1981). Even today, some regions of the pristine Amazon forest are inhabited by local tribes that do not wear shoes or extensive clothing. It is well known however, that many of these indigenous tribes became almost extinct due to the fightings or due to the contagious diseases that the contacts with Western discoverers and colonists procured them in the fifteenth and twentieth centuries (Olson 1991). With the use of fire, man could also fabricate other tools (iron-made in stead of stone-made), which led to numerous wars and conquests, and also led to a constant changing of the inhabited domains.

3.2.1 History of Hygiene and Sanitation

The changes in contacts between man and his biological and microbiological companions are most dramatically observed in the domestic environment. For instance, it is known that - much unlike our postmodern, industrialized societies - common houses in large parts of the so-called ‘civilized’ world didn’t have water-supplied sanitation until the Modern Ages (17th – 18th centuries). From historical sources (references not listed) it is well known that even in famous royal palaces like Versailles (Paris, France) modern sanitation was lacking. For the common people, however, these were unaccessible places. However, the Minoan civilization of Crete (around 1800 BC, at Knossos) was the first to utilize an underground system of clay pipes and a complex network of masonry for sanitation and water supply (for pressurized showers) (Anonymous 1989). Ancient cultures in the Indus Valley, Egypt and Persia were also using a water management system based on aquaducts (Persia) and copper pipes (Indus, Egypt), the latter used for privileged settlements only (Anonymous http://enlightenme.com/ancient_plumbing). The Persian ‘qanats’ (aquaducts) at the city of Zarach (Zārj, Iran), going back to 1000 BC, are still in use today (Anonymous http://enlightenme.com/ancient_plumbing). Later the Greek of Athens and Asia Minor and the Romans developed an indoor plumbing system for water supply, raising suspicion though about the large-scale lead poisoning in Roman culture. Around the same period in China, the Qin and Han Dynasties (200 BC–200 AD) were familiar with the use of plumbing, using bamboo instead of lead pipes. The Mayans in Central-America, and not the Spanish conquerors, also used an indoor system of pressurized water to construct the first known flush toilets (at the Maya city of Palenque, Mexico) (French and Duffy 2010). However, for many centuries much of these technologies - being lost during the Middle Ages - had disappeared from large regions of the world, including from North-Africa, Europe and Central-Asia (Anonymous http://enlightenme.com/ancient_plumbing). Therefore, it is reasonable to assume that the cumulative effects of increased hygiene measures would only appear in the last few centuries, especially in the West. Because although piped water may have been around for centuries, its access for the mass of people was achieved only recently.

Clean sanitation and safe drinking-water aren’t the only characteristics of the modern house, although sustainable access to safe drinking-water is an important one, according to the Unesco and the United Nations (UN) Millennium Development Goals and Targets (UNESCO http://www.unesco.org). Since the domestic space is also the environment where the children are raised during their first years till adulthood (or life-long), it is the domestic environment that has the primary influence on the shaping of the immune system. Chang classified the antigen exposure of young children into five patterns: ‘primitive’, ‘pre-modern’, ‘early modern’, ‘modern’, and ‘ultra-modern’ (Chang 2014). The ‘primitive’ pattern refers to conditions where children are staying in open shelters and are in absence of human waste disposal and sewerage systems, and also lacking soap, detergents, disinfectants, antibiotics and vaccines. These conditions today may only exist in remote, isolated sites in underdeveloped countries. In these conditions, helminth infections are abundant and allergic diseases virtually absent (Chang 2014). Generally, most children in underdeveloped countries and in poorly developed regions in developing countries have a ‘pre-modern’ pattern of antigen exposure (Chang 2014). In the ‘pre-modern’ pattern, access to a number of hygiene measures is limited, but still a lot of helminthic infections occur. From the ‘early modern’ pattern onwards, the helminth infections have disappeared (in Europe and the USA (Bleakley 2007) the deworming programmes were introduced in the first half of the twentieth century). On the other hand, however, the likelihood and severity of allergic diseases has strongly increased with ongoing modernization. Even until in recent decades, in countries like China, India and most of the developing countries, the lack of separated facilities for sewage and drinking water was very common. Nowadays, the use of chemically treated, sterile tap water in the ‘modern’ pattern and the lack of contact with natural water and soil in the ‘ultra-modern’ environment, are accompanied by a further increase in prevalence and severity of allergic diseases (Chang 2014). This is the situation which is most likely to be found among the richest households in the most ‘developed’ regions of developed countries. The finding that also domestic animals may develop symptoms of allergic diseases corroborates the viewpoint that skewing antigen exposure is a likely candidate for the increase in allergy prevalence, and obviously not the changes in child and adolescent behaviour as suggested by Platts-Mills (2015) (like more time spent on television watching and computer gaming) (Platts-Mills 2015).

