4. Hygiene Hypothesis

Question 1

Type 2 immune responses:

Answer 1

Cause atopic dermatitis, food allergy, and asthma, but they originally evolved to combat parasitic infection

Mice lacking type 2 responses (e.g. IL-4 receptor KO) are highly susceptible to parasitic infection

Question 2

Helminth Infection:

Answer 2

i.e. parasitic worm infection

Helminth infection is normal, wild mammals have close to 100% prevalence of parasitic infection

Question 3

Parasites have developed very sophisticated methods of suppressing BLANK to allow their survival

Answer 3

Parasites have developed very sophisticated methods of suppressing host immunity to allow their survival

Question 4

In absence of parasites, immune system is turned too HIGH/LOW due to expecting suppression of parasites -> BLANK and BLANK

Answer 4

In absence of parasites, immune system is turned too HIGH due to expecting suppression of parasites -> Allergies and autoimmunity

Question 5

The Hygiene Hypothesis: (aka Old Friends Hypothesis)

Answer 5

The idea that we need to have parasitic worms in order to have a healthy immune system.

As infections have become less prevalent, allergy has become epidemic.

Regulatory responses can control immune pathologies of Th1 autoimmunity and Th2 allergy

Question 6

Parasite immunomodulators:

Answer 6

Parasitic infections suppress allergy/asthma in humans and mice through the release of soluble parasite immunomodulators, they help the parasite evade the host immune response.

Would like to develop these immunomodulators as novel therapeutics!

Question 7

H. polygyrus Treg (T regulatory cell) induction:

Answer 7

H. polygyrus suppresses Th2 responses in mouse models of asthma

Infection induces Foxp3+ Tregs, and these can suppress allergic responses on transfer

Question 8

HES (H. polygyrus release Excretory/Secretory products)

Answer 8

HES suppresses allergic responses

So the immunomodulatory effects of H. polygyrus can be replicated by HES

HES induces de novo FOXP3 expression through the TGF-β receptor of T-cells

Question 9

What in HES induces Tregs?

Answer 9

Identified Hp-TGM (TGF-β mimic) as inducing Tregs

Question 10

Summary of how H. polygyrus causes immune suppression

Answer 10

H. polygyrus -> HES -> Hp-TGM -> Treg -> Immune Suppression

Question 11

Schistosome Dendritic Cell Suppression:

Answer 11

Schistosome Soluble Egg Antigen (SEA) suppresses LPS-induced Dendritic Cell maturation

• Reduced MHCII
• Reduced IL-12p70

Question 12

What is the main DC-suppressive factor in SEA?

Answer 12

Omega-1

Question 13

Omega-1

Answer 13

The main DC-suppressive factor in SEA

Omega-1 is a glycosylated T2 ribonuclease

Enters DC via mannose receptor (binds glycosylation)

Degrades RNA - Suppresses up-regulation of maturation markers (IL-12, MHCII, CD80)

Question 14

What in HES blocks IL-33 release?

Answer 14

Identified HpARI (H. polygyrus Alarmin Release Inhibitor)

Directly binds to IL-33, preventing IL-33 binding to IL-33 receptor

HpARI also binds to DNA with one domain and IL-33 with another, thus preventing the release of IL-33 from a dead epithelial cell.

Additionally another protein in HES binds and blocks IL-33 receptor: HpBARI (H. polygyrus Binds Alarmin Receptor and Inhibits)