Tutorial 2 - Immunopathology & case studies

Question 1

State the types of hypersensitivity (4)

Answer 1

Type I - immediate hypersense
Type II - cytotoxic/ cytolytic hypersense
Type III - Lytic enzymes
Type IV - delayed hypersense

Question 2

Explain Type I hypersensitivity?

Answer 2

Immediate hypersensitivity:

• mediated IgE, mast cells involved
• reaction occurs within 30 mins exposure

Question 3

Explain Type II hypersensitivity?

Answer 3

Cytotoxic/ cytolytic hypersensitivity:

1. mediated IgG or IgM binding to antigens on cell surface
2. this activates complement cascade
3. leads to cell destruction

Question 4

Explain Type III hypersensitivity?

Answer 4

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)

Question 5

Explain Type IV hypersensitivity?

Answer 5

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

Question 6

With type III hypersensitivity, how long after antibody-antigen interaction does reaction occur?

Answer 6

~hours

Question 7

T/f: Type IV hypersensitivity involves antibody-antigen complex activating a complement system?

Answer 7

false, no antibodies involved, instead cytotoxic T cells (CD8+) and Th1 cells (CD4+)

Question 8

With type IV hypersensitivity, how long after antibody-antigen interaction does reaction occur?

Answer 8

days to weeks

Question 9

explain what is meant by a ‘hypersensitivity’?

Answer 9

a disorder which is caused by an immune response essentially going ‘too far’

Question 10

which type(s) of hypersensitivity involve an immune complex being formed?

Answer 10

type II, III

Question 11

allergic diseases (such as asthma) are which kind of hypersensitivity

Answer 11

• 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

Question 12

allergic diseases affect _% of western world?

Answer 12

20%

Question 13

airbourne allergens produce an IgE (immediate, type I) response in _% of individuals, however only 20% develop clinical symptoms

Answer 13

50%; 20%

Question 14

t/f: allergic diseases likely have a genetic component

Answer 14

true

Question 15

Describe steps in an allergic reaction? (brief)

Answer 15

1. Sensitization - IgE produced in response to allergic stimulus, binds to receptors on mast cells
2. Activation - re-exposure or challenge to antigen triggers mast cells to respond by releasing contents of their granules
3. Effector - inflammatory mediators from mast cells causes a complex response involving various immune cells

Question 16

Examples of allergic diseases?

Answer 16

asthma, rhinitis, eczema, allergies to food

Question 17

Allergen particles are generally?

Answer 17

• small proteins

- small soluble proteins carried on pollen grains or dust mite faeces (for air-bourne)

Question 18

What is it that initially leads to the stimulus of an allergic reaction?

Answer 18

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

Question 19

Where/ by what is IgE produced in allergic reactions?

Answer 19

• by plasma cells

- in lymph nodes & sites of allergic reaction

Question 20

Where is IgE predominantly localized?

Answer 20

• primarily in tissues

- low levels in blood serum

Question 21

What is IgE bound to, and how?

Answer 21

• mast cells

- binds to FcεRI receptor

Question 22

Physiologically, what occurs when IgE and antigen bind?

Answer 22

1. IgE-antigen complex (immune complex) forms
2. this crosslinks FcεRI
3. causes release chemical mediatiors from mast cell
4. leads to allergic reaction

Question 23

What is required for IgE generation?

Answer 23

Th2 cytokines

Question 24

Explain the basic process of IgE generation?

What phase of the allergic reaction process is this?

Answer 24

• 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.

Question 25

In respiratory or gut mucosa, sensitization step of allergic reaction occurs slightly differently. Expand on this.

Answer 25

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)

Question 26

t/f: all allergic diseases are a type I hypersensitivity, and involve the formation of IgE

Answer 26

true (as far as I can tell)

Question 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?

Answer 27

a. ) Mast cells primarily, also basophils b. ) IgE c. ) FcεRI

Question 28

what is FcεRI?

