Lecture 9 Asthma Flashcards
What is an allergy?
Inappropriate response to an innocuous antigen/allergen e.g., Asthma.
What is a hypersensitivity reaction?
A heightened immune response on re-exposure to an allergen.
What is asthma?
An inflammatory disease of the airways of the lung that can lead to airway scarring and irreversible limitation of airflow.
What happens when allergens enter the body?
Allergens are small highly soluble proteins carried on dessicated particles like pollen grains or faeces of dust mites. Contact with airway mucosa leads to the elution of the soluble allergen and this diffuses into the mucosal lining. Allergens elicit increases IgE production in susceptible individuals at low dose. IgE production and increased numbers of eosinophils is influenced by a number of complex genetic and environmental factors.
What do allergens initiate?
An inflammatory response, a Th2 response.
What does asthma result in?
Mucus over production and bronchial smooth muscle cell contraction, leading to airway obstruction and chronic bronchial inflammation.
How do cells and signaling molecules interact during an asthmatic response?
Airway epithelial cells respond to external triggers (allergens, air pollutants and viruses) releasing key signaling molecules (TSLP, IL-33, IL-25). Dendritic cells are activated by epithelial signals (TSLP, IL-33) and interact with helper cells Th2 to promote inflammation. Th2 cells release cytokines that drive inflammatory responses. IL4 promotes IgE production, contributing to allergic reactions, IL5 stimulates eosinophil growth, leading to airway inflammation, IL3 causes mucus production and airway hyperreactivity. Mast cells are activated and release inflammatory mediators worsening asthma symptoms. ILC2 cells are also activated contributing to airway inflammation and muscle contraction.
What happens in IL-13-induced mucous metaplasia?
Airway epithelial cells undergo changes to produce excessive mucus, a hallmark of asthma and other respiratory conditions.
What is the IL-13 signaling pathway?
IL-13 binds to its receptor complex (IL-13Ralpha1 and IL-4Ralpha) on epithelial surface cells. Activates and phosphorylates (P) STAT6 and moves to the nucleus to trigger the expression of STAT6-responsive genes. IL-13 also stimulates the production of CLCA1 which interacts with a putative receptor to activate MAPK signaling. SPDEF is a TF that drives the expression of MUC5AC, a major mucin protein in airway mucus. FOXA2 (forkhead box protein A2) normally suppresses mucus gene expression but IL-13 signaling downregulates FOXA2 lifting this repression and increasing mucus production. IL-13 also induces 15-LO-1 an enzyme that converts arachidonic acid into 15-HETE, 15-HETE promotes mucus production.
What are the two main components of the immune response that lead to IgE production?
Signals that favour differentiation to Th2 and signals from Th2 cells that stimulate B cells to switch to IgE.
What are the steps to mast cells amplifying IgE production?
Allergen penetrates epithelial cell surfaces and induces synthesis of IgE. IgE cross-links IgE receptor on mast cells and also on eosinophils and basophils. This activates mast cells, eosinophils and basophils to express CD40L and IL-4. CD40L and IL-4 stimulates isotype switching by B cells and the production of more IgE.
What do eosinophils and mast cells do in allergic reactions?
E- killing of antibody-coated parasites. Mast cells- Release of granules containing histamine and other active agents. When activated multivalent antigen cross-links bound IgE antibody, causing release of granule contents.
What does IgE bind to on mast cells?
Binds to a high affinity Fc receptor FcERI on mast cells. Activated mast cells provide contact and secreted signals to B cells to stimulate IgE production.
What do the pre formed granules released from mast cells do?
Histamine- Vasoactive amine that causes increased blood flow. Prostaglandins-vasodilators and constrictors. Other protein inflammatory mediators produced by mast cell degranulation e.g., TNFalpha.
What happens in chronic inflammation of asthma?
Mast cells and TH2 cells secrete cytokines e.g., IL4, IL5 that augment eosinophil activation and degranulation. TH2 cells augment B cell production of IgE. Tissue injury and continued presence of increased TH2 cells, eosinophils and other leukocytes such as neutrophils leads to chronic inflammation. Cells cause remodeling of airways which leads to narrowing and increased mucus secretion.
When does chronic inflammation occur?
In absence of further exposure to allergen. Airway becomes hyper-reactive.
