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Self-recognition, tolerance and hypersensitivity Flashcards

1
Q

Define tolerance

A

Immune cells not reacting to antigens

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2
Q

Types of tolerance

A
  • Self tolerance
  • Neonatal tolerance
  • Acquired tolerance
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3
Q

What is self tolerance?

A

Tolerance to innate antigens

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4
Q

What is neonatal tolerance?

A

Tolerance to antigens encountered within hours of being born

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5
Q

What is acquired tolerance?

A

Tolerance to antigens that are encountered throughout life

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6
Q

What is the development of self-tolerance and self-recognition key in?

A

The maturation of T and B cells

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7
Q

What does the breakdown of immunological tolerance lead to?

A

Autoimmune disease

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8
Q

What are immature T cells positively selected for?

A

Recognition of self-MHC molecules

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9
Q

What are immature T cells negatively selected for?

A

Non-recognition of self-peptides

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10
Q

What happens to immature T cells that are not selected in the thymus?

A

Apoptosis

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11
Q

What type of selection do immature B cells undergo in the bone marrow?

A

Negative selection for recognition of self-MHC molecules or other self-antigens

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12
Q

What do T cells have to do in order to correctly function?

A
  • Recognise self-MHC molecules
  • Display self-tolerance
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13
Q

Do B cells show self tolerance?

A

Yes

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14
Q

How do pre T cells in thymus develop self-recognition?

A

Positive selection

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15
Q

How many of the T cells produced will become fully mature immunocompetent cells?

A

1-5%

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16
Q

What happens to self-reactive T cells?

A

Deletion after they leave the thymus should they contact an unrecognised self-protein

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17
Q

What type of tolerance is oral tolerance?

A

Acquired

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18
Q

What is oral tolerance?

A

The acquired ability to not react to antigens in the gut

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19
Q

What occurs when oral tolerance breaks down?

A

Possibly inflammatory bowel disease

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20
Q

What theory explains maternal tolerance?

A

EU-FEDS (eutherian fetoembryonic defense system)

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21
Q

What are the 4 types of hypersensitivity classifications?

A
  • Type 1: IgE mediated (immediate)
  • Type 2: Cytotoxic reaction (complement lysis/ADCC)
  • Type 3: Immune complex reaction (complement activation)
  • Type 4: T-cell mediated (delayed)
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22
Q

What does ADCC stand for?

A

Antibody-dependent cellular cytotoxicity

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23
Q

How long does each type of hypersensitivity classification take to have an effect?

A
  1. 30 minutes
  2. Days
  3. 6-8 hours
  4. 48-72 hours
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24
Q

What is the immune reactant, antigen and effector mechanism of type 1 hypersensitivity?

