Hypersensitivity and allergy

Question 1

are allergies a kind of hypersensitivity?

Answer 1

yes

Question 2

Definition of hypersensitivity

Answer 2

an overreaction to harmless molecules which results in an immune response that causes inflammation and tissue damage

Question 3

what branches of the immune system are involved in hypersensitvity?

Answer 3

always adaptive and sometimes innate

Question 4

allergy is a term often used for

Answer 4

type 1 hypersensitivity reactions

Question 5

type 2, 3 and 4 hypersensitivites play a role in …?

Answer 5

autoimmune diseases and transplant rejection

Question 6

What do Th2 cells fight?

Answer 6

helminths and cause allergies

they help the eradication of parasitic helminths that cause the expression of Il-4 (converts naive T cells to Th2)

Question 7

what does Il-4 do to naive t cells?

Answer 7

causes differentiation into Th2 cells

Question 8

what does Il4 do to B cells?

Answer 8

causes them to class switch

Question 9

name 2 kinds of cell that produce Il-4 and Il-5

Answer 9

Th2 and APC’s

Question 10

action of Il5

Answer 10

much like Il-4, induces the produciton of eosinophils.

Produced by Th2 and APCs

Question 11

forms of allergens

Answer 11

inhaled- dust mite faeces, plant pollen

injected- insect venom, drugs

ingested- peanuts, shellfish

contact- plant oil, metal

Question 12

many allergens share ___ with pothogen antigens

Answer 12

a molecular component

Question 13

2 most common allergens

Answer 13

pollen - respiratory tract entry causing wheezing, sneezing and mucous production

peanuts- ingested and absorbed into blood stream causing systemic oedema and vasoconstriction and anaphylaxis

Question 14

normal function of IgE

Answer 14

gets rid of multicellular parasites which are too large to be phagocytosed

respiratory tract- sneezing, coughing, increased mucous flow

Skin- itch induced scratching

GI tract- vomiting, diarrhoea

Question 15

name 3 cells involved in type 1 hypersensitivity

Answer 15

mast cells

eosinophils

basophils

Question 16

mast cells in type 1 hypersensitivity

Answer 16

• have Fc receptors (bind to constant region antibodies) all over its surface (in particular the Fc epsilon R1 receptor
• one mast cell can bind to different IgEs which recognise different antigens
• Release histamine (extremely cytotoxic) and other mediators
• Tissue resident cells are found predominantly in mucosal tissues near the surface and in CT near blood vessles

Question 17

eosinophils

Answer 17

have IgE receptors

highly toxic response

number of eosinophils increased by Th2 cells (Il4, 13 and 5)

small number in blood, resident to CT and mucosa

can synthesise cytokines (IL4, 5)

contain preformed mediators (enzymes in their granules that can breakdoen DNA)

Question 18

Basophils

Answer 18

• possibly initiate Th2 responses by secreting IL-4 and IL-13 at the beginning of the immune response
• recruited during infections and activated by TLRs
• can help switch B cells to IgE production

Question 19

Type 1 hypersensitivity- 1st exposure to harmless antigen

Answer 19

1. Allergen is picked up by an antigen presenting cell (e.g, dendritic)
2. Allergen is taken to lymph node
3. Allergen is presented to T cells in combination with Il-4 and 5 which help activate B cells to produce IgE. Basophils may help initiate these Th2 interactions with B cells by secreting IL4+5, converting naive t cells to Th2
4. Plasma cell will then produce lots of IgE
5. IgE specific to that allergen then binds to Fc Receptors (usually FcσR1) on mast cell surfaces
6. Allergen is then cleared from the body- mainly through IgE

Question 20

Type 1 hypersensitivity- 2nd exposure to harmless mediators

Answer 20

Allergens bind to the variable region of IgE on mast cells

Cross linking of multiple IgE molecules which enhances signalling into mast cells

