Z MICI3115 > Hypersensitivity > Flashcards

Hypersensitivity Flashcards

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1
Q

Define hypersensitivity reactions

A

Exaggerated and inappropriate immune response against otherwise harmless antigens causing pathologic tissue damage, pain, and discomfort

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2
Q

What kind of response is type I hypersensitivity

A

Inappropriate Th2

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3
Q

Mechanism of type I hypersensitivity

A

Th2 cytokines promote IgE which stimulates mast cells, basophils, and eosinophils

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4
Q

Hygiene hypothesis

A

Early exposure to microbes calibrates the immune system to better appreciate what is “pathogenic” vs “innocuous” to respond with an appropriate level of tolerance

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5
Q

Evidence for the hygiene hypothesis

A
  • Inverse correlation between parasitic diseases and allergy incidence
  • Allergies are more common in the western world where microbial exposure is altered
  • A healthy immune system is linked to early life factors that impact the microbiome (eg, breastfeeding, exposure to pets)
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6
Q

Predisposing environmental factors regulating allergy

A

Make allergy more likely
- air pollution
- cigarettes
- low microbial diversity and low fiber diet

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7
Q

Protective environmental factors regulating allergy

A

Make allergy less likely
- Exposure to microbes, probiotics
- High microbial diversity and high fiber diet
- early exposures
- breastfeeding

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8
Q

Impact of environment on IgE specificities hypothesis

A

Antigen specificities of IgE repertoire is influenced by environmental exposure

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9
Q

What makes an allergen

A

High soluble proteins/glycoproteins that induce T cell responses

Contain more than one epitope

Enzmatic protease activities

PAMPs

Enter mucosal surface at low concentrations

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10
Q

Allergens often have similarities to ________ antigens

A

Helminths

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11
Q

Enzymatic protease activities of allergens

A

Disrupt epithelial barriers, activate complement, or stimulate protease-activated receptor

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12
Q

Low concentration of allergens

A

As they enter the mucosal surfaces favouring a Th2 response

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13
Q

Four phase of an allergic reaction

A

Priming, sensitisation, activation, effector

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14
Q

Allergy priming mechanism

A

Commiting to heavy chain synthesis

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15
Q

Allergy priming and IL-4

A

Drives class switching to IgG3 and IgE

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16
Q

Early IgE in allergy

A

Low affinity with little somatic hypermutation and leaving the germinal center early

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17
Q

IgG3 B cells in allergy

A

Undergo somatic hypermutation to switch to other IgGs and eventually IgE (gene order, towards high affinity)

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18
Q

Ability of IgG in complement fixation

A

IgG3 >_ IgG1 > IgG2 > IgG4

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19
Q

Ability of IgG in FcγR binding during allergy

A

IgG3 > IgG1»_space; IgG4 > IgG2

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20
Q

Why do some B cells switch to to IgG4 during allergy

A

Binds to inhibitory FcγRIIB to oppose activation and regulate excessive immunity (limit damage in chronic infection)