A
  • Immune reactant: IgE
  • Antigen: soluble antigen
  • Effector mechanism: mast-cell activation
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25
What is the immune reactant, antigen and effector mechanism of type 2 hypersensitivity?
* Immune reactant: IgG * Antigen: cell or matrix associated antigen/cell surface receptor * Effector mechanism: Complement FcR+ cells (phagocytes, NK cells)/antibody alters signalling
26
What is the immune reactant, antigen and effector mechanism of type 3 hypersensitivity?
* Immune reactant: IgG * Antigen: soluble antigen * Effector mechanism: complement phagocytes
27
What is the immune reactant, antigen and effector mechanism of type 4 hypersensitivity?
* Immune reactant: T1 helper cells/T2 helper cells/CTL * Antigen: soluble antigen/Cell associated antigen * Effector mechanism: macrophage activation/IgE production, eosinophil activation, mastocytosis/cytotoxicity
28
Examples of type 1 hypersensitivity reactions
* Allergic rhinitis * Allergic asthma * Atopic eczema * Systemic anaphylaxis * Drug allergies
29
Examples of type 2 hypersensitivity reactions
* Antigen mediated: drug allergies (e.g. penicillin) * Cell surface receptor: chronic urticaria (antibody against FcεRI alpha chain)
30
Examples of type 3 hypersensitivity reactions
* Serum sickness * Arthus reaction
31
Examples of type 4 hypersensitivity reactions
* Helper T1: * Allergic contact dermatitis * Tuberculin reaction * Helper T2: * Chronic asthma * Chronic allergic rhinitis * CTL: * Graft rejection * Allergic contact dermatitis to poison ivy
32
What does CTL stand for?
Cytotoxic T lymphocyte
33
General properties of allergens
* Small 15,000-40,000 (molecular weight) proteins * Soluble * Long-lasting in the environment * Low dose of allergen required * Mucosal exposure * Often proteases * Most allergens promote T2 helper cells
34
Organ manifestation of type 1 reactions
* 45% - skin/mucosa * 25% - respiratory tract * 20% - gastointestinal * 10% - cardiovascular system
35
Label the protease-mediated type 1 hypersensitivity reaction from a to d
1. Der p 1 cleaves occludin in tight junctions and enters mucosa. 2. Dendritic cell primes cell in lymph node. 3. Plasma cell travels back to mucosa and produces Der p 1 specific IgE antibodies. 4. Der p 1 specific IgE binds to mast cell; Der p 1 triggers mast cell degranulation.
36
What does Der p stand for?
Dermatophagoides pteronyssinus
37
What are the allergens of Der p 1-14?
1. Cysteine protease 2. Unknown 3. Trypsin (serine protease) 4. Amylase 5. Unknown 6. Chymotrypsin (serine protease) 7. Unknown 8. Glutathione transferase 9. Collagenase (serine protease) 10. Tropomyosin 14. Apolipophorin like protein
38
What has proteinase allergens?
* Fungi * Insects * Plants * Parasites * Drugs
39
Are most allergens proteases?
No
40
Label the mast cell activation diagram from a to b
a - IgE secreted by plasma cells binds to a high-affinity Fc receptor (FcεRI) on mast cells. b - Activated mast cells provide contact and secreted signals to B cells to stimulate IgE production.
41
What are the images on the left and right?
* Left: resting mast cell * Right: activated mast cell
42
Examples of mast cell enzymes
* Tryptase * Chymase * Cathepsin G * Carboxypeptidase
43
Examples of mast cell toxic mediators
* Histamine * Heparin
44
Examples of mast cell cytokines
* IL-4, IL-13 * IL-3, IL-5, GM-CSF (Granulocyte-macrophage colony-stimulating factor) * TNF-α (Tumor necrosis factor alpha)
45
An example of a mast cell chemokine
CCL3 (Chemokine ligand 3)
46
Examples of mast cell lipid mediators
* Prostaglandins D2 and E2, leukotrienes C4/D4/E4 * Platelet activating factor
47
Biological effects of mast cell enzymes
Remodelling of connective tissue matrix
48
Biological effects of mast cell toxic mediators
* Toxic to parasites * Increases vascular permeability * Causes smooth muscle contraction * Anticoagulation
49
Biological effects of mast cell cytokines
* IL-4, IL-13 * Stimulates and amplifies helper T2 cell response * IL-3, IL-5, GM-CSF * Promotes eosinophil production and activation * TNF-α * Promotes inflammation * Stimulates cytokine production by many cell types * Activates endothelium
