Tutorial 2 - Immunopathology & case studies Flashcards
1
Q
State the types of hypersensitivity (4)
A
Type I - immediate hypersense
Type II - cytotoxic/ cytolytic hypersense
Type III - Lytic enzymes
Type IV - delayed hypersense
2
Q
Explain Type I hypersensitivity?
A
Immediate hypersensitivity:
- mediated IgE, mast cells involved
- reaction occurs within 30 mins exposure
3
Q
Explain Type II hypersensitivity?
A
Cytotoxic/ cytolytic hypersensitivity:
- mediated IgG or IgM binding to antigens on cell surface
- this activates complement cascade
- leads to cell destruction
4
Q
Explain Type III hypersensitivity?
A
Lytic enzymes:
1. mediated IgG or IgM binding to antigens on cell surface (forming Ag-IgM or Ag-IgG complex)
2. complex activates complement cascade
3. granulocytes (ie. neutrophils) attracted to site of activation
4. damage caused by release of lytic enzymes
(reaction occurs within hours of challenge to antigen)
5
Q
Explain Type IV hypersensitivity?
A
Delayed-type hypersensitivity:
- no antibodies involved, instead cytotoxic T cells (CD8+) and Th1 cells (CD4+)
1. mediated by Th1 cells, upon their activation they release cytokines
2. causes accumulation and activation macrophages, plus activation cytotoxic T cells
3. these macrophages and cytotoxic T cells cause local damage
6
Q
With type III hypersensitivity, how long after antibody-antigen interaction does reaction occur?
A
~hours
7
Q
T/f: Type IV hypersensitivity involves antibody-antigen complex activating a complement system?
A
false, no antibodies involved, instead cytotoxic T cells (CD8+) and Th1 cells (CD4+)
8
Q
With type IV hypersensitivity, how long after antibody-antigen interaction does reaction occur?
A
days to weeks
9
Q
explain what is meant by a ‘hypersensitivity’?
A
a disorder which is caused by an immune response essentially going ‘too far’
10
Q
which type(s) of hypersensitivity involve an immune complex being formed?
A
type II, III
11
Q
allergic diseases (such as asthma) are which kind of hypersensitivity
A
- type I (immediate), IgE involved
- pollen, irritant particles such as smoke etc. are inhaled and this causes an asthma attack within ~30 mins
- bronchoconstriction occurs on the already swollen and mucus producing airways, hard for air to flow
12
Q
allergic diseases affect _% of western world?
A
20%
13
Q
airbourne allergens produce an IgE (immediate, type I) response in _% of individuals, however only 20% develop clinical symptoms
A
50%; 20%
14
Q
t/f: allergic diseases likely have a genetic component
A
true
15
Q
Describe steps in an allergic reaction? (brief)
A
- Sensitization - IgE produced in response to allergic stimulus, binds to receptors on mast cells
- Activation - re-exposure or challenge to antigen triggers mast cells to respond by releasing contents of their granules
- Effector - inflammatory mediators from mast cells causes a complex response involving various immune cells
16
Q
Examples of allergic diseases?
A
asthma, rhinitis, eczema, allergies to food
17
Q
Allergen particles are generally?
A
- small proteins
- small soluble proteins carried on pollen grains or dust mite faeces (for air-bourne)
18
Q
What is it that initially leads to the stimulus of an allergic reaction?
A
Subsequent exposure - when an individual who’s produced IgE in response to an antigen in the past is then re-exposed to this same antigen
19
Q
Where/ by what is IgE produced in allergic reactions?
A
- by plasma cells
- in lymph nodes & sites of allergic reaction
20
Q
Where is IgE predominantly localized?
A
- primarily in tissues
- low levels in blood serum
21
Q
What is IgE bound to, and how?
A
- mast cells
- binds to FcεRI receptor
22
Q
Physiologically, what occurs when IgE and antigen bind?
A
- IgE-antigen complex (immune complex) forms
- this crosslinks FcεRI
- causes release chemical mediatiors from mast cell
- leads to allergic reaction
23
Q
What is required for IgE generation?
A
Th2 cytokines
24
Q
Explain the basic process of IgE generation?
What phase of the allergic reaction process is this?
