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Unit 13 > Hypersensitivity and Allergy > Flashcards

Hypersensitivity and Allergy Flashcards

1
Q

What is a hypersensitivity reaction?

A

An immune response, that is an overreaction to a harmless substance which causes inflammation and tissue damage.

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2
Q

What are the different types of hypersensitivity?
What is similar about them all?

A

Classified at I to IV
All contain components of the adaptive immune system.

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3
Q

What conditions tend to show a type 1 hypersensitivity reaction?

A

Allergic rhinitis
Allergic asthma
Eczema

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4
Q

What conditions tend to show a type II hyper sensitivity reaction?

A

Some drug allergies
Chronic urticaria

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5
Q

What conditions tend to show a type III hypersensitivity reaction?

A

Serum sickness (aka antibodies against anti-venom plasma)
Arthus reaction (after a vaccination)

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6
Q

What conditions tend to be type IV hypersensitivity reactions?

A

Macrophages activation - allergic contact dermatitis
Eosinophil activation - chronic asthma, chronic allergic rhinits
Cytotoxicity - graft rejection, allergic contact, dermatitis to poison ivy.

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7
Q

Basic terms
What is a type 1 hypersensitivity response?

A

IgE major player
Binds to soluble antigens - forms immunecomplex
Results in mainly mast cell activation (normally an anti-parasitic response) - degradation has rapid and delay immune/inflammatory response to harmless antigen.

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8
Q

Basic
What is a type 2 hypersensitivity reaction?

A

Characterised by IgG
IgG binds to cell bound antigen.
Mimics anti-bacterial response against a harmless antigen.
Results in complement and phagocytes activation

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9
Q

Basic
What is a type 3 hypersensitivity reaction?

A

Characterised by IgG
Binds to soluble antigen - form a immune complex
Activates complement and phagocytes.

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10
Q

Basic
What are the different types of a type 4 hypersensitivity reaction?

A

Cell mediated - triggered by soluble or cell bound antigens
A. Macrophages activation by Th1
B. Th2 activate eosinophils
C. Cytotoxicity.

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11
Q

What is the normal function of IgE?

A

Removal of extracellular parasites, particularly multicellular helminths, too large to be phagocytosed.
Carries out this response by binding to receptors on surface of mast cells, eosinophils and basophils (granulocytes).

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12
Q

What are the normal effects of IgE response in different areas of the body?

A

Respiratory tract - sneezing, coughing, increased mucus flow
Skin - itch induced scratching
Gastrointesinsal tract - vomiting, diarrhoea
These are all physiological to help remove parasites from the body.

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13
Q

Where are mast cells mostly found?

A

Tisse resident cells
Mainly in mucosal tissues near body surfaces
Connective tissue near blood vessels

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14
Q

What is the role of a mast cell in a hypersensitivity response?

A

Express Fc epsilon receptor on surface
Binds to constant region of IgE
Leads to mast cell with mainly surface bound IgE, with a range of specificities awaiting activation.
When IgE antigen binds - IgE crosslikned - signalling complexes brought together - activates the mast cell to degranulate.

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15
Q

What are some of the mediators released from mast cells?

A

Enzymes - carboxypeptidase
Amines - histamine
Proteoglycan - heparin
Cytokines - TNF alpha
Chemokines - CCL3
Lipid mediators - platelet activating factor, Prostaglandins and leukotrienes

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16
Q

What is the role of enzymes released by mast cells?

A

Are preformed in granules
Includes tryptase, chymase, cathepsin G, carboxypeptidase
Help remodel connective tissue - remove parasite bound in connective tissue - also damage proteins on the surface of the parasite.

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17
Q

What is the role of amines released by mast cells>

A

Are preformed in granules
Includes histamine
Increased vascular permeability and vasodilation, causes smooth muscle contraction (in bronchioles) - aids wound healing.

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18
Q

What is the role of cytokines produced by mast cells?

