Week 7: Hypersensitivity Flashcards
1
Q
What is another name for hypersensitivity disorders?
A
Immunopathologies
2
Q
How are HS reactions classified?
A
- Amount of time they take to develop
- Duration of the reaction
- Whether antibodies or T cells mediate the response
3
Q
What are the amount of time classification?
A
- Immediate
- Subacute
- Delayed-type
4
Q
What determines whether antibodies or T cells mediate the response?
A
- Type of antibody involved (IgE, IgG, IgM)
- Cytotoxic or helper T cells
5
Q
Who are Gell and Coombs?
A
Developed a classification scheme to discriminate between the various types of hypersensitivity
6
Q
How are immune responses classified?
A
Based on the immune mechanism not the disease
7
Q
Which class are antibody mediated?
A
Types 1, II, III
8
Q
Which class is T cell mediated?
A
Type IV
9
Q
What causes HS disorders?
A
The involvement of more than 1 type of immune mechanisms
10
Q
What is type 1 HS?
A
- Allergic HS reactions
- Immediate form of HS
11
Q
What antibody is involved with Type 1?
A
IgE-mediated degranulation of mast cells or basophils
12
Q
How fast is Type 1?
A
Minutes of antigen presentation
13
Q
What is an allergen?
A
An antigen that provokes an allergy
14
Q
Describe the structure of allergens?
A
- Highly soluble proteins or glycoproteins and multiple epitopes
- Have enzymatic activity
- Contains PAMPs
15
Q
What is an allergy?
A
A type 1 HS response to an allergen that is non-antigenic in most individuals
16
Q
How many individuals have allergies?
A
30% (adults)
40% (children)
17
Q
What is atopy?
A
The susceptibility to develop immediate HS reactions become IgE sensitization to environmental allerges
18
Q
What cause atopicity?
A
- Influenced by genetic and environmental factors
- Both parent are atopic, child has a high chance of IgE mediated allergy
19
Q
How can environmental factor that can develop allergies?
A
- More developed countries have increased atopic allergies
- More families moved to urban from rural gain early life exposure
- Microbiome play a role in allergen tolerance
20
Q
What is the hygiene hypothesis?
A
Proposes that less hygienic environments predispose children to infections early in childhood that help to protect against the development of atopy and allergic asthma
Skew the immune response from a TH2 to a TH1 response
21
Q
What are common allergic reactions?
A
- Eczema
- Allergic rhinitis
- Asthma
- Food allergy
- Severe: systemic anaphylaxis
22
Q
What is IgE involvement to allergies?
A
- Mediates mast cell dregranulation
23
Q
What factors affect allergic symptoms?
A
Route of entry and dose of antigen
24
Q
What is sensitization?
A
- Initial encounter with the allergen leads to the production of allergen-specific IgE antibodies
- Antibodies lead to degranulation of mast cells in the tissues
25
How does TH2 play a role in Type 1 HS?
1. APC presents allergen to naive T cells and induce effector cell differentiation
2. TH2 secrete IL4 and 13
3. B cell undergo class switching to produce IgE antibodies
4. IgE memory cells and plasma cells are produced
26
What is the role of IgE antibodies in T1 HS?
Cross-linking Fcε receptors on the surfaces of innate immune cells
27
Describe the outcome of a high affinity IgE receptor, FcεRI?
1. Responsible for most symptoms
2. Always expressed on mast and basophils
3. Signaling through this receptor leads to degranulation
28
Describe the outcome of a low affinity IgE receptor, FcεRII?
1. Found on IgE expressing B cells
2. Suppresses IgE production
29
What happens there is FcεRI signaling in mast and bosphils?
1. Degranulation
2. Synthesis of inflammatory cytokines
3. Conversion of arachidonic acid into leukotriene and prostaglandins
30
How does degranulation induce allergy symptoms?
1. Degranulation of mast cells, basophils, eosinophils is caused by crosslinking of FcεRI receptors
2. Granules contains inflammatory mediators acting on local and secondary effector cells
3. Mediators lead to increases in vascular permeability and inflammation (only tissue damage)
31
What is the difference between primary and secondary mediators?
