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M1 Immunology > Hypersensitivity > Flashcards

Hypersensitivity Flashcards

1
Q

What is a hypersensitivity response?

A

A immune response that is exaggerated/inappropriate rxn harmful to the host

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2
Q

How many types of hypersensitivity are there?

A

4

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3
Q

What is an allergen?

A

An antigenic molecule that can elicit an allergic response in an atopic individual

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4
Q

What are the 2 main reasons for atopy in an atopic individual?

A

1) Genetic
2) Environment

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5
Q

What is Type 1 hypersensitivity?

A

IgE and mast cell mediated (“A for allergic”) hypersensitivity rxn

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6
Q

What are the 2 phases of Type 1 hypersensitivity?

A

1) Immediate
- tissue dmg, smooth muscle contraction, dizziness

2) late phase
- inflammation

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7
Q

Why are there no symptoms when an atopic individual first encounters an allergen?

A

1st time sensitisation occurs
(Mast Cell FcεR1 do not have IgE bound to them)

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8
Q

What are the 4 steps of sensitisation in type 1 hypersensitivity rxn?

A

1) Allergen exposure
2) Activation of Th2 and Tfh
3) B cell isotype switching from IgM to IgE
4) IgE binds to FcεR1 on Mast cells, sensitising them

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9
Q

What happens in an atopic individual upon 2nd exposure to an allergen?

A

1) Allergens bind to IgE on FcεR1 on Mast cells
2) Causes the crosslinks of FcR which activates mast cells
3) Mast cells secrete mediators of (i) degranulation (ii) lipid mediators (iii) cytokines

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10
Q

Describe what is meant by IgE amplication?

A

Activated (post-sensitised) mast cells express (i) CD40L and (ii) secrete IL-4 which activates Plasma cells to produce more IgE, which sensitises more mast cells

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11
Q

Why is tissue damage prevalent in type 1 hypersensitivity?

A

IgE is predominantly localised in tissues

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12
Q

What is the late phase reaction in type 1 hypersensitivity?

A

a delayed inflammatory reaction due to:
i) continuous release of inflammatory mediators (eg. TNF-α, IL-4/5/13) by mast cells
ii) Recruitment of leukocytes

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13
Q

How can type 1 hypersensitivity progress to type 4?

A

Via T cell recruitment in the late phase reaction of type 1 hypersensitivity

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14
Q

What are some common examples of type 1 hypersensitivity reactions?

A

Local and systemic anaphylaxis
(eg. hayfever, asthma, hives, food allergies, eczema)

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15
Q

What are 3 main effects of FcR crosslinking upon allergen binding (in order of their occurrence)?

A

1) Exocytosis of pre-formed vasoactive amines and proteases in granules

2) Enzymatic modification of Arachidonic acid
- to secrete (i) prostaglandins →vascular dilation (ii) Leukotrienes → smooth muscle contraction

3) Transcriptional activation of cytokine genes → late phase inflammatory reaction

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16
Q

What is the main vasoactive amine released from mast cell degranulation in type 1 hypersensitivity?

A

Histamines

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17
Q

What are 3 effects of histamines?

A

1) dilation of small blood vessels
2) ↑vascular permeability
3) intestinal and bronchial smooth muscle contraction

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18
Q

What are 2 main proteases released in mast cell degranulation and what are their effects?

A

1) Tryptase
- cleave fibrinogen → activate collagenase

2) Chymase
- degrades epidermal basement membrane
- stimulate mucus secretion

BOTH cause local tissue damage

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19
Q

What are the functions of the 3 main lipid mediators secreted in the enzymatic modification of arachidonic acid in type 1 hypersensitivity reactions?

A

1) Prostaglandins
- vascular dilation and neutrophil chemotaxis

2) Leukotrienes
- prolonged smooth muscle contraction

3) Platelet activating factor
- bronchoconstriction

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20
Q

What are some cytokines/chemokines that are secreted in the late phase of type 1 hypersensitivity reactions upon transcriptional activation of cytokine genes?

A

1) TNF-α (activate endothelial cells)
2) IL-4/13 (Th2 activation)
3) IL-5 (activate eosinophils)

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21
Q

Explain the time differential between the 3 downstream effects of FcR crosslinking upon allergen binding.