A

Some are preformed in granules such as TNF-alpha - this promotes inflammation, activation of multiple types of leukocytes and activated endothelium - so increased permeability

Some are synthesised during allergic reaction
IL-4, IL-13 - stimulate and amplify Th2 responses
IL-3, IL-5. GM-CSF - promote eosinophil production and activation

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19
Q

What is the role of chemokines produced by mast cells?

A

Are synthesised during the allergic reaction
CCL3, CXCL8 - attract monocytes, macrophages and neutrophils

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20
Q

What is the role of lipid mediators produced by mast cells?

A

Synthesised during the allergic reaction
Prostglandins D2, E2 - increase vascular permeability
Leukotrienes C4, D4 and E4 - smooth muscle contraction and mucus secretion.
Platelet activating factor - recruit and activate leukocytes, amplify lipid mediates, activates neuts, eosin and platelets.

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21
Q

What is the basic role of eosinophils involved in type 1 hypersensitivity reactions?

A

Present in small numbers in the blood
Found in connective tissue under mucosal surfaces
Have recepros for IgE on surface
Contain preformed toxic mediators in granules which are released when receptor crosslinking occurs.
Can also secrete cytokines - contribute to an inflammatory response.
Mainly associated with parasitic or hypersensitive responses.

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22
Q

What pre-formed toxic mediators do eosinophils contain?
What do they do>

A

MBP - major basic protein - mainy roles - damage cell membrane to increase permeability, stimulate masts to release histamine, increase superoxide formation in alveolar macrophages
ECP - eosinophil cationic protein - cytotoxic and non-cytotoxic activity.

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23
Q

What activates eosinophils in a type 1 hypersensitivity reaction>

A

Th2 cells
- secrete cytokines (IL-5) that promotes development and survival of eosinophils
- stimulates activated endothelial and epithelial cells to release chemokines (eotaxin) to recruit eosinophils to site of inflammation
Eosinophils give a later response than masts.

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24
Q

What is the role of basophils in a type 1 hypersensitivity reaction?

A

Are minor numbers in peripheral blood and not normally found in peripheral tissue
Can be recruited to site of inflam and activates by PAMPs, cytokines, lipid mediator and IgE.
Express Fc epsilon receptor - degranulate on crosslinking of receptors.
Release histamine
Release cytokines such a IL-4 and IL-13 may initiate Th2 response
May help B cell switch to produce IgE.

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25
Q

In a type 1 hypersensitiviy reaction what in basic terms happens on initial exposure to an harmless antigen?

A

Allergen enters the body - mainly invades mucosal surfaces
Antigen is picked up and presented on a PAPC
In lymph node Activated T and B cells respectively, activated B cell undergoes class switching to IgE.
Plasma cell produced IgE becomes bound to Fc epsilon receptor on the surface of mast cells.
Allergen has normally gone so not activated.
This is known as sensitisation

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26
Q

Why is the antigen normally gone at the end of the sensitisation phase of hypersensitivity reactions?

A

Allergen is gone
Is potentially a combination of factors
Only present originally in small number, can be cleared by innate pathways whilst the adaptive immune response takes longer to produce IgE antibodies, by time IgE produced antigen has been cleared.

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27
Q

What happens in the second exposure to an antigen in a type 1 hypersensitivity reaction?

A

The antigen binds to an crosslinks IgE found on mast cell surface, brings signalling machinery together - strong activation signal.
Mast cell is activated and degranulates immediately.
Granule content - cause vasodilation and increased vascular permeability.

28
Q

What allergen properties affect the type of reaction seen clinically in a hypersensitivity scenario?

A

The dose of the antigen - influence severity
The route of expose - influence type of symptoms.

29
Q

What are the different routes of exposure to an allergen?

A

Intravenous
Subcutaneous
Inhalation
Ingestion.

30
Q

What features are seen in a response to an intravenous allergen?

