Hypersensitivity and allergy Flashcards
are allergies a kind of hypersensitivity?
yes
Definition of hypersensitivity
an overreaction to harmless molecules which results in an immune response that causes inflammation and tissue damage
what branches of the immune system are involved in hypersensitvity?
always adaptive and sometimes innate
allergy is a term often used for
type 1 hypersensitivity reactions
type 2, 3 and 4 hypersensitivites play a role in …?
autoimmune diseases and transplant rejection
What do Th2 cells fight?
helminths and cause allergies
they help the eradication of parasitic helminths that cause the expression of Il-4 (converts naive T cells to Th2)
what does Il-4 do to naive t cells?
causes differentiation into Th2 cells
what does Il4 do to B cells?
causes them to class switch
name 2 kinds of cell that produce Il-4 and Il-5
Th2 and APC’s
action of Il5
much like Il-4, induces the produciton of eosinophils.
Produced by Th2 and APCs
forms of allergens
inhaled- dust mite faeces, plant pollen
injected- insect venom, drugs
ingested- peanuts, shellfish
contact- plant oil, metal
many allergens share ___ with pothogen antigens
a molecular component
2 most common allergens
pollen - respiratory tract entry causing wheezing, sneezing and mucous production
peanuts- ingested and absorbed into blood stream causing systemic oedema and vasoconstriction and anaphylaxis
normal function of IgE
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
name 3 cells involved in type 1 hypersensitivity
mast cells
eosinophils
basophils
mast cells in type 1 hypersensitivity
- 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
eosinophils
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)
Basophils
- 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
Type 1 hypersensitivity- 1st exposure to harmless antigen
- Allergen is picked up by an antigen presenting cell (e.g, dendritic)
- Allergen is taken to lymph node
- 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
- Plasma cell will then produce lots of IgE
- IgE specific to that allergen then binds to Fc Receptors (usually FcσR1) on mast cell surfaces
- Allergen is then cleared from the body- mainly through IgE
Type 1 hypersensitivity- 2nd exposure to harmless mediators
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
mast cell mediators
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
Allergen dose and route (4) of exposure is linked to the reaction
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
Allergy test
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
Asthma general hypersensitivty facts
Involves more than type 1 hypersensitivity
Can have early and late hypersensitivity reactions
Airway becomes hypersensitive to many non-specific triggers (inc. cold air)
Immediate phase of asthma reaction
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
Late phase asthmatic reaction
- 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
Why do we overreact to certain antigens
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
Hygiene hypothesis of hypersensivity
- 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
Developing countries // factors for non-allergic
Large family size
Rural homes, livestock
Intestinal microbiotia more variable
Low antibiotic use
Poor sanitsation
Atopy
- “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
Some of the genes involved in atopy (chromosome 5, 6 and 11)
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
Type II hypersensitivity mechanism of incompatible blood transfusion
- 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
Type II hypsensitivity
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
Type 3 hypersensitivity
- 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.
Serum sickness
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
Type III hypersensitivity mechanism
- 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
Type IV hypersensitivity
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
Delayed type hypersensitivity reactions
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
Allergic contact dermatitis
Type IV hypersensitivity
Actication of CD4 and CD8 cells by highly reactive small molecules (haptens)
- ReactIve molecule binds as a hapten to an endogenous protein
- This is recognised and taken up by Langerhans cells
- Peptides are recognused by T helper cells which secrete IFN gamma
- Keratinocytes are activated and secrete proinflam cytokines and chemokines
- 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
Transplant rejection
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.
Graft vs host disease
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
Adrenaline (epinephrine)
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