3.2.2 Antigen Exposure and Living in (Ultra)Modern Environments

Whereas contacts with microbial species are virtually absent in these (ultra)modern environments, a few environmental antigens are persistently sticking to the presence of humans: (a) the common dust mite (Dermatophagoides pteronyssinus and D. farinae, from Europe and America respectively), that is living on skin cells people have shed; and (b) the common pets, like dogs and cats, shedding dander (dead skin from dogs, cats and other warm-blooded animals). In allergic reactions to dust mite, it is often not the mite itself but proteins in their droppings which cause the allergy. Dust mites prefer a warm and humid environment, which is rich in human skin remains and are mostly found in bedding, upholstered furniture and carpeting. Because people tend to breathe more deeply during sleep, allergies to dust mite antigen and also to pet dander are the most frequent causes of asthma.

On the other hand, milder hypersensitivity ailments of the respiratory system, like allergic rhinitis, are often caused by antigens caught during outdoor activities, when the breathing is swifter and less deep. These outdoor antigens in a modern, urban or cultivated environment often belong to also a limited number of species (see Sect. 3.4 below). Very well known are the pollen from birch (Betula sp.) or from Japanese Hemlock or Tsuga (Tsuga sieboldii) trees, or the grass pollen (Timothy grass, Phleum pratense, or Bermuda grass or Dog’s Tooth grass, Cynodon sp.). Also here, the hypersensitivity is not directed towards the pollen as a whole, but to specific proteins present in or released from the pollen at a certain time.

3.2.3 Antigen Exposure and Living in Rural Communities

Few studies have addressed the prevalence of allergic diseases in ‘primitive’ and ‘pre-modern’ communities, precisely because here the prevalence is very low or absent (Chang 2014). However, a striking connection between a low prevalence of autoimmune diseases and the living conditions in a rural community in Nigeria was already reported in Greenwood (1968). Moreover, high levels of serum IgE were found in rural areas in Venezuela (Lynch et al. 1998) and Indonesia (Hamid et al. 2013), corresponding with low prevalences of allergic diseases too (Chang 2014). On the contrary, the incidence of these disorders in the United States of America and Europe appears to have doubled in some decades of last century, especially during the 1960s and 1970s (Rook and Brunet 2005). The asthma prevalence rate among Taiwanese children was only 1% when the first recordings were made in the 1980 s, but nowadays its rate has raised to about 15% (Chang et al. 2007). The prevalence of asthma in children of the USA has further increased by 38% between 1980 and 2003 (Versini et al. 2015).

Until recently, both in developed and developing countries, a variety of interspecies contacts would occur within the domestic environment (Fig. 1). In the urban environment, especially the older districts of town, old houses would harbor a variety of vermin animals (rats, house mouse, cockroaches, flies, fleas and lice), but due to the moisture and lack of ventilation, also many fungi and molds. On the countryside, moreover, especially in colder climate zones, in old farm homes a part was even reserved to shelter the cattle and poultry (Fig. 2). So the farmer could easily milk the cows and collect the eggs without leaving his farm. This form of cohabitation is often still the case in underdeveloped regions. With the cattle and the poultry living indoor, a lot of parasites would become in close contact with humans, in addition to a greater abundance of vermin animals. Moreover, living in tightly enclosed shelters enhances the exposure to indoor antigens (Chang 2014).

Open image in new window

Open image in new window

3.3.1 Changes in Food Processing

Several methods have been used from archaeological times till recent history. Drying fruits and vegetables was already known around 12,000 years ago, which method in later cultures was also applied to fish, game and meat from domestic animals (Nummer 2002). In medieval times until recently, also curing with salt (sodium chloride, but also nitrates), sugaring, pickling and smoking of foods were common practices. From the nineteenth century on, and especially in the twentieth century, after the venue of electric refrigerators and freezers, cooling, freezing, but also canning, heating (according to the temperature path followed called pasteurizing, after Louis Pasteur [1822–1895], or sterilizing of [canned] foods) became standard techniques. Since the second industrial revolution in the twentieth century, also irradiation, vacuum packing and the use of artificial food additives are used widespread in the industrialized world.

All these methods are based on the concept of killing the microorganisms or avoiding contact between microbes and the food products. In contrast to the former methods, in food fermentation (using yeasts) a very different strategy has been followed. Fermentation has also been an important alternative to combat food degradation in several ancient until modern cultures, and became very popular in particular for the production of alcoholic drinks (beers, wines…). This was mainly because the alcohol would kill the unwanted microorganisms. Fermentation, however, appeared to be essential for the production of dairy products like cheese too, and in some regions was and is still used in many more applications (like the use of fermented beans, soybeans and cabbage in contemporary China and Taiwan). Historical sources and the absence of a word for cabbage in Sanskrit and other ancient Eastern languages suggests the relatively young history of these typically winter foods in Central- and East-Asia. Probably, these winter foods were introduced following the trade with European merchants. Fermented cabbage, also known as the German term ‘Sauerkraut’ is well known both in Central and Eastern Europe as well as in Northern China (‘suan tsai’). Fermented tofu (from soybean cream) is a conspicuously odorous ingredient very popular in local Chinese cuisine.