A

Systemic response
Release of histamine - increase blood vessel permeability
Anaphylatic shock

31
Q

What features are seen in a response to a subcutaneous allergen?

A

Local release of histamine causes odema and reddening of the area
Typical wheal and flare reaction
Wheal - inc permeability fluid into surrounding tissue
Flare - inc vasodilation of bv causes redness.

32
Q

What features are seen in a response to a inhaled allergen?

A

In upper airways - nasal irritation and increased mucus production

In lower airways - contraction of smooth muscle and increased mucus production

Present as runny nose, bronchoconstriction.

33
Q

What does a hypersensitivity reaction from ingestion of an allergen tend to present?

A

Contraction of smooth muscle.
Increased fluid loss from inc permeability of GIT barrier
Antigen may enter the bloodstream if absorbed from the gut.

Results in diarrhoea, urticaria, atopic eczema and anaphylaxis.

34
Q

What type of hypersensitivity reaction is allergic asthma?

A

Type 1 hypersensitivity reaction.
Airway becomes hypersensitive to many non-sepcific triggers - including cold air, pollutants, dust etc.

35
Q

What happens within the immediate response in allergic asthma?

A

Mast cells already sensitised
Within 30 mins exposure - mast degranulate
Cause increased blood vessel permeability.
Mast cell cytokines release:
IL 4 and IL13 - Th2 response and mucus production
IL-3 and IL-5 - eosinophil production and recruitment
Histamine - causes smooth muscle contraction, increased vascular permeability and increased mucus production.
Leukotrienes - slightly delayed synthesis - promote smooth muscle contraction and increased vascular permeability.

36
Q

What happens in the later response in allergic asthma?

A

The late phase - beings within 12 hours - mediators are synthesised de novo and recruited cells take action to further damage tissue, promote inflammation and mucus production.
Eosinophils are activates by Th2 producing IL-5 - produce type 2 cytokines, enzymes, toxins and leukotrienes - this damages the airway.
Th2 cells - stimulate mucus production, recuit eosinophils, trigger fibroblasts to synthesise collagen
Smooth muscle cells constrict narrowing the airway as a chronic response.

37
Q

Why is the body predisposed for an allergic reaction against allergens?

A

*Most multicellular parasites infect through skin and mucosal tissue - hence distribution of mast cells - means tissue is predisposed to Th2 responses due to content of enviro.

Parasites can use proteases to end body - we have allergic reactions where proteases are the allergens (similar structure??)

Response mimics anti-parasitic response - must be expelled by muscle contraction and enzymatic breakdown

*Many allergens are soluble in mucosa and present as low doses - favours Th2 over Th1 response.

  • = key ideas.
38
Q

What is the hygeine hypothesis related to hypersensitivity reactions?

A

Westernized countries suffer more from hypersensitivity diseases because of increased hygiene, good sanitation, low oral faecal burden, smaller family size, urban environments - less exposure to antigens

Whilst developing countries - larger family sizes, rural lise style, more transiet intestinal microflora, low antibiotics, lots of parasite and poor santiation for high oral feacal burden - suffer less from allergens.

Due to inc early childhood immune response - causes a shift from Th2 to TH1 responses, reduces IgE production.

39
Q

What is meant by atopy in terms of allergic reactions?

A

A tendency to develop allergic diseases
40% of caucasians are atopic - have higher levels fo IgE and eosinophils in their blood.
Has a strong genetic link - polymorphisms predispose to allergic reactions.

40
Q

What genetics predispose someone to be atopic? (inc risk of allergens)

A

Polymorphisms on chromones 5 (mainly), also 6 and 11
MHC II - enhanced presentation of allergen peptides.
IL-4R - increased signalling from IL-4
IL-4 - variation in IL-4 expression
Fc epsilon receptor - IgE binding
Cluster of cytokines genes including IL-3,4,5,13 on chromonse 5 - increase responsiveness.

41
Q

What are the two methods of initiating a type 2 hypersensitivity reaction?

