Immunity-L14-Type I Allergies and Hypothesis

what is allergy?

an immune response to innocuous harmless antigens such as pollen, dust mites, food proteins and nickel

key features of allergies/hypersensitivity- what do they induce?

• induces adaptive response

• induces a immunological memory

• and when re-exposed- exaggerate inflammation and tissue damage

how can allergies enter the body?(4)

1. inhaled- pollen, animal dander, mould

2. injected- via vaccines, drugs, therapeutic proteins

3. ingested- via food, oral drugs

4. contact- with plants, industrial products in factors, metals

types of hypersensitivity- 4 types

1. type I- Immediate hypersensitivity: IgE mediated- binds allergen and cross links with FceRI on mast cells- degranulation of histamine: hay fever, asthma, urticaria, anaphalaxis

2. type II(cell surface antigens)/III(soluble antigens)- Antibody mediated hypersensitivity- IgG/IgM- binds cell surface antigens- complement activation and Fc mediated killing

3. type IV- delayed T cell mediated- Th1 mediated like tuberculin skin test, Th2 eosinophil rich inflammation, CD8- kill targets cells like graft rejection

discuss type I hypersensitivity- what is is called, describe first exposure and re-exposure:

also called allergy- rapid onset and usually IgE mediated of mast cell degranulation. responding to non infectious innocuous antigens

first exposure:

• APC presents to T cells- get Th2 cells and produced IL-4 and IL-13

• IL-4 allows for IgE for allergen specific

• binds FceRI on mast cells, basophils and eosinophils

reexposure:

• allergen cross links IgE on mast cells- release histamine, cytokines, prostaglandins and lead to allergic symptoms

give key examples of IgE mediated allergic reactions and features(5)

1. food allergy- nuts, shellfish, milk- systemic absorption: vomiting, diarrhoea, hives. restricted to the get. systemic absorption: anaphalaxis

2. asthma- animal hair and dander- airway constriction and chronic inflammation

3. hay fevever- swelling of nasal mucosa

4. acute uriticia- increased vascular permeability

5. systemic anaphalyxis- widespread permeability- shock

why do IgE type allergies- induce a Th2 response and IgE class switching?(5)

• proteins have carb side chains and are active proteases

• low doses favour Th2

• highly soluble and penetrate mucosal barriers and is stable

• peptides that bind MHC II

• misdirected anti parasite response? Th2/IgE- usually for parasite defense

how does Der p1 promote allergies- what is the danger signal and how does it get in?

• house dust mite

• it is a protease allergen- cleaves tight junctions in epithelial cells and icnreases barrier permeability- can penetrate epithelium and access immune cells

• taken up by APC- presented to T cells and drives Th2 response and IgE

!! the protease is the danger signal

what experiments show proteases are a major driver of allergic reactions?

1. SPINK5 deficiency- it is a protein inhibitor defect- shows increased eosinophils, mast cells and T cells

what are the 2 IgE receptors and their roles in allergy?(2)

1. FceRI- high affinity- on mast cells and stable binding sites. cross links by allergen which causes degranulation of histamine, prostaglandins etc

2. c type lectin- low affinity- recognise carbohydrate structures and involved in allergen sensing but less potent

why dont allergic individuals have lots of circulating IgE? what happens upon re-exposure?

IgE doesn’t circulate like IgG- captured quickly by high affinity FceRI on mast cells and basophils and can remain on the cells for weeks and

• serum IgE is low but tissue bound IgE is high and potent

• when exposed again- allergen cross links IgE and FceRI and immediate mast cell activation

• doesn’t rely on chemotaxis

how is IgE produced and regulated during allergy?

• made by plasma cells in the lymph nodes and at sites of allergy

• IL-4 driven by Th2 polarisation with CD40-CD40L costim induced B cell class switching

• Th1 responses suppress IgE

what genetic factors increase the susceptibility to allergic disease?

• polymorphism in the IL--4 promotor induces a higher IL-4 for DC to make IL-4 to drive Th2 response by DCs and T cells make IL-4 for IgE

• have a higher affinity IgE receptor

• MHC II genes make it better at responding

• TCR locus- recognises process peptides from allergen better

why hasn’t allergy prevalence always been high if the susceptibility genes exist?

• genome hasn’t changed but environmental factors like urbanisation, western lifestyle, processed food has

explain the hygiene hypothesis

• early life exposure to microbes drives immune balance and counteracts excessive Th2/IgE responses

• modern hygiene, Antibiotics and reduced infections remove this exposure and makes immune system more biased towards Th2

discuss the counter regulation hypothesis

• allergy reflects failed regulation rather just a Th1/Th2 ibbalance

• Tregs FOXP3, IL-10, TGF beta suppresses responses usually but susceptible atopic people show weaker regulatory control of Th2 response

• loss of Tregs causes more severe allergic inflammation

discuss the epithelial barrier hypothesis

• modern exposures of detergents, pollutants, microplastics and food emulsifiers damage dight junctions in the skin/lung

• this increases allergen penetration and immune activation and IgE sensitisation

• barrier disuprtion also promotes colonisation of S.aureus driving chronic allergies