Hypersensitivity 21/02/23 Flashcards
(42 cards)
What is a hypersensitivity reaction?
An exaggerated or inappropriate immune response to an antigen/immunogen, causing tissue damage.
What are causes of hypersensitivity reactions?
Inhaled material - pollen
Injected material - insect venom
Ingested material - peanuts
Contacted materials - metal
What are the classifications of different hypersensitivity reactions?
Type 1 (immediate) - IgE antibody caused by e.g. hay fever or allergic asthma.
Type 2 (cytotoxic) - IgG, IgM antibodies caused by e.g. blood transfusion reactions.
Type 3 (complex mediated) - IgG, IgM antibodies caused by e.g. farmers lung.
Type 4 (delayed) - T lymphocytes and macrophages caused by e.g. contact dermatitis.
What is type 1 hypersensitivity?
An immediate reaction after contact with an immunogen or known as ‘immediate’ hypersensitivity. A humoral response involving the production of IgE antibody by plasma cells.
What is the immunogen referred to as?
An allergen.
What is the prevalence of allergies using the hygiene hypothesis?
IgE production is a normal response to parasitic infections. Most multicellular parasites do not multiply in the human body. Parasites less antigenic than other pathogens and too big to phagocytose. They trigger an TH2 response, B cells produce parasite-specific IgE and this triggers an inflammatory response. This ejects parasites from human host. The hygiene hypothesis suggests that parasitic infections are an endemic to tropical countries and epidemic allergy affects the industrialised countries which aren’t exposed to parasitic infections typically. Inverse correlation between incidence of parasitic infection and of allergic disease.
What is the structure of IgE?
All immunoglobulins are composed of two light chains and two identical heavy chains. The heavy chain differentiates the various immunoglobulin isotypes. The heavy chain in IgE is epsilon. IgE is a monomer and consists of four constant regions in contrast with other immunoglobulins that contain only three constant regions. Due to this extra region, the weight of IgE is 190 kDa compared with 150 kDa for IgG.
What is the mechanism behind type 1 hypersenitivity?
IgE bind to Fc receptors on the surface of mast cells and basophils. Reactions due to specific triggering of IgE-sensitised mast cells by the allergen. This leads to release of
pharmacological mediators of inflammation, for example, asthma, hay fever, and urticaria.
What is an allergen?
An immunogen which causes an allergy.
What causes allergenicity?
-Sensitisation route
-Genetics of recipient
-Ability to evoke a Th2 mediated response
What is atopy?
Atopy is the genetic predisposition to produce IgE.
What are the genetics of atopy?
Subjects with a family history of Type I hypersensitivity have:
-Normal serum IgE levels = 0.1-0.4 mg/ml
-Levels x10 in atopic
-The inherited atopy is multigenic mapped to several loci
-Chromosome 5: coding regions for IL-3,4,5, 13, GM-CSF
-Chromosome 11: beta chain of high affinity IgE R
-Chromosome 6: MHC genes
What are the two types of IgE receptors?
Two types which are found on different cell types and differ 1000 fold in their affinity for IgE. High affinity receptor FceRI (Kd=1-2 x 10-9 M). Low affinity receptor FceRII (CD23) (Kd=1x10-6 M). Bound IgE is stable for weeks vs days when unbound.
What is the high affinity IgE receptor?
Expressed constitutively on mast cells and basophils. Can bind IgE in serum despite its low concentration. Also expressed in low levels on Eosinophils, monocytes, and platelets. Receptor has 4 polypeptide chains (a, b, 2 identical g chains or a, and 2 g chains (on monocytes and platelets)). Mice lacking FceRI alpha chain are resistant to
anaphylaxis.
What is the low affinity IgE receptor?
Has a single membrane spanning domain. Two isoforms: CD 23 and CD 23a. Proteolytic cleavage of CD23 generates soluble CD23.
What is omalizumab?
Omalizumab binds to the site on IgE that is normally bound by FcεRI. By blocking this site, IgE-mediated allergic responses are inhibited, because mast cells and basophils are unable to arm themselves with allergen-specific IgE via FcεRI on their cell surfaces.
What is the role of the mast cell?
Key cell in the orchestration of the inflammatory response. They are found in skin, connective tissues, and mucosal epithelial tissue of respiratory, digestive and genitourinary tract. They express high affinity IgE receptors on their surface and can rapidly sense PAMPs and DAMPS, via PRRs expressed in/on the cell surface. Many cytoplasmic granules contain preformed mediators such as histamine, heparin, chymase, and tryptase. Membrane-derived mediators are leukotrienes and prostaglandins.
What is mast cell degranulation?
It is initiated by IgE mast cell receptors cross linkage with the allergen. This leads to the linking of anti-isotype Ab with the IgE receptors and then anti-idiotype Ab. This results in enhanced calcium influx by ionophore that increases membrane permeability to calcium. This leads to the release of mast cell mediators such as histamine, heparin, chymase, and tryptase.
What is IgE receptor cross-linkage?
Activates protein tyrosine kinase (Lyn). Leads to phosphorylation reactions and generation of second messengers. Uptake of extracellular calcium and the release of intracellular calcium stores. Activation of phospholipase A2 enzyme, leading to formation of arachidonic acid and the generation of membrane derived mediators (same as previous flashcard).
What are the sequence of events in a type 1 hypersensitivity reaction?
- Allergen absorbed through mucosa
- APC presents processed allergen
- B cells produce specific IgE with T cell help
- Allergen specific IgE binds to mast cell via Fc receptors
- Re-exposure: Allergen cross-links surface – bound IgE
- Mast cell degranulation
What are the consequences of type 1 hypersensivity?
-Anaphylactic shock usually due to systemic release of mast cell mediators
-Anaphylaxis generalised type I reaction, leading to vasodilation and constriction of bronchial smooth muscle and can result in death
-Food allergies can result in local or systemic anaphylaxis
-Hay fever (allergic rhinitis) affects about 10% of the population due to airborne allergens triggering mast cell degranulation in nasal mucosa
-Allergic asthma
What is allergic asthma?
-Bronchial hyperreactivity
-Inflammatory infiltrate into the mucosa and submucosa
-Epithelial layer denudation/damage
-Goblet cell hyperplasia and excessive mucus secretion
-Oedema
-Bronchoconstriction
How does house dust mites induce allergic asthma?
-HDM protease allergens disrupt epithelial barrier function
-Tissue injury → DAMPs
-Cytokine upregulation (IL-5, IL-13)
-Eosinophil recruitment
What is type 2 hypersensitivity?
This is also known as cytotoxic hypersensitivity. Antibodies directed against antigen on surface of specific cells or tissues. Involves antibodies IgM and IgG. The antibodies interact with complement components and immune cells.