Primary: Preformed and stored in granules
Secondary: synthesized after cell activation and degranulation
32
What is the effect of histamine?
Increased vascular permeability and smooth muscle contraction, increased mucus secretion
33
What is the effect of leukotriene?
Increased vascular permeability and contraction of pulmonary smooth muscles
34
What is the effect of prostaglandins?
Vasodilation, contraction of pulmonary smooth muscles, platelet aggregation, pain
35
What mediators act in the early phase of T1 HS?
1. Histamine and receptors
2. Leukotrienes/ Prostaglandins
36
What are the major components of mast cell granules?
Histamine
37
What symptoms do histamine stimulate?
Itching, sneezing through neural receptors
38
What histamine receptors cause an allergic effect?
H1, 2, and 4
39
How many histamine receptors?
H1, 2, 3 , 4
40
What is the function of H1 receptor?
Induce contraction of intestinal or bronchial smooth muscles, increased local blood flow and vessel permeability and increased mucus secretion (30 seconds)
41
What are the functions of H2 receptors?
On mast cells and basophils suppresses degranulation (negative feedback)
42
What are the functions of H4 receptors?
Mediate chemotaxis of mast cells
43
What H receptor is not apart of T1 HS?
3
44
Examples of primary mediators?
Histamine
45
Examples of secondary mediators?
Leukotrienes, prostaglandins
46
How are leukotrienes formed?
Produced from phospholipids (arachidonic acids) in the plasma membrane
47
How does leukotrienes differ from histamine?
1, Enhances asthmatic responses following histamine
2. 1000x more effective bronchodilator
3. More potent stimulator of permeability and mucous secretion
48
What does prostoglandin recruit?
TH2, eosinophils, and basophils
49
What are the late phase mediators?
Cytokines and chemokines
50
What secretes cytokines?
Mast, basophils, and eosinophils
51
What is the function of IL4 and 13?
Stimulate TH2 responses to increase IGE production by B cells
52
What is the function of IL8?
Attracts neutrophils, monocytes, mast cells, basophils, and T cells
53
What is the function of IL5?
Increases the number and activity of eosinophils
54
What is the function of IL9?
Increases the number and activity of mast cells
55
What is the function of TNF-a?
Potent that contributes to shock in systemic anaphylasis
56
What is the early response of T1HS?
1. Occur within minutes of allergen exposure
2. Mediated by mast cell/basophil granule release of histamine, leukotrienes, and prostaglandins
57
What is the late response of T1HS?
1. Hours later, from recruited cells
2. Cytokines (IL-8, TNF-a) released from mast cells increase expression of chemokines and CAMs on endothelium facilitating influx of neutrophils, eosinophils, and TH2 cells
3. Eosinophils play a large role in late-phase recruiting neutrophils and degranulation
58
What are the functions of eosinophils in late phase?
1. Release toxic granule proteins and free radicals to kill microbes and parasites
2. Produce secondary chemical mediators including prostaglandins, leukotriene, and cytokines
59
How is an inflammatory response amplified?
1. Eosinophilia
2. Tissue remodeling (thickens basement membrane and narrows airways)
3. Asthma
60
What is the outcome of mast cell activation?
1. Mast cells line external mucosal surfaces
2. Provoke unpleasant reactions to innocuous antigens
3. Response due to antigen dose and route of entry
61
Describe Type 1 reaction for penicillin?
1. Penicillin has a b-lactam ring that can be cleaved and covalently attach to proteins in the body
2. Creates a new foreign epitope
3. New epitope is presented to T cells to generate a TH2 response and generation of IgE antibody against penicillin.
4. Creates a penicillin sensitized individual
62
What are the physical early phase responses?
Wheal and flare
63
What is wheal?
1. Raised area
2. Histamine and other mediators produced by mast cells in skin and increased permeability
64
What is flare?
The redness of spreading outward from raised area due to dilation of blood vessels around area
65
What is the physical late phase response?
