Lecture 3: Helminths and the Hygiene Hypothesis Flashcards
How did the idea of the hygiene hypothesis start?
In the second half of the last century we noticed a big increase in inflammatory diseases (e.g. type 1 diabetes, Crohn’s, MS), in particular in Western countries. At the same time we saw a decrease in general infectious diseases (e.g. hepatitis A, mumps, measles, tuberculosis) and parasitic worms in Western countries. In the Netherlands before WWII helminths infections were quite common in children and nowadays it is quite rare.
What is particular about the asthma prevalence?
Asthma is more prevalent in Western countries, but is also rising fast in urban areas of developing countries.
Who formulated the hygiene hypothesis and how did they come to it?
David Strachan first coined the hygiene hypothesis. He did a study that found that birth order influenced hay fever risk. The first-born had the highest risk of hay fever and this chance was lower for child 2, even lower for child 3, etc. Because of this, he proposed that children have less chance of hay fever because they are exposed to the germs of older siblings. By reducing the family size, the exposure decreases and hay fever increases. However, decreasing family size is not the only change made by the average Western person compared to a century ago.
What lifestyle changes did the average Western person make compared to one or two centuries ago?
Living in cities instead of rural areas, food patterns changed from slow food to fast food (although some people start eating slow food again), decreased activity during work: sedentary jobs instead of physical labour, spending a lot of time indoors instead of outdoors, improved housing with central heating, good isolation and less humidity, improved healthcare system, improved sanitation.
What negative side effects did the improved healthcare system and sanitation have?
Microbes were discovered to cause disease and health was seen as the absence of microbes. Therefore, it was seen as important to use antimicrobial agents, have more preventative strategies and more cleanliness. This first happened in hospitals, but was taken over to homes.
What is the “old friends” hypothesis?
The “old friends” hypothesis was proposed by Graham Rook in 2003 as an alternative to or refinement of the hygiene hypothesis, originally brought forward by Strachan in 1989 as an explanation for the rise in allergic disease. The old friends were already there to train our immune system and are tolerated at the expense of tissue damage. Our immune system has evolved in their continuous presence. E.g. lactobacilli, saprophytic mycobacteria (in soil or organic material), parasitic worms.
What is the impact of the “old friends” on the immune system?
In an analysis comparing immune cell subsets of people living in rural areas (more contact with “old friends”) and people living in urban areas (less contact with “old friends”), they showed that there was quite a difference between the immune systems of these populations. There is an hypothesis that because of these immune system differences, vaccines and drugs work differently on people and lead to accelerated inflammatory diseases in people living in urban areas.
What is the general conclusion from a meta-analysis about the effect of helminths on asthma and allergies?
It varied a lot per species. Some helminths decreased allergies and asthma, some did not and some increased. The timing in the studies analysed also varied, so that might influence the outcomes. This does not mean that the outcomes of these studies are not valuable, it just shows how complex this area of research is.
What led to the interest in “early priming”?
The type of helminth infection, the intensity of helminth infection, the age of the patient and the pathology due to the worm infections. E.g. in pregnant women who were given anti-helminth treatment, you see that their child has an increased risk of developing eczema and wheeze at 1 and 5 years, but the effect was no longer visible at the age of 9. These studies suggest a role of early priming.
Why is early priming important for the immune system?
The immune system of young children is less developed than that of adults. This means that the immune system is still susceptible from signals from outside. During this time the inflammatory and regulatory parts of the immune system are still being developed.
What was found about helminths and allergic asthma during animal studies?
Mice with helminths had less eosinophils in their lungs (indicative of allergy). Mice with helminths respond less to an asthma-challenge test than uninfected mice.
What happens to the immune response over the course of an helminth infection?
First, there is an inflammatory reaction. When the infection becomes chronic, the amount of regulatory T cells (which decrease inflammation) increase. This increased regulatory T cell population may lead to suppressing immune responses to allergens, auto-antigens and maybe more gut-related inflammation as a bystander effect. A mechanism by which regulatory T cells inhibit effector T cells is by starving them of cytokines or nutrients, driving competition or apoptosis by granzyme b or perforin. Regulatory T cells can also drive repair responses with amphiregulin
What are the negative effects of helminth infections (beside the helminth infection)?
- Reduced immune responses, increased susceptibility and reduced immunopathology to/of bacterial/viral/protozoan infections
- Possible reduced anti-tumour immunity, tumorigenic factors
- Reduced immune responses to and reduced efficacy of vaccines
What are the positive effects of helminth infections?
- Reduced incidence and increased atopy on drug cure of allergies and asthma (but no change found in clinical trials)
- Reduced incidence and suppression of pathology of auto-immune diseases
- Reduced incidence and suppression of pathology during clinical trials of inflammatory bowel disease
Why is Joel Weinstock important?
He was the first doctor that dared to give his patients helminth eggs as treatment. Patients received 2500 mature whipworm (Trichuris) eggs every two weeks during 12 weeks. They showed significant improvement by week 6 after initiation of T.suis treatment. He got this idea, because there are a lot of pig farmers in his area, but very little pig farmers among his patients.
