Lecture 08:Allergens [Very Hard MCQ set 1]

Allergen Sources

• Allergens originate from various sources, including pollen, fungi, insects, domestic animals, and certain foods.
• Grass pollen grains are a common allergen source, leading to hay fever.
• A high IgE test result typically indicates an allergy. IgE antibodies signal an allergic reaction.

Aerodynamic Properties of Allergens

• Grass pollen allergens, when inhaled, can be as little as 10ng/day.
• Allergens are eluted from pollen grains and become airborne upon disturbance.
• Major inhaled allergens share characteristics such as becoming airborne and the presence of relevant molecules.
• Protein epitopes serve as the primary targets for IgE antibodies.

Allergens from Domestic Animals

• Fel D1 is a key allergen originating from cats (felis domesticus).
• Fel D1 protein is constantly airborne, with individuals inhaling approximately 1ug daily, a significantly higher quantity compared to mite or pollen allergens.
• Testing reveals that 90% of individuals allergic to cats exhibit an IgE antibody response to Fel D1.
• Testing methods include skin prick tests, where a small amount of cat allergen is introduced into the skin, and serum testing for IgE.
• Symptoms, such as nasal, eye, and lung issues, can manifest within 30 minutes of entering a house with a cat.
• Airborne allergen assays show that Fel D1 particles are smaller than mite particles or pollen grains.
• These particles can float for extended periods with minimal air disturbance and easily transfer to public places via clothing
• Immunization typically does not induce a persistent IgE response.

Routes of IgE Production

• IgE production occurs through two main routes of antigen introduction.
• Early animal research indicated that low doses of antigens are most effective at causing an IgE response
• Later research using CFA-antigens and emulsion agents resulted in a greater IgG antibody response and long-lived IgE antibodies from germinal center microstructures.

Allergic Reactions and Symptoms

• Allergic reactions manifest in various symptoms, for example:
• Breathing difficulties
• Itching
• Sneezing
• Headache
• Red or watery eyes
• Hives or rash

Grass Pollen Allergens

• Windborne pollen properties reflect their role, being released in dry, windy conditions and carried by the wind.
• Upon contact with wet surfaces, proteins are released, forming a pollen tube that triggers a human IgE response.
• Lol p1 is a main grass-related allergen.
• Pollen allergens can induce IgA and IgG antibody responses.
• IgA contributes to mucosal immunity and neutralization, found in saliva, tears, and mucous.
• IgG facilitates opsonization, neutralization, complement activation, and antibody-dependent cellular cytotoxicity, engaging NK cells to eliminate antibody-coated target cells.

Dust Mites

• The main dust mite allergen, Der P1, is found in fecal particles.
• Mite fecal pellets contain a wide range of substances.
• These substances act on pathways that trigger an innate immune response, including TLR4 and TLR9.
• Toll-like receptor activation leads to the production of pro-inflammatory cytokines and inflammation.

Cat Dander

• Fel D1 is the primary cat dander allergen, targeting IgE when inhaled.
• Active immunization of cats against Fel D1 involves vaccination with Fel-CuMV vaccines.
• This activates the immune system, prompting B cells to secrete anti-Fel D1 antibodies.
• Circulating anti-Fel D1 IgG antibodies bind to the Fel D1 allergen in the cat's body, reducing its reactivity in secretions.

Anaphylaxis

• Characterized as a severe, life-threatening allergic reaction.
• Occurs within seconds or minutes of exposure, leading to an immune response.
• Immune release includes histamine, neutral proteases (trypase and chymase), and proteoglycans (e.g., heparin).
• Symptoms include the body going into shock, with a drop in blood pressure, airway narrowing, rapid weak pulse, skin rash, nausea, and vomiting.
• Treatment involves an epinephrine injection, followed by emergency medical attention.