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21
Q

FcεRII/CD23 affinity

A

Low affinity

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22
Q

FcεRI affinity

A

High affinity

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23
Q

Function of FcεRII

A

regulates IgE production by B cells

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24
Q

FcεRI function

A

primarily on mast cells, basophils and eosinophils, binds IgE for sensitisation

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25
Structure of FcεRI
FcεRIα and β/γ signalling chains (tetrameric receptor) that has roles in activation and degranulation
26
FcεRI on other immune cells (monocytes, DCs)
FcεRIα and γ chain only expresses (trimeric receptor that internalises and degrades IgE immune complexes
27
Function of IgE conformational changes
Ensure that each IgE molecule can only be bound by one type of FcεR at a time
28
CD23 structure
Is a C-type lectin expressed on activated and memory B cells as a braided trimer
29
Membrane CD23
Lectin domain binds soluble IgE and uses negative feedback loop that suppresses IgE synthesis
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How is CD23 bound
When IgE isnt bound, can be cleaved by ADAM10
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Soluble CD23
Binds to CD21 (CR2) and IgE-BCR to increase IgE synthesis and plasma cell differentiation
32
Atopic individuals have;
Increased soluble CD23 (FcεRII)
33
Half-life of serum IgE
2-3 days
34
Sensitisation function
IgE binds FcεRI on mast cells with high affinity Need cross-linking of ~100 IgE and FcεRI complexes for optimal activation
35
FcεRI activation function
Requires cross-linking of at least two FcεRI receptors (threshold) Strength of signalling impacted by affinity and concentration of allergen
36
Transduction of FcεRI crosslinking
Activation of tyrosine kinase Lyn, phosphorylation of ITAMs, recruitment of Syk, activation of LAT, SLP-76, PLCγ
37
PLCγ in FcεRI transduction
Causes downstream signalling via PKC, MAPK -> Degranulation, cytokines, leukotrienes, prostaglandins,
38
Mast cell preformed mediators
Immediate response that peaks within minutes enzymes toxic mediators - histamine TNF-α
39
Mast cell synthesised mediators
Late phase response, appears 6-8 hours later Cytokines, chemokines, lipid mediators
40
Allergic skin response immediate effects
Histamine induces vascular leakage and increased blood flow (edema and redness)
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Allergic skin response late effects
CysLTs cause edema Cytokines cause cell recruitment and activation
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Atopic asthma immediate response
Histamine causes edema and bronchoconstriction via smooth muscle contraction
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Atopic asthma late response
CysLTs cause edema, bronchoconstriction, mucus secretion Cytokines cause cell recruitment and activaion
44
Mechanism of early allergic asthma response
IgE-FcεRI crossinking - vasodilation, mucus production, bronchoconstriction
45
Mechanism of late allergic asthma response
Cytokines produced by activated mast cells. recruitment of eosinophils and neutrophils Tissue damage
46
Mechanism of third allergic asthma response
Eosinophils, basophils, fibroblasts promote tissue remodeling and reduced lung flexibility
47
Chronic inflammation of allergic asthma response
Chronic inflammation can lead to irreversible remodeling of lung tissue and loss of function
48
Severe allergic response can lead to
Systemic anaphylaxis When an allergen is injected/absorbed into the bloodstrean Can be fatal due to asphyxiation
49
Why do some people get more allergies than others
Environmental features may prime individuals for allergies Genetic pattern of inheritance may predispose (50% ~ 50% risk)
50
Gene loci implicated in allergies
MHC/HLA Protteolytic enzymes Pathogen sensing Epithelial barrier integrity Immune tolerance Th2 pathway cytokines and receptors Transcription factors FcεR alleles
51
Atopy
Increased propensity to produce IgE which is usually the least abundant serum Ig
52
Pharmacologic means to manage type I hypersensitivity
Antihistamines Mast cell stabilisers Epinephrine Leukotriene antagonists Corticosteroids Salmeterol
53
Immunotherapy to manage type I hypersensitivity
Hyposensitisation therapy Oral sensitisation Anti-IgE (omalizumab) Anti-IL-5 (mepolizumab)
54
Antihistamines
Block H1 and H2 receptors to reduce edema
55
Mast cell stabilisers
Sodium cromoglycate, olopatadine Reduce mast cell degranulation by stabilising the cell membrane
56
Epinephrine
EpiPen, AR agonist Reverses the effects of histamine on smooth muscle (constriction) and vasculature (dilation); stimulates cAMP levels in mast cells and basophils to reduce degranulation
57
Leukotriene antagonists (montelukast)
Block cysteinyl leukotriene receptor -> reduce bronchoconstriction and inflammation
58
Corticosteroids
Multiple anti-inflammatory effects and side effects
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Salmeterol
Long acting β2-AR agonist Bronchodilator
60
Hyposensitisation therapy
Repeated subcutaneous injections of the allergen to induce allergen-specific IgG4. Removes the allergen before it can trigger IgE sensitised mast cells and basophils. May also cause a shift towards a Th1 response
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Oral sensitisation
Small, increasing amounts of food are administered over time to allergic individuals to initiate immune tolerance by triggering class switching to make IgA instead of IgE
62
Anti-IgE immunotherapy
Omalizumab A recombinant IgG antibody that binds to free IgE so it cant bind FcεR to cause mast cell/basophil sensitisation
63
Ant-IL-5 Immunotherapy
Mepolizumab Reduces the number of eosinophils by binding their growth factor
64
Type II hypersensitivity
Antibody responses against surface antigenes causing complement activation, ADCC, or phagocytosis and thus tissue damage
65
TII hypersensitivity and protein modifications