A

IgG antibodies involved
Intrinsic - antibodies bind to self antigen on cell surface
Extrinsic - antibodies bind to neo-antigen or foreign antigen bound to a cell surfaces

42
Q

What is a good example of a type 2 hypersensitivity reaction?

A

The response to an ABO-incompatible blood transfusion.

For example O patient given A- blood.
Pre-existing A IgG antibodies exist in recipient circulation - bind to antige expressed on rbcs, agglutainates donor rbcs.
Bound antibody activates complement causing inflammation.
Also triggers phagocytosis of the opsonised cell/lysis of cell - through action of complement

43
Q

What are the different pathways of a type 3 hypersensitivity response?

A

Local or systemic depending on site of antigen exposure.
IgG Antibodies bind to soluble antigen and form clumps - immune complexes
May be a foreign antigen - injected anti-venom (eventually removed so self limiting)
May be a self antigen cause autoimmunity - SLE

44
Q

What is the mechanism underpinning SLE?

A

Is a type 3 hypersensitivity reaction
DNA released from damaged cells, DNA acts as antigen
Bound to by IgG
Small immune complexes circulate in the body and deposit in highly vascularised areas.
Postivly charged immune complexes are attracted to the negatively charged basement membrane
Immune complexes activate complement - results in inc vascular permeability nad phagocytes recruitment
Inflammation is triggered, phagocytes take up immune complexes and ROS are produced.
Causes vasculitis.

45
Q

What are the features of all type 4 hypersensitivity reactions?

A

Mediated by antigen-specific T cells.
Are CD4+ helper T cell-dependent and may involve CD8+ cytotoxic T cells

46
Q

What are the different types of Type 4 hypersensitivity response?

A

Delated-type hypersensitivity response
Contact hypersensitivity

47
Q

What is delated type hypersensitivity response? (DTH)

A

Results from activation of T cells in a sensitised individual to the antigen, antigen is unusually resistant to elimination from the immune system.
Antigen specific
CD4+ cells release cytokines to bring about response when exposed to antigen.
Th1 - produced INFy - destroy tissue, pathogens and promote inflammation
Th17 may also be involved - produced INFy
Response occurs 24-48 hours after antigen challenge
Frequently used in diagnostic test methods to confirm previous infection
Is a type 4 hypersensitivity response

48
Q

What antigen does a delayed-type hypersensitivity syndrome normally react against?
What are the normal physiological effects?

A

Reacts against proteins - such as insect venom and mycobacterial proteins

Effect - local skin swelling
Erythema, cellular infiltrate and dermatitis.

49
Q

What is a contact hypersensivitiy syndrome (CHS)?

A

Mediated by CD8+ cells.
Activates of CD4+ and CD8+ T cells by small molecules called hapten which penetrate the skin intact and change the appearance of antigens (cause cryptic antigens) that can then be presented on MHC molecules.

50
Q

What antigens do contact hypersensitivity reactions tend to be against?

A

Antigens tend to be haptens such as poison Ivy or Dinitroflurobenze, alternatively small metal ions such as nickel or chromium.

51
Q

What is the normal physiological response in a contact hypersensitivity reaction?

A

Triggers a local epidermal reaction
Results in erythema, cellular infiltrate, vesicles (small fluid filled blisters on the skin) and intraepidermal abscesses.

52
Q

Give an example and the mechanism underpinning a type 4 hypersensitivity - delayed type hypersensitivity reaction.

A

Used in tuberculin (mantoux) test for latent TB infection
Antigen is given subcutaneously, taken up and presented on MHC by PAPCs.
CD4+ memory cells cells are recruited and recognise the antigen
Cytokines are secreted and act on the vasculature
Phagocytes are recruited to the tissue, fluid leaks into tissue causing oedema.
Inflammatory cytokines, NO and ROS are produced in the tissue
Causes redness and swelling.
Positive response within 24 -72 hours indicates previous infection with the antigen.

