Hypersensitivity 21/02/23

Question 1

What is a hypersensitivity reaction?

Answer 1

An exaggerated or inappropriate immune response to an antigen/immunogen, causing tissue damage.

Question 2

What are causes of hypersensitivity reactions?

Answer 2

Inhaled material - pollen
Injected material - insect venom
Ingested material - peanuts
Contacted materials - metal

Question 3

What are the classifications of different hypersensitivity reactions?

Answer 3

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.

Question 4

What is type 1 hypersensitivity?

Answer 4

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.

Question 5

What is the immunogen referred to as?

Answer 5

An allergen.

Question 6

What is the prevalence of allergies using the hygiene hypothesis?

Answer 6

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.

Question 7

What is the structure of IgE?

Answer 7

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.

Question 8

What is the mechanism behind type 1 hypersenitivity?

Answer 8

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.

Question 9

What is an allergen?

Answer 9

An immunogen which causes an allergy.

Question 10

What causes allergenicity?

Answer 10

-Sensitisation route
-Genetics of recipient
-Ability to evoke a Th2 mediated response

Question 11

What is atopy?

Answer 11

Atopy is the genetic predisposition to produce IgE.

Question 12

What are the genetics of atopy?

Answer 12

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

Question 13

What are the two types of IgE receptors?

Answer 13

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.

Question 14

What is the high affinity IgE receptor?

Answer 14

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.

Question 15

What is the low affinity IgE receptor?

Answer 15

Has a single membrane spanning domain. Two isoforms: CD 23 and CD 23a. Proteolytic cleavage of CD23 generates soluble CD23.

Question 16

What is omalizumab?

Answer 16

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.

Question 17

What is the role of the mast cell?

Answer 17

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.

Question 18

What is mast cell degranulation?

Answer 18

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.

Question 19

What is IgE receptor cross-linkage?

Answer 19

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).

Question 20

What are the sequence of events in a type 1 hypersensitivity reaction?

Answer 20

1. Allergen absorbed through mucosa
2. APC presents processed allergen
3. B cells produce specific IgE with T cell help
4. Allergen specific IgE binds to mast cell via Fc receptors
5. Re-exposure: Allergen cross-links surface – bound IgE
6. Mast cell degranulation

Question 21

What are the consequences of type 1 hypersensivity?

Answer 21

-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

Question 22

What is allergic asthma?

Answer 22

-Bronchial hyperreactivity
-Inflammatory infiltrate into the mucosa and submucosa
-Epithelial layer denudation/damage
-Goblet cell hyperplasia and excessive mucus secretion
-Oedema
-Bronchoconstriction

Question 23

How does house dust mites induce allergic asthma?

Answer 23

-HDM protease allergens disrupt epithelial barrier function
-Tissue injury → DAMPs
-Cytokine upregulation (IL-5, IL-13)
-Eosinophil recruitment

Question 24

What is type 2 hypersensitivity?

Answer 24

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.

Question 25

What are the consequences of type 2 hypersensivity?

Answer 25

Complement activation which leads to cell lysis. Deposition of complement components (opsonisation). Macrophage and neutrophil activation. Lysosomal content release of localised damage. Antibody dependent cell-mediated cytotoxicity and cytotoxic cell binds to the Fc portion of the bound antibody via its FcR.

Question 26

What are the causes of type 2 hypersensitivity?

Answer 26

-Blood transfusion
-Haemolytic disease of the new-born (Rh + father, Rh- mother)
-Hyper acute graft rejection
-Reactions to tissue antigens (goodpasture’s syndrome which is a reaction to basement membrane antigens)

Question 27

What is haemolytic disease of the new-born?

Answer 27

-Known as erythroblastosis fetalis
- It is due to Rhesus incompatibility
-Around 85% of population are Rh+ and 15% of population Rh-
-Antibodies to Rh antigens not normally present in Rh- people
-Sensitisation occurs in women after delivery of Rh+ baby
-Rh antibodies are IgG and can cross placenta
-Problems with second or subsequent pregnancies with Rh + babies

Question 28

What is the effect of anti-Rh antibodies?

Answer 28

-Spontaneous abortion
-Baby born with mild jaundice
-Baby born with Haemolytic Disease of the New-born

Question 29

How to prevent haemolytic disease of the new born?

