https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(05)71142-9.pdf

Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders.

The hygiene hypothesis postulates that an environment with a high incidence of infectious diseases protects against allergic and autoimmune diseases, whereas hygienic surroundings increase the incidence of these disorders This review examines the evidence in support of the hygiene hypothesis and offers a number of mechanisms that could explain the relation between sanitary conditions and susceptibility to allergic and autoimmune diseases

https://www.nejm.org/doi/pdf/10.1056/NEJMra020100

The Effect of Infections on Susceptibility to Autoimmune and Allergic Diseases

According to the 'hygiene hypothesis', the decreasing incidence of infections in western countries and more recently in developing countries is at the origin of the increasing incidence of both autoimmune and allergic diseases. The hygiene hypothesis is based upon epidemiological data, particularly migration studies, showing that subjects migrating from a low-incidence to a high-incidence country acquire the immune disorders with a high incidence at the first generation. However, these data and others showing a correlation between high disease incidence and high socio-economic level do not prove a causal link between infections and immune disorders. Proof of principle of the hygiene hypothesis is brought by animal models and to a lesser degree by intervention trials in humans. Underlying mechanisms are multiple and complex. They include decreased consumption of homeostatic factors and immunoregulation, involving various regulatory T cell subsets and Toll-like receptor stimulation. These mechanisms could originate, to some extent, from changes in microbiota caused by changes in lifestyle, particularly in inflammatory bowel diseases. Taken together, these data open new therapeutic perspectives in the prevention of autoimmune and allergic diseases.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2249.2010.04139.x

The ‘hygiene hypothesis’ for autoimmune and allergic diseases: an update

Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.

/pdf/type-1-diabetes-etiology-immunology-and-therapeutic-55k7uqxdh1.pdf

Type 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies

There has been a steep increase in allergic and autoimmune diseases, reaching epidemic proportions and now affecting more than one billion people worldwide. These diseases are more common in industrialized countries, and their prevalence continues to rise in developing countries in parallel to urbanization and industrialization. Intact skin and mucosal barriers are crucial for the maintenance of tissue homeostasis as they protect host tissues from infections, environmental toxins, pollutants and allergens. A defective epithelial barrier has been demonstrated in allergic and autoimmune conditions such as asthma, atopic dermatitis, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis, coeliac disease and inflammatory bowel disease. In addition, leakiness of the gut epithelium is also implicated in systemic autoimmune and metabolic conditions such as diabetes, obesity, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis and autoimmune hepatitis. Finally, distant inflammatory responses due to a ‘leaky gut’ and microbiome changes are suspected in Alzheimer disease, Parkinson disease, chronic depression and autism spectrum disorders. This article introduces an extended ‘epithelial barrier hypothesis’, which proposes that the increase in epithelial barrier-damaging agents linked to industrialization, urbanization and modern life underlies the rise in allergic, autoimmune and other chronic conditions. Furthermore, it discusses how the immune responses to dysbiotic microbiota that cross the damaged barrier may be involved in the development of these diseases. In this review, Cezmi Akdis discusses how epithelial barrier-damaging agents linked to industrialization, urbanization and modern life may explain the increased prevalence of allergic disease as well as a wide range of autoimmune and metabolic conditions in which immune responses to translocated bacteria have systemic effects.

Does the epithelial barrier hypothesis explain the increase in allergy, autoimmunity and other chronic conditions?

OBJECTIVE--To examine whether children of families moving from an area of low incidence of childhood diabetes to one which is higher show a corresponding rise in disease incidence. DESIGN--Disease incidence study over 12 years. SETTING--Bradford District Metropolitan Council area. SUBJECTS--All subjects aged 0-16 years resident within the study area. MAIN OUTCOME MEASURES--The incidences of childhood diabetes in Asian and non-Asian families. RESULTS--The incidence of diabetes in Asian children increased from 3.1/100,000 per year in 1978-81 to 11.7/100,000 per year in 1988-90 (chi 2 for trend = 4.95, df = 1, p = 0.026) whereas that for other children remained constant at 10.5/100,000 per year. Over the entire study period rates were lower in Asian females (4.9/100,000 per year) than in Asian males (8.8/100,000 per year) whereas the reverse was true for other children (males 9.2/100,000 per year; females 12.0/100,000 per year) (test for common odds ratio: chi 2 = 3.81, df = 1, p = 0.052). CONCLUSIONS--Offspring of this transmigratory population had a rising incidence of childhood diabetes which was approaching that of the indigenous population. The data provide strong evidence for an environmental effect in the aetiology of insulin dependent diabetes.

Evidence for an environmental effect in the aetiology of insulin dependent diabetes in a transmigratory population.

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Evidence for an environmental effect in the aetiology of insulin dependent diabetes in a transmigratory population.