A

1) Granules (proteases and histamine) are preformed and can be immediately exocytosed

2) Lipid mediator (leukotriene, prostaglandin and PAF) secretion is secondary to enzymatic modification which takes time

3) Late phase cytokine release is the slowest as the entire process from transcriptional activation to protein synthesis and release takes considerably longer than the rest (hours later)

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22
Q

What are some effects of mast cell activation?

A

1) GIT
- ↑ fluid secretion + peristalsis
→ diarrhoea/vomiting

2) Airways
- ↓lumen + ↑mucus secretion
→ congestion + mucus
→ wheezing, productive cough

3) Blood vessels
- ↑blood flow + permeability
→ ↑ fluid in tissues
→ ↑flow to lymph nodes, exudate, effector response in tissues

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23
Q

How can systemic anaphylaxis lead to anaphylactic shock?

A

↑ vascular permeability → ↓BP

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24
Q

What are 2 main factors determining the consequences of type 1 hypersensitivity reactions?

A

Dose and route of entry

25
Q

What are the possible routes of entry for allergens and examples of each?

A

1) Inhalation (pollen and dust-mite feces)
2) Oral (food allergies)
3) Intravenous/through skin (insect bites, venom, drugs)

26
Q

How are type 1 hypersensitivity reactions diagnosed

A

1) Clinically
- rapid onset, localised symptoms

2) Investigations
- Total IgE
- Specific IgE
- Serum tryptase (anaphylaxis)

27
Q

What is the treatment for anaphylaxis?

A

IM Epinephrine/Adrenaline
(non-selective adrenoceptor agonist)
- vascular + smooth muscle contraction
- ↑cardiac output to counter shock
- inhibits bronchial smooth muscle contraction

28
Q

How does Epinephrine help with anaphylaxis?

A

It is a non-selective adrenoceptor agonist:
- α: peripheral vascular + smooth muscle constriction
- ß1: ↑cardiac output to counter shock
- ß2: inhibits bronchial smooth muscle contraction

29
Q

What are possible treatments for bronchial asthma?

A

1) Corticosteroids (to ↓inflammation)

2) Leukotriene antagonists (relax bronchial smooth mucle and ↓inflammation)

3) Phosphodiesterase inhibitors (Relax bronchial smooth muscles)

30
Q

What are general treatments for allergic diseases?

A

1) Desensitisation (may induce T cell tolerance in chronic asthma)
2) Anti-IgE Abs
3) Antihistamines
4) Cromolyn (inhibits mast cell degranulation)

31
Q

When are corticosteroids best administered?

A

In the late phase rxn

32
Q

When are antihistamines best administered?

A

Initial response (< effective in late phase rxn)

33
Q

What is the similarity between type 2 and 3 hypersensitivity reactions?

A

They are both mediated by antibodies

34
Q

What is the difference between type 2 and 3 hypersensitivity reactions?

A

Abs in Type 2 HS bind to cell-bound Ags

Abs in Type 3 HS bind to free floating/circulating/soluble Ags to form immune complexes

35
Q

What are the 3 effector mechanisms in Ab-dependent hypersensitivity reactions?

A

1) Complement activation/Complement and FcR-mediated inflammation

2) Opsonisation and phagocytosis

3) Antibody Dependent Cell Cytotoxicity (ADCC)

36
Q

What is the process of complement mediated inflammation? *****

A

1) Ab binds to Ag
2) Ag-bound-IgM/IgG binds to C1→ activate complement system
3) C3a and C5a (pro-inflammatory complement by-products) recruit
4)

37
Q

How does complement/FcR-mediated inflammation cause tissue damage?

A

Via neutrophil enzymes and ROS

38
Q

How does opsonisation and phagocytosis occur in hypersensitivity reactions?

A

It occurs in type 2 and 3.
1) C1 binds to the Ab-Ag complex forming C3b → opsonises cells (marked for phagocytosis)

2) FcR on phagocytes bind to Ag + C3bR bind to C3b → enhanced phagocytosis

39
Q

How does ADCC occur in hypersensitivity reactions?

A

1) IgG bound to Ags on cell surface
2) NK cells recognise Fc of IgG
3) NK cells release granzyme and perforin → apoptosis

40
Q

What are 2 type 2 autoimmune hypersensitivity reactions?

