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MEDSCI 314 > Lecture 23; Allergy and Hypersensitivity > Flashcards

Lecture 23; Allergy and Hypersensitivity Flashcards

1
Q

How do neutrophils contribute to hypersensitivity?

A
  • Particularly in type 2,3 hypersensitivity.
  • Has CR1 receptor, it can C3b, which can be on host cells or immune complexes
  • The result of binding can mean the neutrophil phagocytose or degranulates damaging the host tissue
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2
Q

How do basophils and eosinophils contribute to hypersensitivity?

A
  • Important in type One hypersensitivity reaction.
  • Have Fc receptors which antibody (or autoantibody) on host cell surface or AbAg complex(allergen antibody).
    = degranulation
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3
Q

How do (and monocytes?) macrophages contribute to hypersensitivity?

A
  • Have Fc receptors

- Once bound via Fc receptor they can ADCC, release enzyme products to kill cell

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4
Q

What are hypersensitivity reactions largely driven by?

A

Antibodies

There T cells, B cells and plasma cells are all important

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5
Q

How is the mast cell important in hypersensitivity reactions?

A
  • Important in the sensitisation stage of type one hypersensitivity
  • Have Fc(e) receptor, can bind to allergen specific IgE
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6
Q

Describe the relationship between leukocytes and Fc receptors;

A

There is differential expression of Fc receptors between different leukocytes

  • Different sensitivities
  • Mostly on innate cells
  • Tailors immune response to local environment
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7
Q

What are the two stages of hypersensitivity?

A
  • Sensitisation stage (first encounter of allergen or Ag)
  • Effector Stage (secondary encounter, this is quite different in atopic individuals who a predisposed to allergic reactions )
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8
Q

What are the alternative names for type one hypersensitivity?

A

IgE-mediated HS
Immediate HS
Allergy, atopy

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9
Q

What is the primary immune mediator of type 1 hypersensitivity?

A

Antibody (IgE)

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10
Q

What is the time to symptoms of type 1 hypersensitivity?

A

<1-30 min

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11
Q

What is the mechanism of type one hypersensitivity?

A

Allergens cross-link IgE bound on mast cells and basophils and induce degranulation

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12
Q

What are some examples of type 1 hypersensitivity?

A

Asthma, hay fever, aczema, hives, food allergies, anaphylaxis

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13
Q

What are the alternative names for type 2 hypersensitivity?

A

Direct Antibody-mediated Cytotoxic HS

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14
Q

What is the primary immune mediator of type 2 hypersensitivity?

A

Antibody (IgG or IgM)

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15
Q

What is the time to symptoms of type 2 hypersensitivity?

A

5-8 hr

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16
Q

What is the mechanism of type 2 hypersensitivity?

A

IgG or IgM bind to cell-bound antigen; cell is destroyed by phagocytosis, complement activation or ADCC

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17
Q

What are some examples of type 2 hypersensitivity?

A

Hemolytic anemias, Goodpasture’s syndrome

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18
Q

What are the alternative names for type 3 hypersensitivity?

A

Immune complex- mediated HS

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19
Q

What is the primary immune mediator of type 3 hypersensitivity?

A

Antibody (IgG or IgM)

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20
Q

What is the time to symptoms of type 3 hypersensitivity?

A

4-6 hr

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21
Q

What is the mechanism of type 3 hypersensitivity?

A

Immune complexes trigger complement activation; phagocyte FcR engagement leads to release of lytic mediators

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22
Q

What are some examples of type 3 hypersensitivity?

A

Arthus reaction, aspects of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)

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23
Q

What are the alternative names for type 4 hypersensitivity?

A

Delayed type HS Cell-mediated HS

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24
Q

What is the primary immune mediator of type 4 hypersensitivity?

A

Effector T cells, macrophages

25
Q

What is the time to symptoms of type 4 hypersensitivity?

A

24-72 hr

26
Q

What is the mechanism of type 4 hypersensitivity?

A

Effector T cells produce IFNg and other cytokines promoting macrophage hyperactivation

27
Q

What are some examples of type 4 hypersensitivity?

A

Lesions of TB and leprosy, poison ivy, farmer’s lung

28
Q

What are some common examples of type 1 hyp. allergens;

A

Bee venom
Shrimp
Dog dander
Peanut

29
Q

What are some common sites of allergic reactions?

