Inflammation and Immunity Flashcards
What are the different types of Leukocytes (WBC)?
- Neutrophils (50-70%) contain granules with lysosomal enzymes and bacteria-killing components
- Eosinophils (2-4%) excrete toxic compounds
- Basophils (<1%) accumulate in damaged tissue, release histamine
- Monocytes (2-8%) can enter tissues to engulf pathogens
- Lymphocytes (20-30%) Migrate in and out of blood. Includes T, B and NK cells.
What are the types of Lymphocytes and what is their role in adaptive immunity?
T cells (cell-mediated immunity)
Th cells produce cytokines to direct the immune response
Tc cells produce toxic granules to kill pathogen-infected cells
B cells (humoral immunity) Produce large quantities of antibodies which neutralise foreign objects like bacteria and viruses.
What are cytokines?
Cytokines are protein or polypeptide mediators synthesised and released during inflammation by autocrine or paracrine.
What are the types of cytokines?
- Interleukins (IL) released by macrophages, Th1 and Th2 cells. Can initiate the release of chemokines.
- Chemokines coordinate leukocyte migration. Act on monocytes, eosinophils, neutrophils etc
- Interferons
- Colony-stimulating factors
What are the main types of membrane receptors?
- Ligand gated ion channels (IONOTROPIC) milliseconds
- G protein coupled (METABOTROPIC) seconds
- Enzyme linked (mostly kinases) hours
What are membrane receptors?
Membrane receptors are responsible for the binding of an extracellular signalling molecule and transduction of its messages into one or more intracellular signalling molecules, which changes the cell’s behaviour.
Why study membrane receptors?
Favourite target for drugs for human disease. Most are targeted by small molecules which will bind to the protein. Many of the proteins targeted are kinase-linked receptors, and 1/3 GCPRs. Potential for drugs more specific to individual G proteins.
What must a good drug be?
A gene involved in human disease must first be identified. Design a small molecule that can effect the functions of the protein and is easily producible and taken into the body.
What must a good drug target have?
A binding site!
Could be an agonist binding site, a binding site for another protein that controls signalling, an enzyme with a specific binding site.
What do you need to know to identify about a receptor before identifying it as a good drug target?
The receptors downstream signalling The subtypes of the receptors Its subcellular location (intercellular or membrane-bound) Its structure and binding sites Where it is expressed in the body
How to test the effectiveness of a new drug?
First screen designed small molecules with the receptor to find out if it binds.
Express the receptor in the cell line.
Can test signalling using in vitro assays to measure how much it reacts
Then use an in vivo animal disease model.
What is an allergy?
Disease following an immune response to innocuous antigen. Mostly Ig-E mediated e.g grass & tree pollen, house dust mite faeces (Derp1, a protease that breaks down epithelial barrier), insect remains.
What are hypersensitivity reactions?
Inappropriate or exaggerated immune responses that cause inflammation, tissue injury and disease.
What is Zolair?
Omalizumab. Injection into the bloodstream.
A biological molecule drug used to treat severe asthma. IgE antibody that forms a complex with IgE so it can’t reach mast cell and cause reactions. Doesn’t effect already IgE-bound mast cells. Costs £30,000 per year per person to treat. Continuous treatment needed.
What are the types of respiratory allergy?
Allergic rhinitis (e.g. hayfever): allergen activates mast cells in nasal mucosa and conjunctivae to give symptoms of nasal congestion, sneezing and allergic conjunctivitis.
Allergic Asthma: allergen activates mast cells in the lower respiratory tract
How does sensitization to an allergen occur?
The allergen makes its way into the epithelial space of the airway (may be due to damage to epithelial integrity). Dendritic cells (APCs) internalise the allergens. Dendritic cells migrate to the regional lymph nodes/local muscosa and present the allergen to T lymphocyte using a MHC class II molecule. Interaction is facilitated by Notch and Jagged binding. T cells can transform into Th2 cells which interact with B cells. IL4 and IL3 produced by the Th2 cells cause class switch recombination (changing Ig) to occur. B cells produce allergen-specific IgE which are specific to the allergen which are released into circulation. Mast cells and basophils have receptor for IgE which can lead to the symptoms.
How does mast cell activation cause the symptoms of an allergy?
2 antibodies produced by B cells simultaneously bind to the FcERI receptor on the mast cells. Mast cells become active and release of granules which fuse with the plasma membrane (degranulation) to release mediators (histamine, amines, proteoglycans, serine proteases, enzymes, pepsidases, cytokines and growth factors). These mediators cause the symptoms.
How do the mast cell mediators cause the symptoms of an allergy?
Histamine will cause bronchoconstriction of the lung smooth muscle.
Prostaglandins will cause vasodilation which will lead to increased vascular permeability.
Pepsidases and other enzymes will stimulate nociceptors of sensory nerves causing sneezing, itching or coughing.
More immune cells are recruited and fluid fills the lungs as they move in.
Epithelial cells activate goblet cells for the production of mucous.
Increased leukocyte recruitment sets up for a late phase reaction.
What is the late-phase reaction in Asthma?
6-8 hours after allergen exposure. Resolves in 1-2 days. Chemokines and cytokines recruit and activate other immune cells which cause inflammation and tissue damage.
Eosinophils cause damage by secreting products such as eosinophil basic proteins.
Neutrophils release substances like elastase which causes Matrix Metalloproteinases activation and type II collagen degradation.
Basophils secrete more histamine and have IL-13 receptors. Contributes to bronchoconstriction.
T cells also memorize and continue immune response.
What happens in chronic asthma?
Increased goblet cells. Damaged epithelial layers increasing the risk of other allergic diseases, fibroblasts try to repair but make it stiff and inelastic. Inflammation moves into the submucosa, increased numbers of ECM molecules, myofibroblasts and smooth muscle cells. Increased IgE in circulation.
Epithelial-mesenchymal trophic unit regulates tissue remodelling.
Difficult to study in animals and humans.
What are the treatments for asthma?
- Avoidance - prevent exposure to allergen
- (Cortico)Steroids - limit production of cytokines by transcription inhibition of Cox2. Can’t be used for long time periods due to a lack of immune response.
- B2 adrenoreceptor agonists - relax smooth muscle, inhibit mast cell degranulation and mucous secretion
- Anti-histamines
- Anti-leukotrienes
- Anti-IgE (Omalizumab/Xolair)
What is the hygiene hypothesis?
Advanced living standards encourage reduced exposure to pathogenic and non-pathogenic microorganisms. This leads to an increased allergic response in genetically predisposed individuals.
What effects the likelihood of sensitization?
Host genotype.
Type, concentration, frequency and route of allergen.
Enhancing agents like endotoxin, chitin and environmental pollutants.
Genetic and environmental factors that cause a vulnerable epithelial barrier that favour the Th2 response.
How is allergic inflammation resolved?
Cells undergo apoptosis due to decreased concentration of cytokines.
Decreased differentiation, maturation, proliferation of mast cells.
Emigration away from affected site.