Swelling has spread into the tissues around the site of injection
66
What is localized HS reactions?
Limited to a specific tissue or organ
67
What causes localized HS?
1. Allergen is delivered to skin or mucosal surface activating mast cells, releasing histamine (eczema, hives)
2. Airborne delivered to respiratory tract and activate the mast cells in the nasal epithelium (hay fever, asthma)
68
What is allergic conjunctivitis?
Airborne allergens deposited on conjunctiva of the eye
69
What is systemic anaphylaxis?
1. activate the mast cells is the nasal epithelium
2. Minutes of exposures
70
What causes systemic anaphylaxis?
Caused by wide-spread IgE-mediated degranulation of mast cells and basophils and the systemic effects of the massive release of their granular contents
71
What makes systemic anaphylaxis severe?
1. Reduction of BP causing hypotensive shock
2. Asphyxiation from smooth muscle contraction
3. Fatal
72
What is an immediate treatment for systemic anaphylaxis?
Epinephrine counteracts histamine and leukotrienes
73
What are food allergies made of?
Water-soluble glycoproteins stable to heat, acid, and proteases
74
What are the functions of food allergies?
1. Activate IgE along mucosal surfaces
2. Causes anaphylaxis
3. Voiting and diarrhea
4. Enter blood leading to asthma, systemic anaphylaxis, uticaria
75
What accounts for more anaphylactic responses in children than any other allergy?
Food allergies
76
How does one confirm allergies?
Skin prick testng
77
What is the skin pricking test?
1. Cheap, safe
2. Small quantities of allergen under skin by small prick or scratch
3. Swelling and redness from localized response
4. Histamine is positive control, saline is negative control
78
What are the treatments of Type 1 HS?
1. ANtihistamine
2. Leukotrien antagonist
3. Inhalation CS
4. Topical CS
79
How does antihistamine treat Type 1 HS?
1. Bind and block H1 receptors on target cells
2. First get: cross CNS causing drowsiness
3. Sec gen: Fewer side effects
80
How does leukotriene antagonists treat Type 1 HS?
Similar to antihistmaine
81
How does inhaled CS treat Type 1 HS?
Inhibit innate immune cell activity in airways, treating astha
82
How does topical CS treat Type 1 HS?
Treat allergic reactions of the skin
83
How are IgE receptor signaling regulated?
1. Mast cells express both stimulatory FcεRI receptors and inhibitory FcεRIIB
2. If an allergen binds to both IgG and IgE molecules, it will trigger both Fc receptors.
3. The inhibitory signal predominates (IgG wins).
4. Eliciting IgG antibodies against an allergen leads to desensitization.
5. High levels of allergen-specific IgG antibodies increases the probability that allergens will bind to both stimulatory and inhibitory Fc receptors.
84
What is the preferred treatment for atopic individuals?
Allergy shots
85
What is desentivation immunotherapy?
1. Repeated exposure to allergen toward a TH1 and Treg response
2. TH1 cytokines block TH2 cells and induce IgG antibody production switching from IgE to IgG4 and production of IFN-y which blocks IgE production
3. Allergen specific IgG binding to mast cell FcεRIIb molecules is inhibitory.
4. Oral immunotherapy consists of feeding children increasing amounts of food allergen to generate tolerance
86
What are the characteristics of Type 2 HS?
1. Involves the antibody induced cytotoxicity
2. Antibody directed against a cell surface antigens found on our cell and tissues
3. Subacute
4. 1-3 hrs following exposure
87
What antibodies mediate type 2 HS?
IgG and IgM
88
How does antibody-surface binding lead cell death (Type 2 HS)?
1. Activation of classical complement cascade (MAC)
2. Antibody serves as an opsonin for phagocytes
3. Destruction by ADCC
89
Describe the activation of CDC?
1. Antibody binds to antigent initiating pathway
2. I pentameric IgM or 2 IgG
3. MAC complex activation
4. Lysis of the target cell
90
Describe antibody-mediated opsonization?
