Immune-mediated diseases Flashcards
Describe the hygiene hypothesis
The hygiene hypothesis is simply defined as changes in lifestyle, diet, sanitation & use of medications in industrialized countries have led to a decrease in infectious exposures to the developing immune system that is associated with a rise of allergic and autoimmune disease.
According to the ‘hygiene hypothesis’, changes of lifestyle in industrialized countries have led to a decrease of the infectious burden and are associated with the rise of allergic and autoimmune diseases.
According to the HH, allergies are predominantly diseases of modern industrialised societies. That improved hygiene, vaccination and use of antibiotics has resulted in a lack of immune system exposure to infections that, in essence, ‘educate’ or ‘prime’ or challenge the immune system while it is developing.
Describe the origins of the hygiene hypothesis
The theory emerged from a birth cohort study conducted in the UK known as the National Child Development Study.
Strachan proposed that household size could be protective for allergic disease because siblings are a source of infection.
Birth order appears to be negatively correlated with emergence of allergic disease.
At both 11y and 23y of age, prevalence ofhay-fever (in the previous 12 months) was inversely-related to no. older children in household at age 11 (independent of father’s social class).
Household size (larger families) also appeared to play a role. He proposed that household size could be protective for allergic disease because siblings are a source of infection.
Describe the Th1/Th2 paradigm
The Th1/Th2 paradigm was proposed as a plausible mechanism for the hygiene hypothesis.
In response to an antigen, antigen presenting cells activate T helper cells, which differentiate into Th1 and Th2 cells. Th1 cells are involved in cell-mediated immunity. Dysregulation of Th1 results in autoimmune disease. Th2 cells are involved in allergic response (stimulating release of IgE and cytokines IL-4/5/13), thus dysregulation results in allergic disease.
A balance between Th1 and Th2 cells is necessary for a well-functioning immune system.
Both Th1 and Th2 should be fully-functioning, but if one type of response becomes dominant, the result is de-regulation of immune system and development of disease. If directed against the body’s own cells, Th1 cells can be responsible for autoimmune diseases like MS, whereas the Th2 cells produce an anti-inflammatory response involved in allergic reactions.
The development of the immune system in the neonate and the infant determines whether Th1 and Th2 will be equally balanced.
The immune system is established very early in life. For example, the intrauterine environment is powerfully Th2 (and this so that the foetus is not immunologically rejected). This situation imprints Th2-dominance upon the neonate. Exposure to serial infections over the first 2y of life leads to a balance in Th1/Th2.
In contrast, fewer infections, due to high levels of hygiene or small family size and a longer period of time in which to make and establish Th2 responses to allergens, results in Th2 dominance and delayed maturation of Th1 capacity. This is the proposed mechanism of action of the HH – insufficient stimulation of the Th1 arm of the immune system leads to an overactive Th2 arm, which leads to allergic disease.
However, there are problems with this view in terms of explaining the rise of Th1 mediated autoimmune disease (e.g. Type 1 DM, MS).
Provide an update definition of the hygiene hypothesis
the lower frequency of infections in industrialised countries owing to improved hygiene, vaccination and use of antibiotics may alter the immune system such that it responds inappropriately to innocuous substances.
Note that this definition has since been updated to include microbial exposures.
Describe the ‘old friends’ component of the hygiene hypothesis
Hygiene hypothesis has been broadened to include exposures to commensal microorganisms and parasites – “OLD FRIENDS” that humans have co-evolved with over 10’s of thousands of years and which play an important immunoregulatory or protective role.
Co-evolution with microbes resulted in ‘evolved dependence’, where microbes need to be tolerated, and therefore humans involved regulatory pathways.
With the first transition to agriculture, changes including living in larger groups, in close proximity to fellow humans as well as animals, more orofecal transmission and transmission of animal microbes occurred. This significantly changed the composition of the human microbiome.
A second transition to the modern age, moving into cities with more hygienic practices and less animal contact, as well as the advent of anti-microbial therapies, resulted in less parasites, viral infections, and commensals. The microbiota become disrupted and less varied. Old co-evolved commensals were removed from the microbiome.
Describe supporting evidence for the hygiene hypothesis
Public health measures were taken after the industrial revolution by western countries to limit the spread of infections. These measures comprised decontamination of the water supply, pasteurization and sterilization of milk and other food products, respect of the cold chain procedure (system of storing and transporting vaccines), vaccination against common childhood infections and the wide use of antibiotics.
Postulated relationship between infection and allergy
In countries where good health standards do NOT exist, people are chronically-infected by various pathogens and the prevalence of allergic diseases remains low. Interestingly, several countries that have eradicated common infections see the emergence of allergic diseases.
Mortality, prevalence and incidence of infectious vs non-infectious/allergic disease
Contribution of mortality from infection and noninfectious diseases has changes over the last 100 years, with noninfectious causes comprising a greater share.
The incidence of certain infectious diseases has also decreased, for example syphilis with advent of antibiotics, and dysentery and typhoid as a result of hygiene practices and clean water.
There has been a concomitant decline in infections and an increase in autoimmune diseases and immune-related diseases, like asthma, in western countries. This increase in immune-mediated diseases is likely due to changes in our environment, NOT genetic changes, which would take much longer to manifest themselves.
Part of the increased incidence of these diseases may be attributed to better diagnosis or improved access to medical facilities in economically-developed countries, otherwise known as classification bias. However, this cannot explain the marked increase in immunological disorder prevalence that has occurred over such a short period of time.
