Hygiene Hypothesis: Old Friends Flashcards
(34 cards)
What’s the trend of diseases amongst the years? (increase/decrease)
-Immune regulatory disorders increase (especiallly after 1995, in Westernized countries): MS, Crohn’s, Type I diabetes, asthma
-Infectious diseases decrease: Measles, mumps, TB, HepA, parasite infections
Before WW2: %30-40 of kids had helminth infections, now its very rare.
Due to vaccination + better healthcare
Where’s the asthma/allergy increase observed?
Northern-Southern USA, Australia, Europe: so much asthma
Asia, Russia, Africa: some places hardly any asthma/allergy
Especially increases in urban centres/cities, but less in poor countries/rural areas
Hygiene hypothesis
Found by David Strachan, UK, epidemiologist
He found: first kids have more chance to develop hay fever compared to others
Others have less because they are exposed to germs from older siblings (obv doesn’t count for all germs)
Since westernized countries have less kids: they get more inflammatory diseases
What’s the differences in lifestyle that might effect our prevalence of getting inflammatory diseases?
After WW2 in Europe, now in developing countries:
- People move to cities/urban areas from rural areas
- Food system depends on fast food
- Sitting professions are more common rather than physical labor now
- We are always indoors rather than outdoor
- We have better housing: isolation, central heating, less humidity depending on condition
- We have better healthcare, we can prevent infectious diseases pretty good with antibiotics/penicillin has an important effect + also there’s vaccination
- Sanitation has improved, its often too much, hospital cleanliness for the immunocompromised is the new normal = very high personal hygiene, very clean homes, soaps w antibiotics lmao xD
How do we perceive microbes now?
-We see them as disease source: and think absence of them is key to health
But= microbes can be beneficial!!
Old Friends Hypothesis
Graham Rook, UK, improved hygiene hypothesis
Said that: there was microorganisms back then that were abundant in our system to train our immunity.
They were tolerated, and our immune system evolved with them instead in evolution.
ex: Lactobacilli, mycobacterium from the soil, organic material
Helminths/parasitic worms in gut or blood: Lost: used to provide Tregs/Bregs/antiinflammatory cytokines
Ectoparasites (fleas, lice, mites, ticks): Mostly lost
Carrier states (only): Salmonella, HepA, H.pylori, TB, toxoplasma positivity: Mostly lost
Microbiota of skin, gut, airway, genitalia: Changed/less diverse (due to going indoor, no contact with environmental microbes/food)
Microbiota of the natural environment (soil, animals, air, plants): Less diverse
= They both provided Treg, TLR-2, TGFbeta, SCFA
-50 years ago everyone was positive for HepA IgG, so everyone was infected at some point, no one has it now. Also the same with lice & helminths.
Probably they caused a lot of problems: but they had useful insights to teach our immune system.
How does the immune system change between rural and urban residents?
Mass cytometry study:
(Mass cyt. is like flow cyt. but with metal labeled Abs, causes less spillover so you can use more markers)
-A subset of CD8 T cells, ILCs and gamma delta T cells were lost
-B cell subsets switched to something different
Conclusion: Less exposure to urban life develops immune system differently
-Vaccines and drugs in two different groups might act differently
-In urban: more inflammatory diseases, rural: protected from those
What is the hygiene hypothesis about?
Contact with microbes
How many types of helminths exist?
- Gut-intestinal helminths / blood-lymphatic system helminths
Helminth infections: Observed where, how much, what do they cause?
- Almost 3 billion people are infected with chronic parasitic infections (1/3 of the whole world)
- It’s especially a huge problem in the tropics
- Helminth infection can persist for years, normally immune system is there to fight with them, but often it cant get rid of it
- How do they effect immune system/or whats their effect on allergies/asthma is studied
- In some areas, almost %100 of the kids are infected, they don’t kill, might cause some reaction in some cases: often small complaints so they ignore or don’t notice it at all
- But in some cases: prolonged bladder and liver inflammation can even cause cancer
Association of helminths and allergy/asthma meta-analysis review
- Allergy results: Negative association: once you have helminths, you don’t have allergy! Clear association with hygiene hypothesis
- Asthma results: Not clear, only hookworm showed a negative association
- Ascaris even increased asthma: it has a lung stage that drives a significant immune response in lungs, other worms often have lung stage too but probably not that invasive
- Overall results were inconsistent, the clinical outcome of allergy/asthma varies (severity), IgE levels vary, pathology due to worm infection varies, helminth infection intensity varies etc.
- Also while doing such meta-analysis: there’s a significant difference between results from 2021 and 2006. The environment changes a lot. Even in Indonesia there was 1 plane a week, now there’s a lot even in rural areas, everyone uses cars instead of walking = conclusion is very hard
Antihelminthic treatments results
- In pregnancy: if you use Albendazole/Praziquantel: kids have an increased risk of egzema and wheeze in 1-5 years, but not anymore in 9 years.
- In children: Albendazole/Praziquantel for 2 years: more IgE, more SPT conversion? in Gabon Vietnam / no effect on eczema, IgE reduced, SPT conversion was observed = So there’s environmental difference variability
Why hygiene hypothesis is prevalent on kids and toddlers?
-Early priming: Immune system is immature in kids, susceptible to infections, both adaptive and regulatory arm is developing = so teaching them properly is critical!