50
Biological effects of mast cell chemokine
Attracts monocytes, macrophages and neutrophils
51
Biological effects of mast cell lipid mediators
* Prostaglandins D2 and E2, leukotrienes C4/D4/E4 * Smooth muscle contraction * Chemotaxis of eosinophils, basophils and helper T2 cells * Increase vascular permeability * Stimulate mucus secretion * Bronchoconstriction * Platelet-activating factor * Attracts leukocytes * Amplifies production of lipid mediators * Activates neutrophils, eosinophils and platelets
52
What does mast-cell activation and granule release result in in the gastrointestinal tract?
* Increased fluid secretion and increased peristalsis resulting in: * Expulsion of gastrointestinal tract contents * Diarrhea * Vomiting
53
What does mast-cell activation and granule release result in in the eyes, nasal passages and airways?
* Decreased diameter and increased mucus secretion resulting in: * Congestion and blockage * Wheezing * Coughing * Phlegm * Swelling and mucus secretion in nasal passages
54
What does mast-cell activation and granule release result in in the blood vessels?
* Increased blood flow and permeability resulting in: * Increased fluid in tissues * Increased flow of lymph to lymph nodes * Increased cells and protein in tissues * Increased effector response to tissues * Hypotension leading to potential anaphylactic shock
55
What are the common systemic anaphylactic allergens?
* Drugs * Venoms * Food * Serum
56
What are the routes of entry for systemic anaphylactic allergens?
* Intravenously * Orally
57
What responses to systemic anaphylaxis are there?
* Oedema * Increased vascular permeability * Laryngeal oedema * Circulatory failure * Death
58
What is another term for acute urticaria?
Wheel-and-flare
59
What are common allergens of acute urticaria?
* Animal hair * Insect bites * Allergy testing
60
What are the routes of entry for acute urticaria allergens?
* Through the skin * Systemic
61
What is the response to acute urticaria?
* Local increase in blood flow * Local increase in vascular permeability * Oedema
62
What is seasonal rhinoconjunctivitis commonly known as?
Hay fever
63
What are the common allergens of seasonal rhinoconjunctivitis?
* Pollens * Ragweed * Grass * Trees * Dust-mite faeces
64
What is the route of entry for allergens of seasonal rhinoconjunctivitis?
* Contact with conjunctiva of eye * Nasal mucosa
65
What is the response to seasonal conjunctivitis?
* Oedema of conjunctiva and nasal mucosa * Sneezing
66
What are the common allergens of asthma?
* Danders (cat) * Pollen * Dust mite faeces
67
What is the route of entry for asthma causing allergens?
Inhalation leading to contact with lower respiratory system mucous membrane
68
Response to asthma?
* Bronchial constriction * Increased mucous production * Airway inflammation
69
What are the common food allergens?
* Nuts * Fish * Dairy * Eggs * Soy * Milk
70
What is the route of entry for food allergens?
Orally
71
What is the response to a food allergy?
* Vomiting * Diarrhea * Pruritis (itching) * Urticaria (hives) * Anaphylaxis (rare)
72
What are the IgE-mediated allergic reaction?
* Systemic anaphylaxis * Acute urticaria * Seasonal rhinoconjunctivitis * Asthma * Food allergies
73
What are symptoms of an IgE-mediated allergic reaction to the upper airways and what is it called?
* Rhinitis * Nasal itch * Sneezing * Rhinorrhea * Nasal obstruction
74
What are symptoms of an IgE-mediated allergic reaction to the lower airways and what is it called?
* Asthma * Bronchoconstriction * Mucous hypersecretion * Wheezing * Breathlessness * Cough
75
What does this image show?
Airway inflammation with lymphocytes and eosinophils
76
What does this image show?
Airway remodelling with increased collagen deposited around the airway
77
What does the airway inflammation with lymphocytes and eosinophils lead to?
Airway remodeling hypertrophy
78
What does airway remodelling with increased collagen deposited around the airway lead to?
Fibrosis
79
What are the symptoms of anaphylaxis?
* Extreme hypotension * Airway constriction * Swelling of the epiglottis
80
What is used to treat an anaphylactic allergic reaction?