A
- certain antigens/ routes of antigen presentation favour IgE production
1. antigen presented (at low doses) over mucosal surfaces
2. this favours activation of Th2 cells (instead of Th1)
3. Th2 cells produce Th2 cytokines, which induce IgE generation from plasma cells
This is sensitization step.
25
In respiratory or gut mucosa, sensitization step of allergic reaction occurs slightly differently. Expand on this.
1. allergens encounter dendritic cells or macrophages
2. these cells differentiate into antigen presenting cells (APC)
3. APC's co-stimulatory activity stimulates Th2 cell production
4. Th2 cell cytokines (IL-4, IL-13) cause B cells to differentiate into plasma cells
5. plasma cells produce IgE
(basically - involves dendritic cells and macrophages differentiating into APC's, which co-stimulate Th2 cells; then all the same)
26
t/f: all allergic diseases are a type I hypersensitivity, and involve the formation of IgE
true (as far as I can tell)
27
The second step of allergic reactions is 'activation'.
a. ) What cell(s) does this involve?
b. ) What do these cell(s) have bound to them?
c. ) What receptor do these cells have on them?
a. ) Mast cells primarily, also basophils
b. ) IgE
c. ) FcεRI
28
what is FcεRI?
a high affinity IgE receptor
29
Where are mast cells mostly located, in terms of those involved in allergic reactions?
mucosal and epithelial tissues in vicinity of small BV's & subendothelial CT
30
Where are basophils located, in terms of those related to allergic reactions?
in circulation (fully matured)
31
For how long may IgE persist on cell surfaces?
weeks
32
During activation, when mast cell releases granules, does it die?
Mast cell does not lyse or die; granules can be re-synthesized and cells resume function
33
cytokines released in effector step include?
IL-3, IL-4, IL-5, IL-8, IL-9, TNF-αand GM-CSF
34
Physiologic consequences of IgE mediated mast cell degranulation depend on?
1. dose of antigen
| 2. route of entry to site of allergic reaction
35
Allergic reaction has 3 stages, but overall the allergic response has 2 phases.
What are these phases, how long do they last, and what are they characterized by?
1. Early phase
- minutes
- caused by direct effects on BV and SM due to mediators (ie. histamine)
2. Late phase
- 6-10 hrs after inital allergic reaction
- caused by influx of inflammatory cells attracted by chemokines
36
how long do effects of late phase allergy persist?
several days
37
what is late phase allergic characterised by?
infiltration of:
- eosinophils
- macrophages
- Th2 cells
- chemokines (released by mast cells)
38
which cells dominate in late phase allergic reaction?
eosinophils
39
where are eosinophils produced?
bone marrow
40
what factors recruit eosinophils, making them migrate to site of allergic reaction?
IL-4, chemokines
41
Th2 cells release cytokines promoting growth and differentiation of eosinophils. Which ones specifically? Which is most key?
IL-3, IL-5, GM-CSF
IL-5 is most key
42
How do eosinophils contribute to late phase/ effector phase of allergic reaction?
1. Eosinophils possess FcεRII receptor for IgE antibody, and Fc receptr for IgG
2. IgE and IgG which are bound to an antigen → activate eosinophils → degranulation, releasing...
eosinophillic cationic protein, eosinophillic peroxidase, PAF, leukotrienes, major basic protein
3. These cause extensive tissue damage (particularly to respiratory epithelium - asthma)
43
define anaphylaxis
severe, life threatening allergic reaction
44
what triggers anaphylaxis
allergen in bloodstream, or absorbed into gut or skin
45
anaphylaxis is what kind of hypersensitivity?
type I
46
what's the main critical mediator for anaphylaxis?
histamine, rises within 5 mins and stays elevated for 30-60 minutes
47
stimulation to histamine receptors effect on...
a. ) BV's?
b. ) HR & coronary artery?
c. ) respiratory tract?