A

Respiratory tract
Skin
Gut
Mutliple organs

30
Q

What are some examples of hyp. reactions in the resp tract;

A

Allergic rhinitis
Sinusitis
Asthma

31
Q

What are some examples of hyp. reactions in the skin;

A

Urticaria (weals)

Angioedma

32
Q

What are some examples of hyp. reactions in the gut;

A

Food allergy

33
Q

What are some examples of hyp. reactions in multiple organs

A

Anaphylaxis

34
Q

Describe the sensitisation stage of type one hypersensitivity;

steps 1-4

A
  1. Allergen breached mucosal barrier
  2. Phagocytosed by immature DC
  3. Travels to draining lymph node
  4. Can engage a Naïve T cells which recognise pMHC on mature DC and become activated, differentiate into Th2 effector cells that help activate B cells. Activated B and Th2 cells leave the lymph node.

It is believed that in an atopic individual the response varies as the lymph node environment is rich in IL4, which skews this to Th2 production.

35
Q

Describe the sensitisation stage of type one hypersensitivity;

steps 5-7

A
  1. Travel to where antigen entered body
  2. Th2 cells produce cytokines (IL 4,5,13) that instruct plasma cells to produce IgE
  3. IgE can bind directly to allergen or FceRs on mast cells. Mast cells are sensitised for the effector stage
36
Q

Describe the sensitisation stage of type one hypersensitivity;

steps 8-10

A
  1. Excess IgE taken up by lymphatics
  2. IgE encounters basophils in the blood and
    binds to FceRs to sensitise them
  3. IgE encounters mast cells in other tissues and binds to FceRs to sensitise them
37
Q

What is important at the end of the type one hyp. sensitisation stage?

A
  • lots of sensitised mast cells hanging around

- Also sensitised basophils that can be in circulation

38
Q

Describe the steps in the effector stage in type one hypersensitivity (EARLY PHASE) response;

A
  1. Allergen enters tissue where sensitised mast cells are present (second exposure)
  2. Allergen binds IgE molecules attached to mast cells via FceRs
    3/4. Mast cells degranulate and secrete cytokines/chemokines
  3. Breakdown of mast cells (they die) releases PAF
  4. tissue-specific symptoms of allergic response
  5. Additional leukocytes recruited (e.g. eosinophils and sensitised basophils)
39
Q

What are the factors that mast cells release in type one hyp. (EARLY PHASE)response?

A

Pre-formed

  • Histamine
  • Serotonin
  • Proteases
  • Chemotactic factors

Newly formed
- Chemokines, cytokines, growth factors

PAF (platelet activating factor)
- Leukotrienes and prostaglandins

40
Q

Describe the first two steps of the late stage hyp. type one effector response;

Steps 1-4

A
  1. Recruitment of leukocytes
    2/3/4. Th2 effector cells, activated mast cells and basophils produce cytokines that promote eosinophil recruitment and activation of eosinophils
41
Q

Describe the first two steps of the late stage hyp. type one effector response;

Steps 5-6

A
  1. Cross-linking of Ig-bound FcRs with allergen results in the release of mediators from eosinophils and basophils that promote tissue damage i.e histamine, seratonin, proteases
  2. Recruited neutrophils and macrophages also release mediators that result in tissue destruction

This all occurs 4-6hrs after the early response to secondary exposure

42
Q

What contributes to an individual being susceptible to atopic allergies?

A

Genetic predisposition

Environmental factors

43
Q

What may cause a person to be genetically predisposed to allergies?

A

Certain alleles of;

  • HLA class 2 genes
  • TH2 genes
  • Degranulation response genes
  • Proinflam genes
44
Q

What environmental factors may cause an individual to have atopic allergies?

A
  • Excessive hygiene
  • Antibiotics as child
  • Pollutants
  • Vaccinations as a child
45
Q

What triggereing events can cause someone to have atopic allergies?

A
  • Flare ups of chronic illness
  • Emotional stress
  • Hormones
  • Pollutants
46
Q

What are some therapies for type one hypersensitivity and how do they work?

1-3

A

• Antihistamines
Bind histamine receptors on target organs
• Lipoxygenase antagonists
Block production of leukotrienes from innate immune cell membranes
• Bronchodilators
Block mast cell degranulation and promote smooth muscle relaxation

47
Q

What are some therapies for type one hypersensitivity and how do they work?