Allergen Exposure Routes

• Proteins applied to the skin via the transdermal route can induce inflammation.
• Allergens on the skin cause local infiltration of eosinophils and basophils.
• Eczema, characterized by high skin permeability, is associated with elevated levels of IgE antibodies.
• Stinging insects, like honey bees, jumping ants, and fire ants elicit different responses.
• Bee venom results in a systemic response
• Fire ant stings cause an intense local skin reaction, leading to sensitization and IgE antibody production.
• Sublingual route and oral routes
• Oral exposure can induce tolerance
• Eating a wide range of foods leads to only 5% of the population has allergic reaction.
• Foods with different proteins (e.g., ovalbumin) can induce sensitization and IgE antibody production.

Immune Deviation

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

Immune Mechanisms Underlying Allergic Sensitization

• Allergic sensitization is an immune process mediated by pathogenic Th2 effector cells.
• Th2 cells secrete cytokines (IL-4, 5, and 13).
• Cytokines recruit inflammatory cells to sites of allergen exposure, resulting in hypersensitivity and mucous secretion.
• IL-4 induces IgE class switching, a key step in mast cell activation and inflammation.

Allergens as Ligands for Pattern Recognition Receptors

• Dendritic cells (DCs) initiate Th2 responses to allergens.
• DCs possess various surface receptors that influence their function and T-cell outcomes.
• Microbes can inhibit allergen-induced Th2 responses, as shown in mice studies.
• Allergen with lipopolysaccharide (LPS) at:
• High doses: LPS resulted in a Th1 response.
• Low doses: LPS favored Th2.
• Carbohydrate receptors facilitate the binding of allergens to DCs.

Protein Sequence and T-Cell Response to Allergens

• Allergens with immunodominant T-cell epitopes are recognized by both atopic and non-atopic individuals with HLA-diverse haplotypes.
• Epitopes are parts of antigens that can stimulate an immune response.
• T-cell epitopes that are protective induce the regulatory cytokine IL-10.
• The cat allergen Fel D1 triggers a specific population of T cells (chain 2) in allergic individuals.
• Protein sequence effects on the allergic response: features of different allergens are crucial for Th2 initiation and response in established disease.
• In vivo intradermal injection of allergen peptides in cat-allergic asthmatics worsened asthma.
• The role of Th2 cells and TCR specification in disease pathogenesis was defined, and the injection of a single peptide can activate memory Th2 cells.

Influences on the Quality of T-Cell Response

• Multiple factors contribute to Th2 responses, including the type and dose of allergens, and the specific pathways involved.
• The T-cell response varies, depending on the type and stage of the allergic disease.
• Th9 and Th17 responses are microbial.
• Th2 responses are shown in anaphylactic food allergies (e.g., peanut allergies).
• IL-5: indented, eosinophilic GI diseases
• The nature of T-cell responses is highly heterogeneous.

Takeaways from Injected Allergen

• Increasing the dosing regime of allergen extracts proves clinically effective, shifting the immune response away from Th12 (protective response).
• Tregs (regulatory T cells) are key to developing tolerance.
• IL10 increase (anti-infallmatory)
• Reduced T-cell proliferation
• Reduction of Th2 cytokines
• Increasing IL4 and IgGA suppresses IgE.
• Increasing IgG blocks the binding of allergens to B cells and modulates their delivery to APCs, lowering the T-cell response.

Exposure Site and Allergen Dose Effects

• The site and dose of exposure drive T-cell mediated inflammatory disorders.
• The dose depends on the efficiency of allergen delivery to APCs.
• The site plays a central role for DCs, potentially due to ease of migration.
• Common exposure sites include the skin, respiratory tract, mouth, and gut.

Intersite Sensitization Example

• A high prevalence of eczema in asthma patients exists.
• Th17 is implicated via activation from the skin, causing lung disease following sensitization through the skin.
• The skin microenvironment activates DCs, increasing T-cell responses to allergens.

Genomics

• Gene mutations coding for filaggrin compromise skin integrity.
• DC activation via multiple surface receptors leads to different effector T cells at skin lesions (Th2 and Th17).
• The oral cavity is pro-tolerogenic, populated by T cells.
• It expresses TGF-b, IL-10, IFN-c, Il-17, and DCs expressing TLR2 and TLR4.
• Research indicates that sublingual immunotherapy (SLIT) favors tolerance induction in the oral cavity, mediated by resident APCs.