A

1) Graves disease (AutoAg: TSH receptor → on Thyroid epithelial cells)

2) Myasthenia gravis (AutoAg: AChR → on NMJ)

41
Q

What type of hypersensitivity reaction occurs in Haemolytic disease of new-born (when a Rh- Mother carries a Rh+ child)?

A

Type 2

42
Q

What type of hypersensitivity occurs in Arthus reaction?

A

Local Type 3

43
Q

What type of hypersensitivity occurs in serum sickness, rheumatoid arthritis, necrotising vasculitis, SLE, etc.

A

Systemic Type 3

44
Q

What type of hypersensitivity reaction can occur upon vaccination?

A

Arthus reaction (local type 3)

45
Q

What are the possible treatments for antibody-mediated hypersensitivity reactions?

A

1) Corticosteroids (↓inflammation)
2) Plasmapheresis (↓circulating Abs/immune complexes)
3) IV IgG (compete w pathogenic Ab for FcR binding)
4) Anti-CD20 Ab (↓ B cells)
5) Anti-CD40/CD40L (inhibit Ab prod.)

46
Q

What is type 4 hypersensitivity?

A

It is a delayed T-cell response

47
Q

What are 2 main categories of antigens that can elicit a type 4 hypersensitivity response?

A

1) AutoAgs
2) Environmental Ags (eg. drugs, poison ivy, microbial proteins, etc.)

48
Q

What are the 2 effector mechanisms of type 4 hypersensitvity?

A

1) Cytokine-mediated inflammation
2) T cell-mediated killing of host cells

49
Q

What immune cells are involved in cytokine-mediated inflammation in type 4 hypersensitivity reactions?

A

Th1/2/17

50
Q

What immune cells are involved in T cell-mediating killing of host cells in type 4 hypersensitivity reactions?

A

CD8+ Tc cells

51
Q

How does cytokine-mediated inflammation occur in hypersensitivity reactions?

A

APC present Ag to CD4+ T cells which secrete cytokines to cause inflammation and tissue injury

Th1: Cytokines + IFN-y → M1 activation
Th2: Inflammatory mediators + Eotaxin/IL-5 → eosinophil activation/recruitment, IL-4 → IgE class switching
Th17: IL-17 → chemokines → neutrophil/monocyte recruitment

52
Q

Which cell(s) is responsible for hypersensitivity in contact dermatitis?

A

CD4+ Th1 in Type 4 HS
CD8+ Tc cells

53
Q

Which cell is responsible for hypersensitivity in tuberculin reaction in Tuberculin Skin Test?

A

CD4+ Th1 in Type 4 HS

54
Q

Which cell is responsible for hypersensitivity in chronic asthma?

A

CD4+ Th2 in Type 4 HS

55
Q

Which cell is responsible for hypersensitivity in chronic allergic rhinitis?

A

CD4+ Th2 in Type 4 HS

56
Q

Describe how a Tuberculin Skin Test can test for prior TB exposure.

A

Tuberculin PDD injected
→ processed by local APCs
→ recognised by memory Th1s → cytokines
→ vasodilation + macrophage recruitment
→ visible red lesion

(if process takes >72hrs → naive T cell activation/no prior TB infection)

57
Q

Describe how contact dermatitis may manifest as a hypersensitivity reaction.

A

1) Ag penetrates skins & binds to self proteins

2) Self proteins are taken up by Langerhan’s cells

3) Th1 recognise the Ag (hapten) on APC and secrete IFN-y and other cytokines

4) IFN-y activate keratinocytes which secrete cytokines (IL-1, TNF-α) and chemokines (CXCL8/9/11)

5) Products from both activated keratinocytes and Th1 activate macrophages to secrete pro-inflammatory mediators

58
Q

What are the possible treatments for type 4 hypersensitivity reactions?

A

1) Corticosteroids (↓inflammation)
2) TNF agonist (↓ inflammation esp in RA and IBS)
3) Anti-B7/cytokine receptor antagonists

59
Q

What drug class can be given for all types of hypersensitivity reactions?

A

Corticosteroids

M1 Immunology (9 decks)

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