Cause changes in surface proteins such that IgM and IgG may be induced
66
Drug haptens
Penicillin Naproxen Ibuprofen Modify surface proteins to induce IgM/IgG
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Citrullination
PAD enzymes modify arginine to citrulline to create a new epitope and induce IgM/IgG
68
TII hypersensitivity and breakdown of tolerance
Autoantibodies against self molecules/tissues Ex - myasthenia gravis and grave’s disease
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Mechanism of myasthenia gravis
Tolerance breakdown induce autoantibodies against AChR. Damage to neuromuscular junction and muscle weakness.
70
Mechanism of grave’s disease
Cleavage of TSHR results in an altered epitope to which the body forms autoantibodies. Cause symptoms/hyperthyroidism)
71
Transfusion reactions
TII hypersensitivity reaction Antibody responses against non-self surface antigens including different blood group antigens
72
Blood group A antigen
terminal N-acetylgalactosamine
73
Blood group B antigen
Terminal galactose
74
Blood group O antigen
H antigen Lacks a terminal sugar
75
Rh antigen
Many different alleles but only D is immunogenic
76
What kind of antigens are blood groups made of
T independent carbohydrate epitopes that have a low affinity for IgM and can fix complement
77
Universal donor
O Rh-
78
Universal recipient
AB Rh+
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Hemolytic disease of the newborn mechanism
Rh- mother, Rh+ child. Maternal recognition of fetal RhD as foreign. Usually forms Abs during first Rh+ childbirth, and reacts to subsequent pregnancies as anti-Rh IgG forms (IgG can cross the placenta)
80
Hemolytic disease of the newborn symptoms
Lysis of fetal RBCs -> anemia, jaundice (hemoglobin and bilirubin accumulate)
81
Hemolytic disease of the newborn treatment
Preventable by treating the mother with anti-Rh antibodies (RhoGAM/WinRho) at 28 weeks of gestation and within 24-48 hours of delivery
82
Rejection of transplanted organs
Recognition of ABO or non-self HLA by pre-existing antibodies causes hyperacute rejection (minute to hours)
83
Type III hypersensitivity mechanism
Antibody responses against soluble antigen results in the formation of immune complexes that are deposited Complement activation and FcR activation results in more inflammation and tissue damage
84
Type III hypersensitivity and drug reactions
Porcine insulin, horse diptheria serum (serum sickness), antibiotics, chemotherapeutics
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Type III hypersensitivity and infectious agents
Streptococcus, spores, fungi, hepatitis viruses, EBVs
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Type III hypersensitivity antigens may be;
Foreign or self
87
Self antigens and type III hypersensitivity
Cannot clear such antigens so it is a chronic effects that includes: - SLE - DNA, nuclear protein Abs - Arthritis - rheumatoid factor
88
Properties of TIII hypersensitivity inducing antigens
Multivalent antigens that permit formation of a 3D lattice structure Positive charged antigens (localise to the basement membranes) Frustrated phagocytosis (complexes are bound to tissues and are difficult to internalise - degranulation)
89
Arthus reaction overview
Localised TIII hypersensitivity reaction to intradermal injection of antigen in subject with preformed circulating antibodies against antigen
90
Arthus reaction examples
Repeated drug injections (chemo, biologics), booster vaccines (Tdap), or insect bites
91
Type IV hypersensitivity (DTH)
Initiated by T cells rather than antibodies and develops 1-2 days after antigen re-exposure
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Cells involved in DTH
Macrophages and effectors
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What is the difference between DTH and a normal Th1/Th17 response
Context
94
What kind of immune response is DTH
Chronic Th1, Th17, and CTL in specific pathological contexts
95
Contact dermatitis
DTH caused by poison ivy, metals, drugs Chemical modification of a protein causes T cell recognition of altered peptides
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Haptenation
Chemical modification of protein residues
97
Granulomatous hypersensitivity
DTH Sarcoidosis, TB infection, Crohns Granuloma formation walls off a persistent antigen
98
CTL-mediated DTH
Transplant rejection, toxic epidermal necrolysis CD8 mediated cell killing
99
Autoimmune diseases that are DTH
Multiple sclerosis Rheumatoid arthritis Type 1 diabetes
100
Urushiol toxins
Found in poison ivy, induce Th1, Th17, and CD8 T cells in LN.
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Th1 cells in contact dermatitis
IFNγ and TNF release activate macrophages to release cytokines, ROS, and lytic enzymes, that cause tissue damage
102
Th17 cells in contact dermatitis
Cytokines that recruit inflammatory neutrophils
103
CD8 T cells in contact dermatitis
Recognise modified peptides and mediate killing of skin cells
104
TB as a granuloma reaction
TB can survive in macrophage endosomes after phagocytosis by blocking fusion with lysosomes so that they can proliferate and be released
105
Macrophages in formation of TB granulomas
TB proliferation in macrophages, activated macrophages attempt to wall off. Instead they pack together and change morphology, sometimes fusing, releasing lytic enzymes and causing tissue damage
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T cells in TB granuloma formation
Form a cuff around macrophages to further isolate the persistent trigger
107
Tuberculin skin test
To diagnose exposure -> exhibits kinetics of DTH response, T cell mediate and takes 48-72 hours to develop.
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Which hypersensitivity does penicillin induce
ALL
109
Which hypersensitivity does cat dander induce
Type I and Type IV
110
Which hypersensitivity causes SLE
Type I, Type II, and Type III
111
Which hypersensitivity causes RA
Type II, Type III, Type IV
112
Which hypersensitivity can blood transfusions cause
Type I, Type II, Type IV
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