What’s behind the ‘epidemic of immune-mediated diseases’?
Many infectious diseases have dramatically decreased during the last 100 years in developed countries. Meanwhile, epidemiologic statistics indicate an increasing incidence in allergic disorders, like asthma, rhinitis and atopic dermatitis and autoimmune diseases such as type 1 diabetes, multiple sclerosis (MS) and celiac disease.1 As these diseases impact millions of people especially in Western nations, the increasing trend causes a significant public health problem, and this is why we call it an “epidemic of immune-mediated diseases (IMDs)”.
The problem
The epidemic of IMDs causes an immense health-economic burden due to the increased need for medical care and other societal impacts. For example, when looking at asthma care alone, an average annual cost per patient in Europe is around 1700 euros, meanwhile there are 30 million Europeans affected by the disease.2,3 Also, there are dozens of millions of individuals who are affected by allergic diseases in the EU, and even 90% of these people are untreated or insufficiently treated. This said, there is a potential for savings of billions of euros, if the treatment and prevention were offered at right time to the right people.4
Due to the increasing trajectory of IMDs, their societal payload will get heavier over time. More importantly, the diseases are often diagnosed in early childhood and therefore affect the individuals for a major part of their life. Thus, there is an urgent need to find the causes for this epidemic of IMDs. Genetic factors predispose to these diseases, but the genetic pool has stayed relatively constant over time. Therefore, it seems clear that environmental factors must have a major impact.
Graph 1. The recent trends in the incidence of infectious diseases and IMDs are contrasting. During the last centuries, IMDs have been increasing, while many infections have decreased as well as the contact to environmental microbes. This might be driven by two megatrends, massive biodiversity loss and rapid urbanization. According to our hypotheses, this has made our immune system unable to control its responses against harmless exposures, such as gut microbes, allergens, and viruses, that play a role in the development of IMDs. Not all the trends are similar though; For example, type 1 diabetes incidence has experienced cyclical variations and potentially a new rise during the Covid-19 pandemic.5,6
POTENTIAL EXPLANATIONS
Better diagnosis and access to medical services and the novel powerful diagnostic tools may explain a part of this epidemic. However, they cannot fully explain this rapid change since it has occurred also in severe diseases such as multiple sclerosis and type 1 diabetes which are rarely misdiagnosed.7
Many socioeconomic indicators are associated with the variation in the incidence of IMDs throughout time and geography. For instance, in Europe, there is a link between gross national product and the occurrence of asthma, type 1 diabetes and multiple sclerosis.7 Also, changes in nutrition have been linked to the variation of incidence in type 1 diabetes.8
THE ROLE OF THE EXPOSOME
We believe that identification and modification of these environmental factors (exposome) would be the most effective way to prevent these diseases. Since many IMDs are increasing at the same time, they are likely to share common exposomic risk determinants. In the following, we’ll present some of the suggested hypotheses behind the epidemic.
HYGIENE HYPOTHESIS
The hygiene hypothesis was originally formulated to explain the increase in allergic disorders by the lack of early childhood infections.9 During the last 10 years this concept has been developed further to include the concept of immunological tolerance.10
The hypothesis suggests that the increase of IMD incidence has happened as a response to an increased use of antibiotics, higher hygiene standards, and better socioeconomic circumstances. Animal models and a variety of clinical research have shown that infectious agents may have a risk-reducing effect on IMDs and have thus provided substantial evidence for a possible causal association between reduced exposure to microbes and the concomitant increase in immunological disorders. In addition, the burden of allergic diseases is low in countries in which water and food chains are often affected by microbial contaminations. In contrast, allergic and autoimmune disorders have emerged in countries that have minimized these contaminations and have limited exposure to microbes in the population.1 Interestingly, an accidental mixture of sewage water in tap water in one Finnish municipality for 2 days led to massive microbial exposure and reduced emergence of allergies in children later on.11
Picture 1. Hygiene hypothesis: Washing your hands can protect you against harmful viruses. However, diminished exposure to viruses may also increase the risk of allergic diseases, says the hygiene hypothesis. Corona pandemic is probably the biggest change in handwashing during the last decades – it will surely be a future research topic to see how this plays out in terms of IMD incidence in the coming years.