The most dramatic change in food processing, however, may result from rapid change in the food preferences and taste of the young generations. It is well known that children are easily tempted to follow commercially advertized new food products, both in the East as in the West. The government control on advertisement campaigns (e.g. for highly sugared snack foods or for high fructose syrup) has often been proven to be rather ineffective and slowly running behind the facts (Aksoy and Beghin 2005). As a result, the changes in food habits tend towards increasing the preferences for so-called ‘fast food’ products with a very limited exposure to environmental antigens.

3.3.2 Changes in Food Traffic and Regulations

Following the increased globalization of trafficking of people and food products, an intensification of intercontinental regulations regarding the use of fermented food products has been noticed. For instance the American Food and Drug Administration (FDA) (Scott-Thomas 2010), the European Food Safety Authority (EFSA) (EFSA 2009) and the UN organizations for Food and Agriculture (FAO) have all provided extensive guidance measures and regulations. In many cases these regulations are directed against specific groups of molecules or pathogenic organisms possibly occurring in some fermented foods. For instance, they aimed to constrain the spread of microorganisms and to destroy in particular pathogenic species like Clostridium botulinum, Escherichia coli, Salmonella sp., Listeria sp., etc. (Scott-Thomas 2010). Targeted molecules are e.g. the group of biogenic amines (histamine, tyramine, 2-phenylethylamine but also the aliphatic, degradative products like putrescine and cadaverine, e.g. in wine and cheese fermentation, resp.) (EFSA 2011). Although these molecules may not be toxic in se, at high doses they may constitute a health risk when their metabolism is hampered. These bioamines are either metabolized by oxidative deamination by diamino oxidase (DAO) or by ring-methylation by histamine-N-methyltransferase (HNMT) (the HNMT pathway also involves the monoamine oxidase, MAO). Bioamine metabolism could be hampered in patients suffering from DAO deficiencies (Maintz and Novak 2007), or could be due to alcohol-induced reduction of DAO activity or to drugs containing DAO-inhibitors (Sessa et al. 1984). As a result histamine intoxication may follow, sometimes resulting in allergic symptoms and even asthma (Sattler et al. 1988).

3.3.3 Putative Beneficial Effects of Fermented Foods

Although the use of fermented foods is a much debated topic (see above), there is a growing consensus on the beneficial effects of certain groups of fermented diary products, also called pro-biotics. Moreover, contrary to the adversary effects of lactose-containing milk products, at least for lactose-intolerant subjects the overall effect of (fermented) milk products (with or without lactose) is considered to be positive: for instance, they may alleviate certain inflammatory reactions (Hosoya et al. 2012), whereas deprivation of fermented foods is associated with a fall in innate immune responses (Legrand and Mazurier 2010) and adverse immunological effects (Marcos et al. 2004; Ebringer et al. 2008; Tsai et al. 2012). Many studies reported that lactic acid bacteria as Lactobacillus and Bifidobacterium are effective at enhancing innate and adaptive immunity (Legrand and Mazurier 2010; Tsai et al. 2012), although the mechanisms appear to involve a wide variety of molecules and pathways: from lactoferrin, released from neutrophils upon antigen-nonspecific stimulation (Legrand and Mazurier 2010), to the secretion of polymeric IgA (Tsai et al. 2012), and of IL-17 (Hosoya et al. 2012), milk oligosaccharides and other small dairy molecules (Ebringer et al. 2008) and, finally, the modulation of Dendritic Cell/Natural Killer (DC/NK) cell interactions and a balanced T-helper cell response (Tsai et al. 2012). Also here, changing food habits may either improve or impoverish the beneficial effects of fermented dairy products. The latter may result from the impact of heat processing on the biological activity of milk products (reviewed in Ebringer et al. 2008). In conclusion, it is due to a balanced intestinal microflora and a diversity of biogenic protective molecules that the host’s immune system may function in optimal conditions; the reduction of diversity in microbial species and molecules generally reduces the immune defense capacities of the host.

In contrast to the extensive literature on the immune effects of fermented milk products, few studies have addressed the immune effects of fermented cabbage or fermented vegetables altogether. Interestingly, in animal studies a beneficiary effect of cabbage fermentation extract was found on the immune system of Sprague-Dawley rats (Miyazaki et al. 2001).