Lecture 18: The hygiene hypothesis: parasitic worms and protection against asthma? Flashcards
What do parasitic worms (helminths) cause?
- Intestinal manifestasions
- General weakness
- Impaired cognitive and physical development
- Uncontrolled inflammation leading to elaphantiasis
What are the symptoms of parasitic worm infections?
None or mild symptoms
How do parasitic worms affect the immune system?
Parasitic worms secrete bioactive molecules, which regulate or dampen down the immune system to ensure their survival for many years and also to reduce inflmmatory responses, which can damage the host
Describe adult hookworms
The worms are about 1cm in length and are attached to the villi of the small intestine
What is the main cause of O. volvulus infection?
The larval microfilaria stage released by the adult female worm.
Where do the adult female worm live?
These live in the skin or migrate into the eye
What do adult female worms cause in the eye?
- Lesions such as sclerosing keratitis
- Blindness
What is onchocerciasis often called?
River blindness because the larvae of the vector blackflies live in fast flowing rivers
What do Schistosoma mansoni cause?
Schistosomiasis
What is schistosomiasis?
- One of the most dangerous paristic worm infections
- The combination of enlarged, irregularly fibrosed liver and greatly enlarged spleen is commonly called “Egyptian hepatosplenomegaly”.
What is a major cause of pathology in schistosomiasis?
Eggs released by adult female worms that may lodge ectopically in any tissues, where they cause characteristic granulomas.
What is adult taenia saginata?
Beef tapeworm - can reach 10m in length
What is adult taenia saginata?
Beef tapeworm - can reach 10m in length
What response do helminths induce?
- Th2 response
- Anti inflmmatory response
What is the Th2 response induced by helminths characterized by?
-Cytokines: IL-4, IL-5, IL-13 (decreased IFN-g) -
mainly derived from T cells (role for ILC2s)
- antibodies: IgE
- Effector cells: mast cells, eosinophils
What is the anti-inflammatory response induced by helminths characterized by?
- Cytokines: IL-10, TGF-b; antibodies: IgG4
- Effector cells: alternatively activated
macrophages; regulatory T cells (Tregs) and B
cells (Bregs) - Antigen-specific and non-specific lymphocyte
responses may be inhibited
What does filarial nematode cystatin do?
Suppresses Th2-related inflammation and associated asthma in OVA-induced allergic airway responsiveness model. Effect is associated with inhibition of eosinophil recruitment, reduced specific and total IgE and down regulated IL-4. The effect is dependent on macrophages and IL 10 induction
What is cystatin?
Helminth product, which can block Th2-dependent allergic lung disease in mice
What is OVA?
Ovalbumin (OVA) is often used as a model allergen in mouse models of allergic lung disease.
What does ES62 do?
inhibits allergic airway hyper-responsiveness
What is the effect of subcutaneous ES62
Sensitisation and challenge with OVA induces lung pathology in mice but this is greatly reduced
What is the main mechanism involved in ES62?
Involves inducing a Th1 response (IFN-gamma is a Th1 cytokine), which directly antagonizes the Th2 response (Th1 and Th2 responses counter-regulate each other). ES-62 can also directly block mast cell activation in response to allergen cross-linking.
What are HpARI and HpBARI?
Secreted products of Heligmosomoides polygyrus that target the IL-33 signalling pathway
How does HpARI work?
Binds to IL-33 within necrotic cells preventing its release and thus blocking type 2 responses e.g. ILC2 and eosinophil responses to Alternaria antigen-induced asthma
How does HpBARI work?
(binds alarmin receptor and inhibits): binds ST2 blocking interaction with IL-33, thus preventing IL-33-dependent responses relating to Alternaria-induced asthma.
What are the reasons for helminth therapy failure?
- Timing of treatment versus onset of seasonal allergy
- Mouse models generally try to prevent allergy developing rather than treating already established allergic disease
- Location of parasite may not induce systemic response