Several mechanisms have been suggested to mediate the effect of microbes on the risk of allergies. A deviation in the balance between immunologically central Th1 and Th2 white blood cells has been proposed. Th1-cells mediate inflammatory responses, whereas Th2-cells contribute to allergic reactions (such as IgE-production). Living in an environment where infections are rare may lead to a deficient regulation of the immune system due to the lack of infections that train the immune system. This, in turn, could lead to poorly controlled Th2 responses which contribute to allergic diseases.12
While the hygiene hypothesis has its limitations, it has had a huge scientific impact – it sparked a new era of research. Infections have become an important research topic in the search for the reasons of the increasing trajectory of allergic and other IMDs. It also supports the idea of finding common mechanisms underlying the epidemic of IMDs and has paved the way for possible microbe-based therapies for the prevention and treatment of these diseases.
Biodiversity hypothesis
The saying “even the dirt is clean in the countryside” relates to the concept of the biodiversity hypothesis. In times of urbanization, people have begun to separate themselves from natural environments. The urban lifestyle is characterized by almost sterile food, limited contacts to nature, asphalt and concrete environments which cut our contacts to soil and grass, etc. Together, all these aspects have led to an environment that does not provide the natural stimulation to our immune system which has been the basis of our immune health throughout the evolution. Therefore, the elements required for the healthy establishment and maintenance of immune tolerance to foreign agents appear to be missing in the urban environment.10
This hypothesis is based on the idea that the loss of exposure to natural environmental microbes leads to deficiency of immune system causing immune-mediated diseases. This is a new type of health risk that has been overlooked until recently. In other words, contact with natural habitats enriches the human microbiota, promotes immunological balance, and protects from allergy and inflammatory diseases.13
While not all IMDs follow the same trends, asthma and rhinitis are examples of diseases that have been on the rise in parallel with urbanization. To highlight the impact of environmental factors, some studies have shown that genomic differences most likely can’t explain this because populations with same ancestry are experiencing the “allergy gap” (e.g., in Finnish vs. Russian Karelia and US Amish and Hutterite populations).10 The same kind of gap occurs also in autoimmune diseases.14 As air pollution and common environmental contaminants are not enough to offer an explanation to differences in these examples, changes in immune regulation and its determinants are biologically the most valid argument.
Picture 2. Biodiversity hypothesis. Urban environments have cut our contacts to microbial biodiversity that is present in natural environments. Baby food is often almost sterile, and children rarely pick berries from the wood and walk on bare foots on the forest floor. Therefore, immune system does not face its regulation or so-called training.
The environmental biodiversity affecting human health can be seen as two layers; the inner layer, including gut, skin, respiratory system, which is influenced by the outer layer, such as soil, plants, animals and natural waters. Microbiota diversity and stability are mostly fostered in early childhood, even though interplay between the two layers continues throughout life.10
In both health and sickness, microbial diversity is essential. The diversity of the microbiota on normal skin is high, and for example an exacerbation of allergic disorders may cause an invasion of the opportunistic bacteria and lead to inflammation. Typically, the clinician recommends antibiotics to remove the inflammation since the microbial balance has been disrupted.10 All in all, humans are reliant on planetary health and biological diversity. According to the hypothesis, people could improve their immune system by being close to the nature – touching, consuming, and breathing it.10
Polio hypothesis and natural vaccination hypothesis
The polio hypothesis relies on the assumption that the decrease in microbial infections has paradoxically weakened the immune protection in early infancy in developed countries. The name of this hypothesis refers to polio, a disease where such phenomenon occurred about a hundred years ago when poliovirus infections started to cause paralysis more often than ever before. The underlying cause was related to a delay of the first infection of the babies beyond the age when they were no more protected by maternal poliovirus antibodies. Maternal antibodies are transferred to the newborn during fetal life and in breastmilk protecting the child during the first year of life. The concept of “natural vaccination” relates to the favorable combination where the child who has maternal antibodies in the blood encounters the virus – such child gets superficial infection in the mucosa but not severe diseases, and the infection serves as “natural vaccination” which generates long term immunity against the virus. This all was changed in the 20th century when increased hygiene reduced the circulation of polioviruses, and consequently the first infections occurred too late when maternal antibodies had disappeared from the child. Children were then unprotected and susceptible to the virus which could spread to the blood and cause paralysis. Concomitant decrease in maternal antibody levels further weakened this protection.