1. Antibody binds to target cell surface
2. C3b deposition
3. Fc receptors on phagocytes bind to Fc portion of antibody
4. CR1 or 2 on phagocytic cells recognize C3b
5. Macrophage engulfs and destroys target cell in the phagosome/lysosome
91
Describe ADCC?
1. IgG bind to surface of antigen
2. NK cells fave Fc receptors that bind to the antibodies on the target cell
3. NK cell release its granular contents to kill the target cell
4. Apoptosis of target
92
What is perforin?
Inserts and forms a pore within the target cell membrane
93
What is granzyme?
Fragments the target cell's DNA
94
What are isohemagglutinins?
Most adults have IgM antibodies against AP antigens that aren't expressed
95
How are isohemagglutinins generated?
By microbes expression similar carb antigens to blood group antigens (fructose, galactose, N-acetylgalactosamine)
96
What are the carb antigens found on RBCs?
A, B, H
97
What are the characteristic of type B blood?
1. Have isohemagglutinins for A antigens
2. Tolerate self-B epitopes
3. Produce a transfusion reaction to Type A
4. The anti-A isohemagglutinins will bind to B red blood cells and cause their destruction by complement dependent cytotoxicity
98
What are the isohemagglutinins?
IgM or IgG
99
What antigen do all individuals express?
H
100
What antibodies are produced by O?
A and B
101
Why is a O an universal donor?
Have the H antigen to donate
102
What is a transfusion reaction?
Pre-formed antibodies in the recipient, agglutinate the donor's RBCs resulting in complement mediated cytotoxicity (hemolysis)
103
What is the immediate response of a trasfusion reaction?
1. IgM mediated CDC that results in the buildup of free hemoglobin which is metabolized to bilirubin
2. RBCs and antibodies can also agglutinate and be phagocytized by macrophages
104
What are the physical symptoms of transfusion reaction?
High levels of bilirubin can cause fever, chills, nausea, blood clots within the vessels, jaundice, and anemia
105
How does hemolytic disease develop in a new born?
1. Caused by maternal IgG for specific ABH antigens that cross the placenta and lyse fetal RBCs
106
What is erythroblastosis fetalis?
Severe hemolytic disease of the newborn
107
How does the erythroblastosis fetalis occur in a child?
1. Develops when the mother and child express different Rh antigens
2. Occurs when the mother is Rh- and the father is Rh+ that generates a Rh+ fetus
3. Fetal RBCs enter the maternal circulation and RBCs and antibodies can agglutinate and be phagocytized by macrophages
4. Mother develop anti-Rh antibodies that will cause hemolytic diseases in subsequent pregnancies
108
What is Rh factor?
Protein found on the outside of RBCs
109
What happens if the mother has IgG anti-Rh memory cells when comes the 2nd pregnancy?
1. Activation of these memory B cells in 2nd pregnancy generates IgG antibodies that can cross placenta and damage fetal RBCs
2. Causes a toxic buildup of bilirubin that can lead to jaundice and brain damage to fetus
110
What is RHOGAM?
1. Anit Rh antibodies that treats a mother with anti-Rh memory cells during 2nd pregnancy
2. Binds to fetal RBCs in maternal circulation and neutralizes fetal Rh+ antigens and preventing B cell activation and the generation of B memory cells
111
What induces Type 2 hemolytic anemia?
1. Antibiotics: b-lactam, streptomycin
2. NSAIDS: ibuprofen, naproxen
112
What occurs during drug-induced thrombocytopenia?
1. Drug binds covalently to the cell surface proteins
2. Modifies the surface antigens of the RBC or platelet
3. IgG are generated against the drug-protein complex
4. Lysis of cell that drug-cell complex by CDC
113
What occurs during Type 2 HS?
Antibodies bind to there drug-protein complexes and induce CDC or opsonization by macrophages primary in the spleen
114
What cell drug complexes effect type 2 HS?
1. Anemia RBCs targets
2. Thrombocytopenia-platelets targeted
3. Agranulocytosis-granulocytes targeted