Mast cell releases its granule contents which have immediate effect

Question 21

mast cell mediators

Answer 21

Enzyme- tryptase- remodelling of connective tissue

Toxic mediator- histamine- poison parasites, increase vascular permeability

Cytokine- TNF-à - promotes inflammation

Cytokine- Il-4- stimulates and amplifies Th2 responses

Cytokine- Il-3- promotes eosinophil production and activation

Chemokine- CCL3- attracts innate immune cells

Lipid mediator- platelet activating factor- attracts leukocytes, activates neutrophils

Question 22

Allergen dose and route (4) of exposure is linked to the reaction

Answer 22

Intravenous- histamine casues systemic increase in blood vessel permeability→ systemic anaphylatic shock

Subcutaneous → local release of histamine causes oedema and reddening of the area → wheel and flare reaction

Inhalation→ upper airway (increased mucous production irritates nasal) lower airways (contraction of smooth muscle and increased mucous)

Ingestion → contraction of lung sm muscle, increased fluid loss, antigen enters blood vessel → atopic eczema, anaphylaxis

Question 23

Allergy test

Answer 23

performed in an allergy clinic

receive a small skin prick for a list of suspected allergens that you may be allergic to

look for subcutaneous wheel and flare reaction for allergic reaction

Question 24

Asthma general hypersensitivty facts

Answer 24

Involves more than type 1 hypersensitivity

Can have early and late hypersensitivity reactions

Airway becomes hypersensitive to many non-specific triggers (inc. cold air)

Question 25

Immediate phase of asthma reaction

Answer 25

Mast cells activate

increase blood vessel permeability

Cytokine secretion (Il-4,13 - mucous secretion and Th2 recruitment)

(Il-3, 5 eosinophil production and recruitment)

Leukotrienes produced causing smooth muscle contraction and increased vessel permeabilty

Question 26

Late phase asthmatic reaction

Answer 26

• Synthesised mediators are released from mast cells and further recruitment of cells leading to more tissue damage and mucous production
• Smooth muscle cell- thickening of smooth muscle causes thr airways to constict
• Collagen synthesised by fibroblasts

Question 27

Why do we overreact to certain antigens

Answer 27

Cross-reactivity between adaptive immune cells and parasite/allergen antigens

Multicellular parasites infect through skin and mucosal tissues, so these areas are predisposed as Th2 environments

Allergens are soluble in the mucosa and present at relatively low doses. Low antigen doses favour Th2 iver Th1

Parasitic worms use proteases to access the body and we respond to several proteases as allergens e.g., DERP 1 in faeces of dust mites

Question 28

Hygiene hypothesis of hypersensivity

Answer 28

• Suggests that allergy incidence is present where parasites have been eliminated
• In the West in our recent history sanitisation of food and water, increased hygiene and medical advances have caused allergies and autoimmunity to increase

Question 29

Developing countries // factors for non-allergic

Answer 29

Large family size

Rural homes, livestock

Intestinal microbiotia more variable

Low antibiotic use

Poor sanitsation

Question 30

Atopy

Answer 30

• “genetic tendency to develop allergic diseases”
• 40% in europe
• Suggests that you have a genetic background or group of polymorphic genes that predispose you to allergy
• Individuals have high IgE and eosinophils present in blood

Polymirphic genes are often on chromosome 5, 6 and 11

If you are atopic in a hygienic environment you’re even more likley to develop allergies

Question 31

Some of the genes involved in atopy (chromosome 5, 6 and 11)

Answer 31

MHC II- enhanced presentation of allergen peptides on APCs

Chain of TCR- enhanced recognition of allergen peptiodes

IL-4 receptor- increased signalling from Il-4

Il-4 - variation in Il-4 expression

FCσRI- IgE binding

On chromosome 5 there is a cluster of genes for Il4, 5 etc. all involved in isotype switching, eosinophil survival and mast cell proliferation

Question 32

Type II hypersensitivity mechanism of incompatible blood transfusion

Answer 32

• Patient who has O+ is given A type blood in a transfusion
• Antibodies towards the A antigen cause agglutination of the cells
• This can initiate complement deposition and inflammation
• Macrophages will recognise the antibodies bound to the cells and phagocytose them

Question 33

Type II hypsensitivity

Answer 33

Linked to igG

IgG antibodies bind to cellular or extra cellular matrix antigens causing destruciton of cell.