Answer 28

a high affinity IgE receptor

Question 29

Where are mast cells mostly located, in terms of those involved in allergic reactions?

Answer 29

mucosal and epithelial tissues in vicinity of small BV's & subendothelial CT

Question 30

Where are basophils located, in terms of those related to allergic reactions?

Answer 30

in circulation (fully matured)

Question 31

For how long may IgE persist on cell surfaces?

Answer 31

weeks

Question 32

During activation, when mast cell releases granules, does it die?

Answer 32

Mast cell does not lyse or die; granules can be re-synthesized and cells resume function

Question 33

cytokines released in effector step include?

Answer 33

IL-3, IL-4, IL-5, IL-8, IL-9, TNF-αand GM-CSF

Question 34

Physiologic consequences of IgE mediated mast cell degranulation depend on?

Answer 34

1. dose of antigen | 2. route of entry to site of allergic reaction

Question 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?

Answer 35

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

Question 36

how long do effects of late phase allergy persist?

Answer 36

several days

Question 37

what is late phase allergic characterised by?

Answer 37

infiltration of: - eosinophils - macrophages - Th2 cells - chemokines (released by mast cells)

Question 38

which cells dominate in late phase allergic reaction?

Answer 38

eosinophils

Question 39

where are eosinophils produced?

Answer 39

bone marrow

Question 40

what factors recruit eosinophils, making them migrate to site of allergic reaction?

Answer 40

IL-4, chemokines

Question 41

Th2 cells release cytokines promoting growth and differentiation of eosinophils. Which ones specifically? Which is most key?

Answer 41

IL-3, IL-5, GM-CSF IL-5 is most key

Question 42

How do eosinophils contribute to late phase/ effector phase of allergic reaction?

Answer 42

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)

Question 43

define anaphylaxis

Answer 43

severe, life threatening allergic reaction

Question 44

what triggers anaphylaxis

Answer 44

allergen in bloodstream, or absorbed into gut or skin

Question 45

anaphylaxis is what kind of hypersensitivity?

Answer 45

type I

Question 46

what's the main critical mediator for anaphylaxis?

Answer 46

histamine, rises within 5 mins and stays elevated for 30-60 minutes

Question 47

stimulation to histamine receptors effect on... a. ) BV's? b. ) HR & coronary artery? c. ) respiratory tract?

Answer 47

1. increased vascular permeability causing urticaria, angioedema 2. increased HR, coronary artery vasospasm 3. contraction smooth muscle bronchiole tract & GIT; wheezing, short breath

Question 48

Major causes of death associated with anaphylaxis?

Answer 48

massive edema, shock, bronchiole constriction

Question 49

define asthma

Answer 49

- chronic disease of lower airways | - episodes of reversible airflow limitation

Question 50

t/f: allergy is key in all asthma

Answer 50

false, only most

Question 51

airway hyperreactivity (wheeze) in asthma is caused by what cytokines/ chemical mediators?

Answer 51

late phase reactions: - IL-13, histamine and leukotrienes involved - IL-13 stimulates mucus secretion

Question 52

airway hyperreactivity - define

Answer 52

bronchial contraction stimulated by non-specific stimuli (ie. histamine), involving SM

Question 53

Describe some of the late phase reactions occurring in asthma?

Answer 53

1. Eosinophil inflitration causes chronic inflammation bronchial mucosa 2. Mucus build up, edema, damaged epithelium overall effect is occlusion of bronchial lumen

Question 54

List some asthma triggers from non-Th2 priming stimuli?

Answer 54

cigarette smoke, strong perfume, air pollution, infection this suggests not all asthma is totally Th2 mediated

Question 55

State the 2 types of asthma phenotypes?

Answer 55

Allergic and non-allergic

Question 56

Main difference between 2 phenotypes of asthma?

Answer 56

allergic - Th2 and thus IgE mediated | non-allergic - not Th2 mediated, instead associated with exposure to irritants

Question 57

Innate lymphoid cells: a. ) function like? b. ) react to?