1. increased vascular permeability causing urticaria, angioedema
2. increased HR, coronary artery vasospasm
3. contraction smooth muscle bronchiole tract & GIT; wheezing, short breath
48
Major causes of death associated with anaphylaxis?
massive edema, shock, bronchiole constriction
49
define asthma
- chronic disease of lower airways
| - episodes of reversible airflow limitation
50
t/f: allergy is key in all asthma
false, only most
51
airway hyperreactivity (wheeze) in asthma is caused by what cytokines/ chemical mediators?
late phase reactions:
- IL-13, histamine and leukotrienes involved
- IL-13 stimulates mucus secretion
52
airway hyperreactivity - define
bronchial contraction stimulated by non-specific stimuli (ie. histamine), involving SM
53
Describe some of the late phase reactions occurring in asthma?
1. Eosinophil inflitration causes chronic inflammation bronchial mucosa
2. Mucus build up, edema, damaged epithelium
overall effect is occlusion of bronchial lumen
54
List some asthma triggers from non-Th2 priming stimuli?
cigarette smoke, strong perfume, air pollution, infection
this suggests not all asthma is totally Th2 mediated
55
State the 2 types of asthma phenotypes?
Allergic and non-allergic
56
Main difference between 2 phenotypes of asthma?
allergic - Th2 and thus IgE mediated
| non-allergic - not Th2 mediated, instead associated with exposure to irritants
57
Innate lymphoid cells:
a. ) function like?
b. ) react to?
- function like adaptive T cells
| - react promptly to wide range of innate signals
58
ILC2's secrete large quantities of?
IL-5, IL-13 (type 2 cytokines)
59
ILC2's have receptors for?
IL-33 (AKA ST2), IL-25
60
ILC2's function like in?
type 2 immunity
| type 1 immunity - cell mediated, type 2 - humoral
61
ILC2's means what?
type 2 innate lymphoid cells
62
ILC2's function like which cell?
ILC2's function in which type of asthma?
TH2 helper cells
non-allergic asthma
63
process of non-allergic asthma?
1. irritant or infection acts on lung epithelium
2. triggers rapid release IL-33
3. activates ICL2's through ST2 receptors
4. leads to release of type 2 cytokines: IL-5 and IL-13
5. cytokines induce inflammatory cell infiltration, mucus production, airway hyperresponsiveness, EOSINOPHIL INFILTRATION
64
Describe some recent, evolving concepts with regard to asthma?
1. allergen-derived proteases act on epithelial cells, doing 2 things:
a. ) active protease-activated receptors, stimulate production of epithelial derived pro-T helper type 2 (Th2) cytokines such as IL-25 and IL-33
b. ) disrupt epithelial barrier, facilitating allergen delivery across epithelium
2. direct activation inflammatory cells (dendritic cells, pulmonary macrophages) exacerbating inflammatory response by eosinophils
65
define 'atopy'?
genetic tendency to develop allergy
66
state the main TH2 cytokines?
IL-4, IL-13
67
Name the mediators released by mast cells, as well as their effects?
1. Preformed mediators
- Histamine
- binding to H1 receptor (smooth muscle) → contraction
- binding to H1 receptor (endothelial cell) → vascular permeability, edema
- binding to H2 receptor → mucus secretion (respiratory mucosa), release stomach acid (gut mucosa)
2. Synthesized mediators
- Leukotrienes, prostoglandins → contraction bronchial and tracheal smooth muscle, vascular permeability, mucus secretion
- contribute to prolonged bronchospasm & mucus build up
- cytokines, chemokines → recruitment inflammatory cells (neutrophils, eosinophils, basophils, macrophages, lymphocytes)
- platelet activating factor (PAF) → causes platelets to aggregate → release mediators (ie. histamine)
68
What cell types and cytokines are involved in the late stage of allergy?
1. Eosinophils possess FcεRII receptor for IgE, and Fc receptor for IgG. When IgE or IgG bind to antigen they activate eosinophil causing degranulation. This releases eosinophillic cationic protein, eosinophillic peroxidase, PAF, leukotrienes and major basic protein. All of these cytokines cause major tissue damage.
2. Cytokine IL-8 from mast cells at allergy site stimulates neutrophils to migrate to the site. The neutrophil possesses Fc receptors for IgG, when antigen binds to the IgG this activates the neutrophil. Activated neutrophil phagocytoses the antigen-antibody complex, and releases leukotrienes and lysosomal enzymes causing tissue damage.
3. Infiltrating Th2 lymphocytes release cytokines to further perpetuate the response, stimulating a second wave of muscle contraction and sustained edema.