there are 2 ways which this can be initiated:

• Intrinsic-* antibodies to an antigen which we normally make
• Extrinsic*- something from outside e.g., an infection or drug that attaches

Example is an incompatible blood transfusion

Question 34

Type 3 hypersensitivity

Answer 34

• Can be local or systemic, depending on the site of exposure
• Preformed antibodies recognise and react to an antigen and form clumps (complexes)
• Serum sickness
• Reaction to a slef antigen can casue autoimmunity e.g., SLE systemic lupus erythamatous

occurs when there is accumulation of immune complexes (antigen-antibody complexes) that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. Such reactions may progress to immune complex diseases.

Question 35

Serum sickness

Answer 35

Systemic reaction to ingested foreign antigen e.g., anti-venom and occasionallu therapeutic monoclonal antibodies

Antigen in serum sickness is removed and is slef limiting

Question 36

Type III hypersensitivity mechanism

Answer 36

• Antibodies bind to the antigen
• Small complexes circulate in the body and deposit in the highly vascularised areas.
• Positively charged complexesa re attracted to the negaively charged basement membrane
• Deposited complexes are recognised by the complement which results in vasodilation and chemotaxis
• Phagocytes attempt to clear the complexes and induce inflammation
• Neutrophils release ROS

Question 37

Type IV hypersensitivity

Answer 37

Mediated by antigen specific T cells reacting just as they would do to a pathogen

CD4 T cell dependant

Delayed as it takes time for antigens to be chopped up and presented

Involves

a) delayed type hypersensitivity reactions
b) allergic contact dermatitis
c) transplant rejection

AIDS as decline in CD4 cells

Question 38

Delayed type hypersensitivity reactions

Answer 38

Type IV hypersensitivity

Mediated by antigen specific T cells which have been previously sensitised to the allergen e.g., tuberculin (mantoux) test for latent TB

takes 24-72 hours

• antigen is injected into the sucutaneous tissue, taken up and presented
• T helper effector cells are recruited and recognise the antigen, producing cytokines which act on the vasculature
• Causes recruitment of phagocytes and oedema.
• High levels of inflammatory cytokines, nitric oxide and oxygen radicals

Question 39

Allergic contact dermatitis

Answer 39

Type IV hypersensitivity

Actication of CD4 and CD8 cells by highly reactive small molecules (haptens)

1. ReactIve molecule binds as a hapten to an endogenous protein
2. This is recognised and taken up by Langerhans cells
3. Peptides are recognused by T helper cells which secrete IFN gamma
4. Keratinocytes are activated and secrete proinflam cytokines and chemokines
5. Cytokines from keratinocytes and T cells activate macrophages further causinf inflammation and macrophages release NO

Haptens means that self-proteins are modified, meaning that innate and adaptive immune system react to self-proteins

Question 40

Transplant rejection

Answer 40

Hyperacute (immediate) reaction- type II preformed antibodies eg mismatched blood donation

Acute- Type IV T cell mediated immune response

Chronic- type IV t cell mediated

Polymorphic slef-proteins presented on the MHC can be recognised as forighn. These are more slowly rejected

Direct recognition- donor APCs in the graft migrate to the lymph nodes and stimulate autoreactive T cells

Indirect recognition- ecipient APCs take up and process proteins from the graft and present them.

Question 41

Graft vs host disease

Answer 41

Transplantation of haematopoietic stem cells from donor peripheral blood, bone marrow or foetal cord blood is used to treat diseases.

These include tumours such as leukaemias and lymphomas and also primary immunodeficiency diseases.

For this to work, the recipients bone marrow must be destroyed by irradiation and chemotherapy.

However, mature lymphocytes in the HSc graft can atatck the recipeint tissues causing damage to skin, intestines and liver

Question 42

Adrenaline (epinephrine)

Answer 42

Most important drug for treating an anaphylactic reaction

Alpha-receptor agonist → reverses peripheral vasodilation and reduces oedema

beta-receptorn activity dilates the bronchial airways, increases the force of myocardial contraction and suppresses histamine and leukotriene releasae