Answer 29

Prevention - treat the mother with anti-Rh antibodies (Rhogam) within 72 hours of birth of each Rh+ child. Anti-Rh antibody bind RBC before B cell activation.

Question 30

What is type 3 hypersensivity?

Answer 30

Antibodies are directed against soluble antigens in serum. Can also be directed against widely distributed antigen. Deposited antigen-antibody complexes lead to damage in affect organs (activate complement, initiate inflammation). It is also termed: immune complex hypersensitivity.

Question 31

What are causes of type 3 hypersensitivity?

Answer 31

In persistent infection:
-Antibodies formed against microbial antigens (eg. Chronic Hep B)
In autoimmunity:
-Antibodies formed against self antigens
-Immune complexes deposited in the kidney, joint, arteries, skin, lungs

Question 32

What are the different types of type 3 hypersensitivity reactions?

Answer 32

Localised - e.g. arthus reaction
Generalised - e.g. serum sickness

Question 33

What is the Arthus reaction?

Answer 33

Appears within 4-8 hours after injection (intradermal, subcutaneous) of an antigen
into an animal with high levels of specific circulating antibody. Leads to complement activation (C3a, C5a), mast cell degranulation, neutrophil, and chemotaxis. Neutrophils is unable to phagocytose the immune complexes, leading to release of
lytic enzymes and resultant tissue damage.

Question 34

What is intrinsic allergic alveolitis?

Answer 34

An occupational disease due to inhalation of immunogenic proteins or spores.

For example:
 Farmer’s Lung
 Mushroom worker’s disease
 Coffee worker’s disease
 Cheese worker’s disease

Question 35

What is farmers lung?

Answer 35

Starts with mild cough in winter. Progressively worse over successive winters. Due to sensitisation to spores of thermophilic actinomycetes which grow in damp hay. Years of exposure lead to high levels of circulating IgG to spore antigens. Immune complexes (IgG/antigen) precipitate in lung. Complement activated results in inflammation. Destruction of alveolar tissue and fibrosis (repair of damage) occur.
Treatment is early diagnosis and avoidance and corticosteroids.

Question 36

What is type 4 hypersensivity?

Answer 36

Called DTH: delayed type hypersensitivity reaction. Takes > 12 hours to develop. Can develop within 72 hours or after weeks of exposure. Mediated by T lymphocytes and
macrophages. For example: the tuberculin test. Determines previous infection by M. tuberculosis, or previous exposure to BCG vaccine. Includes ‘contact hypersensitivity’ (e.g. reaction to nickel, chemicals, etc).

Question 37

What is contact hypersensitivity?

Answer 37

Dermatitis caused by exposure to:
 biological stains
 hair dyes
 urushiol (poison ivy)
 nickel salts
 mercuric salts (tattoos)

Question 38

How do the different types of contact hypersensitivity occur?

Answer 38

Sensitisation - initial contact leads to a cell mediated immune response (requires
Langerhans cells)
Chemicals - not immunogens but act as haptens after binding to skin proteins
-Subsequent contact - TH1 respond to the APC by releasing cytokines
-Cytokines - attract and activate monocytes

Question 39

What is coeliac disease?

Answer 39

 A chronic condition of the upper small intestine
 Allergic + autoimmune features
 Reaction to gluten (antigen is gliadin)
 Also termed gluten-sensitive enteropathy
 Increased T lymphocytes, macrophages
 Consequences - villous atrophy in small bowel and malabsorption

Question 40

What are the mechanisms behind coeliac disease?

Answer 40

Peptides produced from gluten (eg. Giadin) do not bind to MHC II molecules. Tissue glutaminase (an enzyme), modify gliadin now binds to APC. Giadin consequent activation of T lymphocytes and cytokine release and activate/kill epithelial cells.

Question 41

What does aspirin (acetyl salicylate) block to reduce inflammation?

Answer 41

Cyclooxygenase pathway.

Question 42

What are leukotrienes?

Answer 42

The activities of leukotrienes are similar to those of histamine, but leukotrienes are much more potent than histamine and are principally responsible for the symptoms observed in the latter stages of allergic reactions. The effects mediated by leukotrienes include inflammation, smooth muscle contraction, airway constriction, and mucus secretion.