53
Q

What is the mechanism underpinning allergic contact dermatitis?

A

For example poison ivy
Reactive molecule is taken up - acts as a hapten binding to an endogenous proteins - changing its shape
Recognised and taken up by Langerhan cells in the epidermis
Peptides are recognise by CD4+ cells and secrete IFNy.
Keratinocytes are activates and secrete pro-inflammatory cytokines and chemokines.
Activates macrophages.
Macrophages cause further inflammation and release NO.

54
Q

How does posion Ivy activate Allergic Contact dermatitis?

A

Poison Ivy contains Urushiol
Crosses the cell membrane and is chemically modified becoming a hapten
It binds o intracellular proteins making neo-antigens, which can then elecit a T cell response, including CD8+ cytotoxic T cells.

55
Q

What are the three different types of hypersensitivity response within transplant rejection?

A

Hyperacute - type 2 response
Acute - type 4 response
Chronic - type 4 response

56
Q

What is the hyperacute hypersensitivity response in transplant rejection?

A

Hyperacute - type 2 response.
Immediate caused by pre-existing antibodies, for example mismatched blood group donation (anti A/B antibodies already in recipient circulation)

57
Q

What is the acute hypersensitivity response in transplant rejection?

A

Type IV response
Takes weeks or months to occur
Caused by T cell response
Donor MHC migrates to recipient lymph node - activates recipient T cell - MHC mismatching***
Can be reversible and is easier to treat with immunosuppressants

58
Q

What is the chronic hypersensitive response in transplant rejection?

A

Type IV response
Takes months or years to occur
Caused by a T cell response.
Recipient T cell migrates into donor organ, takes up and presents donor antigen to the recipient.
Is harder to treat, can cause fibrosis and vascular changes in transplanted organ - so no longer functional.

59
Q

What is the role of major histocompatibility complexes in transplant rejection?

A

Major HC - expressed by all nucleated cells.
T cell receptors recognise peptide and MHC complexes.
We contain different other antigens to other people, which can be presented on MHC, hence all people receiving an organ transplant must receive anti-rejection drugs.

60
Q

What is a minor histocompatibility antigen?

A

Are not Major histocompatability complexes
Are presented on MHC - can cause organ rejection even when MHC is identical
Can active a transplant rejection - tend to be normal polymorphic self (donor) proteins presented on recipient MHC
Result in slower rejection or the donated organ.

61
Q

What is an alloantigen?

A

Antigens which differ between members of the same species (polymorphic gene) capable or inducing the production of alloantibodies and an immune response.

62
Q

What is direct recognition in terms of organ transplant rejection?

A

Donors APC in the graft migrate to the lymph nodes and stimulate auto-reactive T cells
(Recipient T cells react against foreign MHC molecule on donor)

63
Q

What is indirect recognition in terms of organ transplant rejection?

A

Recipient APCs take up and process proteins from the graft and present them
Is alloantigen can cause immune response and tissue/organ rejection.

64
Q

What is meant by graft v host disease?

A

When mature lymphocytes in the graft/donated tissue can attack the recipient tissue (alloantigens).
Most common in scenarios where the host is immunosuppressed so unable to hold own immune response against the graft.

65
Q

What transplant is Graft v Host disease most common in?
What happens?

A

Most common after a haematopoietic stem cell transplantation
Used in treatment of leukaemia, lymphomas and primary immunodefiecicnets
Donor cells are taken from peripheral cord blood or bone marrow
The recipient bone marrow is partial or fully ablated - so immunocompromised
A mismatch of major or minor histocompatibility antigens results in graft tissue targeting the host tissue as mature immune cells in graft

66
Q

How does graft v host disease in a haemopoetic stem cell transplant present?

A

Skin damage
Liver damage
GIT damage
Rash, jaundice, diarrhoea and GIT hemorrhage.

Unit 13 (22 decks)

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