Picture 3. Mothers transfer immune protection against viruses which they have encountered to their babies (antibodies are transferred during pregnancy and in breast milk). Polio hypothesis proposes that this protection has weakened making the infants now susceptible for viruses that can cause IMDs.
The polio hypothesis was originally launched to explain possible contribution of a potential diabetogenic virus, enterovirus, to the increasing incidence of type 1 diabetes.15,16 This hypothesis has later been expanded to explain the increase in other chronic diseases, including other IMDs.17 The hypothesis is also supported by several studies showing that there is an inverse relationship between type 1 diabetes and enterovirus infections.15,16
Other hypotheses
In addition to the key hypotheses described above many other hypotheses have been proposed. These include for example the effect of pollutants or radiation on the immune system 18,19 as well as the increased energy intake that leads to obesity and low-grade inflammation. Obesity and rapid growth in childhood could also increase the burden of insulin producing cells in the pancreas which has been proposed to contribute to the development of type 1 diabetes (e.g., accelerator hypothesis 20,21).
Picture 4. Increasing body weight may stress insulin producing cells in the pancreas making them work harder and expressing proteins that can make the immune system attack against these cells. This hypothesis has been launched to explain the increase in type 1 diabetes, but it does not work for other IMDs.
How to tackle the epidemic?
As complex as the human body and the biological pathways are, there won’t be just one simple answer to the question. We can state that exposome likely plays a key role in the increased incidence of IMDs and that our health is dependent on the health of the environment. That said, there is a real need for exposomic health research.
To investigate human health needs in the context of planetary health, multidisciplinary and innovative approaches are much needed. Societal functions like city planning, food and energy production should increasingly focus on public health matters. As biodiversity loss and rapid urbanization are intertwined and global warming is already happening, the conservation of nature should draw an increasing attention when protecting human health. We predict that nature-based solutions, such as making urban environments “green” by bringing nature’s biodiversity into urban spaces, will take place at a new scale when the environmental health knowledge deepens, and preventive actions get more attention among the wider public.
Picture 5. “The key question is – Why do urbanized populations react with inflammation when they come into contact with natural factors like pollen, food, or animals? They appear to be becoming increasingly allergic to nature, Homo sapiens’ ancestral habitat.” – T. Haahtela 2019
HEDIMED has the privilege to investigate the hot topics in exposomic health questions with novel settings. Our research consortium comprises research groups and birth-cohort studies from countries with different incidences of immune-mediated diseases, and the availability of new technologies and data creates a great potential for new findings in the key questions of environmental health. In addition, HEDIMED takes a unique step forward by studying the effect of standardized early-life exposures to putative protective factors (natural microbial biodiversity, probiotics, polyunsaturated fatty acids) on the risk of IMDs. We believe that these kinds of controlled clinical trials pave the way for the breakthroughs that will eventually offer the solution to the prevention of IMDs.
Importantly, informing stakeholders of the most promising avenues for the control of environmental threats will take place to create a widely accepted consensus on the importance of the topic.
Authors
The blog post was written and planned by Henna Numminen and Heikki Hyöty. The final version was modified in consultation with Lars Stene and Leena Hakola, with editions by Daniel Schmidtmann.
Sources:
- Bach, JF. 2018. The hygiene hypothesis in autoimmunity: the role of pathogens and commensals. Nat Rev Immunol, 18:105–120.
- Nunes, C., Pereira, A.M. & Morais-Almeida, M. 2017. Asthma costs and social impact. Asthma res and pract, 3:1.
- European Federation of Allergy and Airways Diseases Patients’ Associations 2022. Asthma in Europe. Available from https://www.efanet.org/malaga-london-declaration/asthma-in-europe. Read in March 2022.
- Zuberbier, T., Lötvall, J., Simoens, S., Subramanian, S. V. & Church, M. K. 2014. Economic burden of inadequate management of allergic diseases in the European Union: a GA(2) LEN review. Allergy, 69:1275-9.