4. Mast cells release preformed (histamine) and synthesized (prostoglandins, leukotrienes) mediators.
69
a. ) What cell releases histamine?
b. ) Histamine on H1 receptor on smooth muscle?
c. ) Histamine on H1 receptor on endothelial cell?
d. ) Histamine on H2 receptor on respiratory epithelium?
e. ) Histamine on H2 receptor on gut mucosa?
f. ) What type of mediator is histamine?
a. ) Mast cells.
b. ) Contraction
c. ) vascular permeability, edema
d. ) mucus secretion
e. ) release stomach acid
f. ) preformed
70
difference between IgG and IgM?
IgG is more specific to antigen, prevalent in late phase, memory antibody
IgM has greater avidity (strength), prevalent in early phase
71
Name diseases associated with type 1 hypersensitivity?
asthma, allergies, rhinitis, eczema
72
Explain what happens in anaphylaxis?
1. allergen in bloodstream, on skin or GIT
2. rapid, type 1 hypersensitivity allergic reaction. This involves mast cells, IgE, inflammatory mediators etc. (sensitization, activation, reaction)
3. Histamine is a critical mediator in anaphylaxis sharply rising after 5 minutes and staying high for 30-60 mins. Histamine binds to H-receptors, causing...
a. ) increased BV permeability leading to urticaria, angioedema
b. ) Increased HR, coronary artery vasospasm
c. ) contraction SM of GIT and respiratory tract leading to wheezing, shortness of breath, nausea etc.
4. Eventually death may result due to the shock, edema, bronchiole constriction
73
How may anaphylaxis be treated?
adrenaline
- relaxes SM
- reduces vascular permeability (stimulates formation tight gap-junctions)
- improves CO (stopping vascular collapse)
overall changes blood pressure, saves life
74
state the function of the following cytokine:
| Interleukin-3 (IL-3)
promotes growth and differentiation of eosinophils
75
state the function of the following cytokine:
| Chemokines
recruits eosinophils causing them to migrate
76
state the function of the following cytokine:
| GM-CSF
promotes growth and differentiation of eosinophils
77
for the following cytokine, state which cell(s) release it and its function:
IL-4
released by T-helper cell type 2 (TH2 cell), causes:
- B cell to differentiate into plasma cell and produce IgE specifically
- recruits eosinophils, causing them to migrate to site
78
for the following cytokine, state which cell(s) release it and its function:
IL-13
released by TH2 cells and ICL2's, causes:
- B cell to differentiate into plasma cell and produce IgE specifically
- airway hyperreactivity (wheezing, mucus secretion)
79
for the following cytokine, state which cell(s) release it and its function:
IL-5
released by TH2's & ICL2's, causes:
| -promotes growth and differentiation of eosinophils
80
for the following cytokine, state which cell(s) release it and its function:
IL-8
released by mast cells, causes neutrophils to migrate to site
81
multiple sclerosis - what type of hypersensitivity?
type IV, an autoimmune disease which is cell mediated
82
explain the aetiology behind multiple sclerosis?
An interplay between environment and genetic factors:
1. Genes - if twin has it, 1/4 chance other does
2. Infection - endogenous retrovirus (EBV)
3. Environment - migration, low vitamin D
83
explain the pathogenesis behind multiple sclerosis?
1. BBB breakdown - when individual sick BBB becomes more permeable then when infection cleared BBB tightens up and T cells trapped inside
2. Autoimmunology - immune system attacks nervous system forming plaques/ lesions. Destroys oligodendrocytes causing demyelination.
3. Inflammation - T cell attacks on myelin triggers inflammation, antibodies & cytokines stimulated, destruction of tissue
84
is multiple sclerosis cell mediated or humoral? What substances or cells are involved?
- cell mediated
- T cells (T helper CD4, cytotoxic CD8)
- APC's
- B cells
85
What're the 4 types of multiple sclerosis?
1. Benign MS
2. Relapsing Remittent MS
3. Secondary Chronic Progressive MS
4. Primary progressive MS
86
Distinguish between ICL1 and ICL2?
```
ICL1 = non-cytotoxic, tissue resident, fight bacteria
ICL2 = non-allergic asthma function
```