Schisto / H. polygyrus (Pig hookworm) animal study- airway responsiveness results
OVA model + once they give Schisto, allergic airway inflammation = BAL eosinophilia numbers decrease
Airway hyperresponsiveness: once you give methacholine inhaled, once you have asthma: you respond greatly in low doses, if you don’t: you respond in very high dose
OVA: hyperresponsive
OVA+ Schisto: acted like no asthma at all
= Both immunological and functional level = asthma reduced
Similar results in pig hookworm: decreased eosinophils w infection, and less immune cell invasion in tissue
Schisto infection :Immune responses step by step
1) Cercariea step: Weak Th1
Schistosome - Adult worm
2) Eggs: strong type II response: macrophage, DCs, IL-4, IL-5, IL-13
3) Chronic stage: Treg, Breg, reg. DCs, IL-10 and TGFbeta increase
Regulatory network cells/and what they secrete?
Tregs= Foxp3, IL-10
Bregs= TGFbeta, IL-10
Alternatively activated macrophages
regulatory DCs
What does Tregs do? / on other immune cells for suppression
They block everything around them! Can use either of these mechanisms depending on circumstances:
- Inhibit antigen presentation to T cells/they can prevent access to DCs by surrounding them
- Modulate B cells
- Tissue remodeling
- Inhibit innate cells
- Downregulate Teffs (Th1/Th2) or kill them w granzyme perforin
- They secrete IL-10, TGFbeta, IL-35
- They can starve Teffs w cytokine deprivation: eg. they express IL-2R, so they collect all IL-2 around and it needed for T cell growth
- They can deprive adenosine
- they can change nutrient balance around (glycolysis, oxphos substrates)
- they can suppress DCs directly with checkpoint inhibitors eg. CTLA4, LAG3
How do T regs suppress the overall environment? /benefits
- They protect from autoimmunity: If T cell recognizes autoantigen, they prevent its development to Teff = helps differentiating self/nonself
- Critical in mucosa response, there’s a lot of microbes in microbiota, T-regs avoid building response to every microbe = also avoid allergies
- They drive tissue repair: Secrete amphiregulin, induce epithelial/fibroblast repair
Schisto /H.polygyrus study - Treg results
H.polygyrus secretes HES, and increases Foxp3+ Tregs
Schisto also show increased Foxp3+ Tregs
Deworming then malaria infection study
After 9 months of deworming (compared to worm control): TNF-alpha response to plasmodium increased significantly
- CTLA4 on CD4 T cells decreased/brake released
- So helminth makes the response much more suppressed: cancer cells also use a similar strategy (especially w checkpoint inhibitors).
What’s observed as a bystander effect in kids infected w helminths? -T cells only-
Increased Tregs/enhanced activity
Suppressed Th1, they drive Th2 response tho
Good things/bad things in helminth infection?
The positive effect of helminth infections: -Reduced hyperresponsiveness in allergy/asthma -Reduced autoimmunity -Reduced IBD Negative: -overall suppression to other pathogens -Reduced vaccine response -Reduced anti-tumor immunity
Treatment of IBD with Trichuris suis trials
Joel Weinstock-GI doctor from the USA, thought there’s a lot of pig farms in Texas, and pig farmers don’t really have IBD, or it’s very mild.
So he thought the pigs on the farms are infected with helminths, especially Trichuris (whipworm), and farmers kept continuously getting exposed to its eggs = so they are immune for IBD.
Pro: This can be tested easily in humans because this Trichuris cant infect humans, very controlled infection, you eat eggs, they don’t hatch, they just wash away = temporary exposure
So he gave his patients eggs: every 2 weeks for 12 weeks, 2500 mature eggs. He saw significant improvement in colitis index after week 6
Then they did all those trials for the same eggs on Crohn’s, MS, UC, Rhinitis etc. mostly didn’t work. Only very small-scale ones w selected patients worked, and once it passes to Phase II/III= bummed.
Hookworm larvae trials was the same only worked for limited ppl
Other larvae studies: also didn’t work
Why Trichuris whipworm trials didnt work/criticisms?
1) Maybe it only works for kids:
- The hygiene hypothesis does not say that helminth infection helps adults.
- In low-middle-income countries: the biggest effect is seen on kids.
- Also, the hypothesis says that it’s useful in early priming once their immune system still develops.
- Trying this on adults, also adults with full-blown disease: the effect might not be enough to reduce the whole inflammation
- Also you cant try this on kids with no disease, another half of the world is trying to eliminate these worms completely xDDD But that’s why rather this pig worm trial was good: no one gets infected but gets exposed.
-Egg administration (like in the case of pig worm study) with no infection might not be enough to provide protection at all.
2) Treatment period is short
-Might be, but pharma companies don’t fund that long (more than 5-10 years)
-Also trial participants won’t want that: they want 6m max treatment period.
Irl: those kids have those helminths either all their life/or prolonged exposure at least 2-3 years
3) Insufficient dose
- They cant know that, they just try to make it similar to original infections
- Also ethical committees make you use the lowest dose possible/also no side effects
4) Wrong worm species
- Often ppl in endemic areas are infected w multiple worms instead of one
- Do you need a specific one for each disease for eg.?
5) Ppl immune responses differ
Conclusion: We should rather learn how helminths suppress/teach immunity. What type of molecules they secrete and use those instead, harder to learn but better.