- Patterson, C. C., Harjutsalo, V., Rosenbauer, J. et al. Trends and cyclical variation in the incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study. Diabetologia, 62:408-417.
- Gottesman, B.L., Yu, J., Tanaka, C., Longhurst, C.A., Kim, J.J. 2022. Incidence of New-Onset Type 1 Diabetes Among US Children During the COVID-19 Global Pandemic. JAMA Pediatr,01/2022.
- Bach, J.F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med, 347:911–920.
- Mäkinen, M., Simell, V., Mykkänen, J., Ilonen, J., Veijola, R., Hyöty, H., Knip, M., Simell, O., Toppari, J., & Hermann, R. 2014. An increase in serum 25-hydroxyvitamin D concentrations preceded a plateau in type 1 diabetes incidence in Finnish children. J Clin Endocrinol Metab, 99: E2353-6.
- Strachan, D. P. 1989. Hay fever, hygiene, and household size. BMJ, 299:1259–1260.
- Haahtela, T. 2019. A biodiversity hypothesis. Allergy, 74:1445-1456.
- Kujansuu, E., Kujansuu, L., Paassilta, M., Mustonen, J. & Vaarala, O. 2019. Exposure to sewage water and the development of allergic manifestations in Finnish children. Pediatr Allergy Immunol, 30:598-603.
- Okada, H., Kuhn, C., Feillet, H., & Bach, J.-F. 2010. The hygiene hypothesis for autoimmune and allergic diseases: an update. Clinical and Experimental Immunology, 160: 1–9.
- Haahtela, T., Holgate, S., Pawankar, R., Akdis, C. A., Benjaponpitak, S., Caraballo, L., Demain, J., Portnoy, J. & von Hertzen, L. 2013. The biodiversity hypothesis and allergic disease: world allergy organization position statement. World Allergy Organ J, 6:3.
- Kondrashova, A., Seiskari, T., Ilonen, J., Knip, M., & Hyöty, H. 2013. The “Hygiene hypothesis” and the sharp gradient in the incidence of autoimmune and allergic diseases between Russian Karelia and Finland. APMIS, 121:478–493.
- Viskari, H. R., Koskela, P., Lönnrot, M., Luonuansuu, S., Reunanen, A, Baer, M. & Hyöty, H. 2000. Can enterovirus infections explain the increasing incidence of type 1 diabetes?. Diabetes Care, 23:414-416.
- Viskari, H., Ludvigsson, J., Uibo, R., Salur, L., Marciulionyte, D., Hermann, R., Soltesz, G., Füchtenbusch, M., Ziegler, A.-G., Kondrashova, A., Romanov, A., Knip, M., & Hyöty, H. 2004. Relationship between the incidence of type 1 diabetes and enterovirus infections in different European populations: Results from the EPIVIR project. Journal of Medical Virology, 72:610–617.
- Zinkernagel R. M. 2001. Maternal antibodies, childhood infections, and autoimmune diseases. N Engl J Med, 345:1331-5.
- Ponsonby, A. L., McMichael, A., & Van Der Mei, I. 2002. Ultraviolet radiation and autoimmune disease: insights from epidemiological research. Toxicology, 181:71-78.
- Winans, B., Humble, M. C., & Lawrence, B. P. 2011. Environmental toxicants and the developing immune system: a missing link in the global battle against infectious disease? Reproductive toxicology, 31:327-336.
- Fourlanos, S., Harrison, L.C. & Colman, P. G. 2008. The accelerator hypothesis and increasing incidence of type 1 diabetes. Current Opinion in Endocrinology, Diabetes and Obesity, 15:321-325
- Wilkin, T. J. 2001. The accelerator hypothesis: weight gain as the missing link between Type I and Type II diabetes. Diabetologia, 44:914-22.
Picture text: Haahtela, T., Alenius, H., Lehtimäki, J., Sinkkonen, A., Fyhrquist, N., Hyöty, H. et al. 2021. Immunological resilience and biodiversity for prevention of allergic diseases and asthma. Allergy, 76:3613-3626.