Answer 57

- function like adaptive T cells | - react promptly to wide range of innate signals

Question 58

ILC2's secrete large quantities of?

Answer 58

IL-5, IL-13 (type 2 cytokines)

Question 59

ILC2's have receptors for?

Answer 59

IL-33 (AKA ST2), IL-25

Question 60

ILC2's function like in?

Answer 60

type 2 immunity | type 1 immunity - cell mediated, type 2 - humoral

Question 61

ILC2's means what?

Answer 61

type 2 innate lymphoid cells

Question 62

ILC2's function like which cell? ILC2's function in which type of asthma?

Answer 62

TH2 helper cells non-allergic asthma

Question 63

process of non-allergic asthma?

Answer 63

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

Question 64

Describe some recent, evolving concepts with regard to asthma?

Answer 64

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

Question 65

define 'atopy'?

Answer 65

genetic tendency to develop allergy

Question 66

state the main TH2 cytokines?

Answer 66

IL-4, IL-13

Question 67

Name the mediators released by mast cells, as well as their effects?

Answer 67

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)

Question 68

What cell types and cytokines are involved in the late stage of allergy?

Answer 68

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.

Question 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?

Answer 69

a. ) Mast cells. b. ) Contraction c. ) vascular permeability, edema d. ) mucus secretion e. ) release stomach acid f. ) preformed

Question 70

difference between IgG and IgM?

Answer 70

IgG is more specific to antigen, prevalent in late phase, memory antibody IgM has greater avidity (strength), prevalent in early phase

Question 71

Name diseases associated with type 1 hypersensitivity?

Answer 71

asthma, allergies, rhinitis, eczema

Question 72

Explain what happens in anaphylaxis?

Answer 72

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

Question 73

How may anaphylaxis be treated?

Answer 73

adrenaline - relaxes SM - reduces vascular permeability (stimulates formation tight gap-junctions) - improves CO (stopping vascular collapse) overall changes blood pressure, saves life

Question 74

state the function of the following cytokine: | Interleukin-3 (IL-3)

Answer 74

promotes growth and differentiation of eosinophils

Question 75

state the function of the following cytokine: | Chemokines

Answer 75

recruits eosinophils causing them to migrate

Question 76

state the function of the following cytokine: | GM-CSF

Answer 76

promotes growth and differentiation of eosinophils

Question 77

for the following cytokine, state which cell(s) release it and its function: IL-4

Answer 77

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

Question 78

for the following cytokine, state which cell(s) release it and its function: IL-13

Answer 78

released by TH2 cells and ICL2's, causes: - B cell to differentiate into plasma cell and produce IgE specifically - airway hyperreactivity (wheezing, mucus secretion)

Question 79

for the following cytokine, state which cell(s) release it and its function: IL-5

Answer 79

released by TH2's & ICL2's, causes: | -promotes growth and differentiation of eosinophils

Question 80

for the following cytokine, state which cell(s) release it and its function: IL-8

Answer 80

released by mast cells, causes neutrophils to migrate to site

Question 81

multiple sclerosis - what type of hypersensitivity?

Answer 81

type IV, an autoimmune disease which is cell mediated

Question 82

explain the aetiology behind multiple sclerosis?

Answer 82

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

Question 83

explain the pathogenesis behind multiple sclerosis?

Answer 83

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

Question 84

is multiple sclerosis cell mediated or humoral? What substances or cells are involved?

Answer 84

- cell mediated - T cells (T helper CD4, cytotoxic CD8) - APC's - B cells

Question 85

What're the 4 types of multiple sclerosis?

Answer 85

1. Benign MS 2. Relapsing Remittent MS 3. Secondary Chronic Progressive MS 4. Primary progressive MS

Question 86

Distinguish between ICL1 and ICL2?

Answer 86

``` ICL1 = non-cytotoxic, tissue resident, fight bacteria ICL2 = non-allergic asthma function ```