4-5

A

• Corticosteroids Inhibit cytokine production
• Anti-IgE immunotherapy
Therapeutic mAbs that bind human IgE to reduce free IgE

48
Q

Describe steps 1-3 of type 2 hyp. autoimmune hemolytic anemia;

A
  1. Pathological IgM binding to RBC triggers activation of classical complement pathway
  2. C3b attachment to RBCs
  3. Complement cascade results in MAC formation and RBC lysis
49
Q

Describe steps 4-5 of type 2 hyp. autoimmune hemolytic anemia;

A
  1. If RBC complexed with IgM (that avoid lysis) infiltrates the liver it can be destroyed by resident kupffer cells by C3b-opsonised phagocytosis

alternatively

  1. In the spleen RBCs complexed with pathological IgG can be destroyed by macrophages by FcgR-mediated ADCC
50
Q

Describe steps 1 and 2 of a type 2 hyp response that can cause organ damage;

A
  1. Pathological IgG bind surface antigen on kidney cells initiating classical complement cascade and secretion of chemokines that promote neutrophil recruitment
  2. C3b on kidney cells leads to their death by MAC-mediated lysis
51
Q

Describe steps 3 and 4 of a type 2 hyp response that can cause organ damage;

A
  1. ‘Frustrated phagocytosis’ occurs when neutrophils attempt to phagocytose C3b- coated kidney cells resulting in the release of cytotoxic contents
  2. Pathological IgG-bound kidney cells can also be destroyed by neutrophils and NK cells via FcR-mediated ADCC
52
Q

Describe Type III HS-IC-mediated steps 1-5;

i.e RF

(immune complexes that can lodge in the circulation)

A
  1. Ab binds antigen in the blood
  2. Insoluble ICs form by cross-linking that lodge in small vessels
  3. Complement activation leads to C3b coating of ICs and endothelial cells and MAC-mediated lysis
  4. ICs enter tissues
  5. Complement activation leads to C3b binding tissue cells

(compliment activation can activate anaphylaxin toxins (C5a)

53
Q

Describe Type III HS-IC-mediated steps 6-10;

A
  1. Tissue cells destroyed by MAC-mediated lysis
  2. Mast cells recruited and activated
  3. Mast cells produce mediators leading to vessel permeability
  4. Leukocytes extravasate into tissue
  5. C3b-coated tissue cells are destroyed by CR1 decorated degranulating neutrophils that experience frustrated phagocytosis
54
Q

Describe Type III HS-IC-mediated steps 11-12;

A
  1. Neighbouring cells also destroyed by cytotoxic molecules produced by neutrophils that bind ICs (via C3b-CR1)
  2. NK cells, macrophages and neutrophils can bind ICs via FcRs leading to release of mediators that can kill tissue cells
55
Q

Describe steps 1-6 of Type IV HS-CHRONIC DTH reaction

A
  1. Pathogen enters skin and infects cell
  2. Pathogen antigens recognised by APCs by PRRs
  3. Antigen presented to memory Th cells that then become activated
  4. Macrophages also become activated in response to antigen and release IL-12 and IL-18
  5. Th cells differentiate into TDTH cells
  6. IL-12 and IL-18 also act on NK cells that become activated and release IFNg that fortifies macrophage activation
56
Q

Describe steps 7-9 of Type IV HS-CHRONIC DTH reaction

A
  1. TDTH effector cells produce IFNg and other cytokines that leads to further macrophage recruitment and activation
  2. Macrophages release mediators that damage host skin cells
  3. If the response persists macrophages become hyperactivated resulting in granuloma formation
57
Q

Describe steps 1-5 of Type IV HS-contact hypersensitivity;

A
  1. Contact with poison ivy
  2. The CHS antigen urushiol penetrates the skin and bind self proteins (forms a neo-antigen)
  3. Neo-antigen induces skin cells to produce cytokines and chemokines
  4. Leukocytes are recruited
  5. Macrophages are activated and secrete IFNg
58
Q

Describe steps 6-8 of Type IV HS-contact hypersensitivity;

A
  1. Shed neo-antigen presented to memory TC cells (generated during the sensitisation stage) by LCs
  2. CTLs damage skin cells displaying neo-antigen- derived pMHCs and produce IFNg
  3. IFNg stimulates basophils and mast cells to degranulate augmenting inflammation

MEDSCI 314 (28 decks)

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