Lecture 08:Allergens [Hard MCQ set 1]

Allergen Sources

• Allergens originate from various sources like pollen, fungi, insects, domestic animals, and foods.
• Grass pollen grains are a common cause of hay fever.
• A high IgE test result often indicates an allergy.
• IgE is indicative of an allergic reaction.

Allergen Properties & Exposure

• Major inhaled allergens become airborne and have molecules present to cause reactions.
• Protein epitopes are key targets for IgE antibodies. The grass pollen allergen, when in contact with a wet surface will release proteins, causing a human IgE response.
• Inhaling about 10ng of grass pollen allergens daily is typical.
• Grass pollen allergens are released in windy and dry conditions and are carried by the wind.
• Main grass related allergen is LOL p1.
• When windborne pollen comes in contact with a wet surface, it releases proteins, leading to a human IgE response.

Domestic Animal Allergens

• Cat allergen, Fel D1 (from Felis domesticus), is a protein that's constantly airborne.
• Inhaling approximately 1ug of Fel D1 daily is common, about 100 times more than mite or pollen allergens.
• 90% of cat-allergic individuals show an IgE antibody response to Fel D1 upon testing.
• Skin or serum testing can identify IgE presence related to cat allergens.
• Nasal, eye, and lung symptoms can appear within 30 minutes of entering a house with a cat for sensitized individuals.
• Cat allergen particles are smaller than mite particles or pollen grains, allowing them to float longer and transfer easily.
• The main allergen in cat dander is Fel D1, which targets IgE when inhaled.
• To actively immunize cats against Fel D1, vaccination with Fel-CuMV vaccines activates the immune system.
• This results in B cells secreting anti-Fel D1 antibodies, which circulate through the cat's body and bind to the allergen, lowering its reactivity in cat secretions.

Sensitization & IgE Production

• Immunization doesn't reliably induce a lasting IgE response.
• Early research suggests low-dose antigen introduction is most effective for IgE production.

Allergic Reaction & Symptoms

• Common allergy symptoms include trouble breathing, itching, sneezing, headache, and red/watery eyes.
• Hives or rashes may also occur.

Antibodies Role

• IgA antibodies provide mucosal immunity and neutralization, found in saliva, tears, and mucous
• IgG antibodies enable opsonization, neutralization, complement activation, and antibody-dependent cellular cytotoxicity

Dust Mites

• The main dust mite allergen, Der P1, is found in fecal particles.
• Mite fecal pellets contain various substances that trigger innate immune responses, like TLR4 and TLR9 activation leading to inflammation.
• Main allergen is Der P1 and can be found in fecal particles.
• Toll-like receptor activation results in pro-inflammatory cytokines and inflammation.

Anaphylaxis

• Anaphylaxis is a severe, life-threatening allergic reaction that occurs within seconds or minutes of exposure.
• It results from an immune release of histamine, neutral proteases (trypase and chymase), and proteoglycans like heparin.
• Symptoms include a drop in blood pressure, airway narrowing, rapid weak pulse, skin rash, nausea, and vomiting.
• Treatment involves an epinephrine injection and immediate follow-up at A&E.

Allergen Exposure Routes

• Transdermal exposure to proteins can induce inflammation.
• Allergens on the skin cause local infiltration of eosinophils and basophils.
• Eczema, characterized by high skin permeability, is associated with high IgE antibody levels.
• Systemic responses are typical with bee venom from stinging insects such as honey bees and jumping ants.
• Fire ant stings cause intense local skin reactions, sensitization, and IgE antibody production.
• Oral exposure can induce tolerance; most of the population is not allergic, despite exposure to a wide range of foods.
• Proteins like ovalbumin can induce sensitization and IgE antibody production through the oral route.

Immune Deviation

• Oral exposure to a chemical can induce prolonged tolerance to exposure via the transdermal route.

Immune Mechanisms in Allergic Sensitization

• Allergic sensitization is an immune process mediated by pathogenic Th2 effector cells.
• Th2 cells secrete cytokines IL-4, 5, and 13, which recruit inflammatory cells to sites of allergen exposure and cause hypersensitivity and mucous secretion.
• IL-4 induces IgE class switching, essential for mast cell activation and inflammation.

Allergens and Pattern Recognition Receptors

• Dendritic cells (DCs) initiate Th2 responses to allergens.
• DCs have surface receptors that influence their function and T-cell outcomes.
• Microbes can inhibit allergen-induced Th2 responses.
• High doses of LPS result in a Th1 response, while low doses favor Th2.

Protein Sequence and T-Cell Response

• Allergens with immunodominant T-cell epitopes are recognized by both atopic and non-atopic individuals.
• T-cell epitopes can be protective by inducing the regulatory cytokine IL-10.
• A specific population of T cells (chain 2) responds to the cat allergen Fel D1 in allergic individuals.
• Intradermal injection of allergen peptides in cat-allergic asthmatics can worsen asthma.
• Injection of a single peptide can activate memory Th2 cells.

Influences on T-Cell Response to Allergens

• Multiple factors contribute to Th2 responses, including the type and dose of allergens and the pathways involved.
• T-cell responses vary depending on the type and stage of allergic disease.
• Th9 and 17 responses are associated with microbial factors, while Th2 responses are linked to anaphylactic food allergies like peanut allergy.
• IL-5 is identified with eosinophilic GI diseases, indicating that T-cell responses are highly heterogeneous.

Takeaways from Injected Allergen

• Increasing the dosing regime of injected allergen extract moves the immune response away from a Th12 to a protective response.
• Tregs are key in the development of tolerance: increasing IL10 (anti-inflammatory), reducing T-cell proliferation, and reducing Th2 cytokines.
• Mechanisms include increased IL4 + IgGA, suppressing IgE and increased IgG-blockers binding of allergen to B-cells and modulating delivery to APC.

Exposure Site and Allergen Dose

• The site of exposure and allergen dose are major drivers of T-cell mediated inflammatory disorders.
• Central roles for DCs, with possibility of easy migration. Common exposure sites include the skin, respiratory system, mouth, and gut.
• High prevalence of eczema in asthma patients with Th17 implicated via activation from skin, causing lung disease following sensitization through skin.
• The skin microenvironment activates DCs, increasing T-cell responses to allergens.

Genomics

• Mutations in the gene coding filaggrin compromise skin integrity.
• Common causes include DC activation via multiple surface receptors, leading to different effector T cells at lesions in the skin (Th2 and Th17).
• Pro-tolerogenic environment identifiable in the oral cavity populated by T cells.
• Expressing TGF-b, IL-10- IFN-c, Il-17 and DC expressing TLR2 and TLR4.
• Sublingual immunotherapy (SLIT) favors tolerance induction mediated by resident APCs.