Other risk factors
Several factors, such as socio-economic indices, may explain the difference in the prevalence of immunological disorders according to time and geographical distribution. Other factors are often incriminated, such as air pollution for asthma, but their role has not been demonstrated convincingly. For example, it has been shown that in East Germany before the fall of the Berlin Wall, where the air pollution was greater, the incidence of asthma was lower than in West Germany. Vit D production is linked to sun exposure and has been shown to have immunomodulatory effects.
But their role NOT demonstrated convincingly.
An example is the differing type 1 diabetes rates in Finland vs Russian Karelia, neighbouring geographic regions with similar ethnographic composition and environmental factors.
A confounding variable could be environmental toxins, but these are largely similar across the two areas.
It is less likely to be classification bias, as type 1 diabetes is a largely straightforward diagnosis.
Protective effect of infectious agents
Epidemiological data indicating a direct link between the decreasing level of infectious burden and the rising incidence of immunological disorders.
Several epidemiological studies have investigated the protective effect of infectious agents in allergic diseases. The presence of one or more older siblings protects against development of hayfever and asthma (as demonstrated by skin prick tests and IgE levels), as does attendance at daycare in first 6mo in the case of AD and asthma. Interestingly, exposure to farming and cowsheds early in life prevents atopic diseases, especially if mother is exposed during pregnancy.
Cross-sectional studies reveal that helminth parasites have a strong protective effect against atopy.
We have seen that there is a strong correlation between lifestyle factors and modifications of the incidence of allergic diseases, but this does not prove a causal relationship. The answer to this question comes from animal models of allergic diseases and, to a lesser degree, clinical intervention studies.
- animal models: mycobacteria prevent induction of allergic asthma in rats, by promoting a Th1 response
- clinical intervention studies
- Helminth eradication has been shown to increase atopic skin sensitisation. Encouraging results first shown in a double-blind RCT where Lactobacillus was taken daily by expectant mothers for 2-4 wks before delivery and postnatally for 6mo could decrease significantly the incidence of AD.
- probiotics −double-blind RCT: taken by expectant mothers before delivery and postnatally → decreased incidence atopic dermatitis in infants
Effect of antibiotics in infancy
- 14,572 children in US child cohort study
- 70% received at least 1 antibiotic within the first 2 years of life
- Early antibiotic exposure was associated with an increased risk of a number of chronic conditions of childhood onset (and increased risk with multiple doses)
- However, association DOES NOT equal causation: it could be that children prescribed multiple doses of antibiotics had chronic immune system issues
Describe other postulated mechanisms for the hygiene hypothesis
When considering the multitude of infectious agents that can induce protection from various immunological disorders – not surprising that more than one mechanism has been found. The Th1-Th2 deviation was the first major candidate mechanism for explaining the protective influence of infectious agents on immunological disorders.
Other mechanisms include:
- antigenic competition/homeostasis
- immunoregulation (Treg/T17)
- non-antigenic ligands
- gene-environment interactions (studies with adequate statistical power required)
T-regulatory cells:
- Fundamental role in immunoregulation
- Suppression of both Th1- and Th2-related diseases
Th17 cells:
- Recently identified
- Induction of both autoimmunity and allergy
- Explanation for observations not explained by Th1/Th2
- helminth infection induces proliferatin of Tregs, regulating allergy
- on deworming, Treg reduces, and Th17 is upregulated
- several trials underway examining helminthic therapy for chronic conditions
Discuss reasons for caution when appraising the hygiene hypothesis
The original findings of variation in hayfever with birth irder or SES are:
- real (objectively confirmed)
- consistent
- statistically independent
However, results from studies that have addressed infection more directly as the explanatory factor are disappointing (inconsistent or inconclusive).
Exposure measurement 1
In the ongoing investigations of all studies based on HH, a significant issue is the accuracy and scope of exposure measurement. Early life infections are difficult to measure accurately and precisely and even more difficult to recall. For this reason, a range of proxy markers have been used to indicate a higher probability of early life infection exposure:- sibling number, day care attendance and high residential density.
Exposure measurement 2
Proxies may reflect selection bias related to SES – people living in affluent areas may end up participating more in studies and skewing results.
Exposure measurement 3
Biomarkers of past infection have also been examined:- for example, host IgG seropositivity to hepatitis A virus, Helicobacter pylori, Herpes simplex virus 1 (HSV1),and Cytomegalovirus (CMV), and tuberculin sensitivity, have all been associated with a reduced risk of atopic disease [3]. However, such findings should be interpreted in the context that these measures reflect not only infectious exposures but also the resultant host response [4].
Exposure measurement 4
Non-infectious exposures may also be of importance, e.g. that living on a farm, pet exposure, a probiotic diet and even the bacterial contamination of drinking water associated with reduced risk of allergic disease.Thus, we can conceptualise the relevant exposures as extending beyond infection alone, to include innocuous microbial exposure also. Microbial exposures can not be examined in isolation, but must be untangled from possible confounding factors e.g. socioeconomic status or child nutrition.
Exposure measurement 5
Allergic diseases (e.g. asthma) have increased in incidence over time from the 1950’s to early 2000; with documented decline in major childhood infections, such as whooping cough.
But this may be due to temporal variation in factors that affect non-allergic asthma, such as anxiety, stress, exercise, cold air or dry air, hyperventilation, smoke or other irritants.
Describe the hygiene hypothesis 2.0
A broader theory, which encompasses the life course, rather than simply infancy, to explain rising allergy and autoimmune rates.
- in utero and birth: materal microbial exposure
- neonatal and infancy: microbial exposure, vaccinations and hygiene
- childhood: antibiotics, diet and environmental exposures
- adulthood: delayed infection, travel, housing and medication