Epinephrine as it relaxes bronchiole smooth muscles
81
Individuals with what gene mutation experience cold-induced urticaria?
NLP3 mutants
82
Which enzyme is involved in the truncation of the inhibitory region PLCG2?
Phospholipase
83
Over activation of what gene leads to vibrational urticaria?
GPCR-EMR2
84
In individuals with over activation of GPCR-EMR2, what causes mast cell degranulation?
Overly sensitive mechanotransduction
85
What are eosinophils?
* Granulocyte that mainly kills opsonised parasites * Degranulated by large amounts of IL-5 and IL-3 * Involved in airway remodelling
86
What are the enzymes of eosinophils?
* Eosinophil peroxidase * Eosinophil collagenase * Matrix metalloproteinase-9
87
What are the toxic proteins of eosinophils?
* Major basic protein * Eosinophil cationic protein * Eosinophil-derived neurotoxin
88
What are the cytokines of eosinophils?
* IL-3, IL-5, GM-CSF * TGF-α, TGF-β
89
What is the chemokine of eosinophils?
CXCL8 (IL-8)
90
What are the lipid mediators of eosinophils?
* Leukotrienes C4, D4, E4 * Platelet-activating factor
91
What are the biological effects of eosinophil peroxidase?
* Toxic to targets by catalysing halogenation * Triggers histamine release from mast cells
92
What are the biological effects of eosinophil collagenase?
Remodels connective tissue matrix
93
What are the biological effects of matrix metalloproteinase-9?
Matrix protein degradation
94
What are the biological effects of major basic protein?
* Toxic to parasites and mammalian cells * Triggers histamine release from mast cells
95
What are the biological effects of eosinophil cationic protein?
* Toxic to parasites * Neurotoxin
96
What are the biological effects of eosinophil-derived neurotoxin?
Neurotoxin
97
What are the biological effects of IL-3, IL-5 and GM-CSF?
* Amplification of eosinophil production by bone marrow * Eosinophil activation
98
What are the biological effects of TGF-α and TGF-β?
* Epithelial proliferation * Myofibroblast formation
99
What are the biological effects of CXCL8 (IL-8)?
Promotion of influx of leucocytes
100
What are the biological effects of leukotrienes C4, D4 and E4?
* Smooth muscle contraction * Increased vascular permeability * Increased mucous secretion * Bronchoconstriction
101
What are the biological effects of platelet-activating factor?
* Attraction of leucocytes * Amplification of lipid mediator production * Activation of neutrophils, eosinophils and platelets
102
Why are is allergen sensitivity going up?
* Hygeine hypothesis * Rise in Th1/inflammatory immune defects * Counter regulation hypothesis
103
What are the clinically used target step treatments for type 1 allergic diseases?
* Mediator action * Chronic inflammatory reactions * T2 helper cell response * IgE binding to mast cell
104
What is the mechanism of treatment for mediator action in type 1 allergic disease?
* Inhibit mediator effects on specific receptors * Inhibit specific mediator synthesis
104
What is the mechanism of treatment for chronic inflammatory reactions in type 1 allergic disease?
General anti-inflammatory effects
105
What is the mechanism of treatment for T2 helper cells in type 1 allergic disease?
Induction of regulatory T cells
106
What is the mechanism of treatment for IgE binding to mast cells in type 1 allergic disease?
Bind to IgE Fc region and prevent IgE binding to Fc receptors on mast cells
107
What are the specific approaches for mediator action treatments in type 1 allergic disease?
* Antihistamines, β-blockers * Lipoxygenase inhibitors
108
What is the specific approach for chronic inflammatory reaction treatments in type 1 allergic disease?
Corticosteroids
109
What is the specific approach for T2 helper cell response treatments in type 1 allergic disease?
Desensitisation therapy by injections of specific antigen
110
What is the specific approach for IgE binding to mast cell treatments in type 1 allergic disease?
Anti-IgE antibodies (omalizumab)
111
What are the proposed and under investigation target step treatments for type 1 allergic diseases?
* T2 helper cell activation * Activation of B cell to produce IgE * Mast cell activation * Eosinophil-dependent inflammation
112
What is the mechanism of treatment for T2 helper cell activation in type 1 allergic disease?
Induction of regulatory T cells
113
What is the mechanism of treatment for activation of B cells, to produce IgE, in type 1 allergic disease?
* Block co-stimulation * Inhibit T2 helper cell cytokines
114
What is the mechanism of treatment for mast cell activation in type 1 allergic disease?
Inhibit effects of IgE binding to mast cell
115
What is the mechanism of treatment for eosinophil-dependent inflammation in type 1 allergic disease?
Block cytokine receptors that mediate eosinophil recruitment and activation
116
What are the specific approaches for T2 helper cell activation treatments in type 1 allergic disease?
* Injection of specific antigens * Administration of specific cytokines * Use of adjuvants to stimulate a T1 helper cell response
117
What are the specific approaches for activation of B cells, to produce IgE, treatments in type 1 allergic disease?
* Inhibit CD40L * Inhibit IL-4 or IL-13
118
What is the specific approach for mast cell activation treatments in type 1 allergic disease?
Blockade of IgE receptor
119
What are the specific approaches for eosinophil-dependent inflammation treatments in type 1 allergic disease?
* Inhibit IL-5 * Block CCR3
120
Did IgE responses evolve to cause allergy?
No
121
What did IgE responses evolve to do?
Expel and/or destroy helminth and protozoal pathogens
122
What is atopic dermatitis?
* Chronic inflammation, initiated by IgE, causing apoptosis of keratinocytes. * Leaky skin allergens cause a filaggrin defect that results in keratin fibres being bound together in the skin.
123
What is the antibody that mediates type 1 allergic disease?
IgE
124
What antibody mediates type 2 allergic disease?
IgG
125
What allergic diseases are type 2?
* Haemolytic anaemia * Thrombocytopenia (haemolytic anaemia in infants)
126
What is haemolytic anaemia?
The destruction of blood cells and platelets mediated by IgG antibodies
127
How to IgG antibodies mediate type 2 allergic diseases?
1. Antibodies attach to self epitopes 2. Induce inflammation compliment activation 3. Vasodilation and migration of phagocytes to effected tissue 4. Activation of membrane attack complex
128
What does type 2 allergic antibodies refer to?
Antibodies that target self-tissues
129
What are type 3 allergic diseases characterised by?
IgG mmune complex formation causing an inflammatory immune response
130
What are some type 3 allergic diseases?
* Arthus reaction * Serum sickness * Arthritis * Vasculitis * Nephritis * Farmer's lung
131
Which complement protein sensitises mast cells to respond to IgG immune complexes?
C5
132
What does local inflammation in type 3 allergic reaction cause?
Occlusion of blood vessels due to the build-up of proteins in the immune response
133
What complex causes a type 3 allergic reaction?
Antigen-antibody (IgG) complex
134
What are the two types of type three allergic reaction?
* Local type 3 hypersensitivity * Systemic type 3 hypersensitivity
135
What is a local type 3 allergic reaction?
Local subcutaneous antigens induce an immune response causing localised inflammation that peaks after approximately 7 hours.
136
What is extrinsic allergic alveolitis caused by and what type of allergic reaction is it?
* Inhaled spores * Local type 3 allergic reaction
137
What is a systemic type 3 allergic reaction?
Systemic antigen complex formation causing systemic inflammation
138
What causes post-infectious glomerulonephritis and what type of allergic reaction is it?
* Antibody complexes become stuck in the glomeruli of the kidney inducing an inflammatory response. * Systemic type 3 allergic reaction
139
What is post-infectious glomerulonephritis most commonly caused by?
Streptococcal pharyngitis infections
140
What is another term for type 4 hypersensitivity?
Delayed hypersensitivity
141
What mediated type 4 hypersensitivity?
* T1 helper cells * Cytotoxic T cells
142
In what time frame does a type 4 allergic reaction happen?
24-72 hours after contact with antigen
143
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IMS - Immunology (6 decks)

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