Lecture 4: The lungs- immunology and inflammation

Question 1

What is the single largest infectious cause of death in children worldwide?

Answer 1

Pnuemonia

Question 2

What are the stages in infection?

Answer 2

1. Pathogens adhere to epithelium
2. Local infection, penetration of epithelium
3. Local infection of tissue
4. Adaptive immunity

Question 3

What protects pathogens from adhering to the epithelium?

Answer 3

• Normal flora
• Local chemical factors
• Phagocytes (especially in lung)

Question 4

What protects against local infection, penetration of epithelium?

Answer 4

• Wound healing induced
• Antimicrobial proteins and peptides, phagocytes and complement destroy invading microorganisms

Question 5

What protects against local infections of tissues?

Answer 5

• Complement, cytokines, chemokines Phagocytes, NK cells
• Activation of macrophages
• Dendritic cells migrate to lymph nodes to initiate adaptive immunity
• Blood clotting helps limit spread of infection

Question 6

What protects against adaptive immunity?

Answer 6

• Infection cleared by specific antibody
• T-cell dependanct macrophage activation and cytotoxic T cells

Question 7

What is the first line of defence against infection?

Answer 7

Epithelial surface - epithelial cells held together by tight junctions form a seal against external environment

Question 8

What do epithelial cells secrete?

Answer 8

Mucus - interferes with adhesion and results in expulsion resultin from beating of cilia

Question 9

What do epithelial cells produce?

Answer 9

Antimicrobial peptides such as b-defensins that damage bacterial cell membranes and surfactant proteins A and D that facilitate phagocytosis

Question 10

What does epitheliam penetration result in?

Answer 10

Recognition of pathogen surface molecules by macrophages and subsequent phagocytosis

Question 11

What do activated macrophages secrete?

Answer 11

Cytokines and Chemokines

Question 12

What do cytokines do?

Answer 12

Affect behaviour of other cells

Question 13

What do chemokines do?

Answer 13

Attract other cells

Question 14

Define inflammation

Answer 14

Heat, pain, redness and swelling due to effects of cytokines/other mediators on local blood vessels

Question 15

Name the cytokines

Answer 15

• Il-1B
• TNF-a
• IL-6
• CXCL8
• IL-12

Question 16

What are the local effects of IL-1B

Answer 16

• Activates vascular endothelium
• Activates lymphocytes
• Local tissue destruction increases access of effe tor cells

Question 17

What are the local effects of TNF-a?

Answer 17

• Activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes

Question 18

What are the local effects of IL6

Answer 18

• Lymphocyte activation
• Increased antibody production

Question 19

What are the local effects of CXCL8?

Answer 19

Chemitactic factor recruits neutrophils, basophils and T cells to site of infection

Question 20

What are the local effects of IL12?

Answer 20

• Activates NK cells
• Induces the differentiation of CD4 T cells into Th 1 cells

Question 21

What are the systemic effects of IL-1B?

Answer 21

Fewer production of IL6

Question 22

What are the systemic effects of TNF-a?

Answer 22

• Fever
• Mobilization of metabolites
• Shock

Question 23

What are the systemic effects of IL6?

Answer 23

• Fever
• Induces acute phase protein prodcution

Question 24

What ingests pathogens in infected tissues?

Answer 24

Immature dendritic cells - this is dependant on Pathogen Recognition Receptors (PPRs) or macropinocytosis

Question 25

What do dendritic cells mature and migrate to?

Answer 25

Peripheral lymphoid organs and present pathogen antigens to T cells

Question 26

Where do immature dendritic cells reside?

Answer 26

In peripheral tissues

Question 27

How do dedritic cells migrate?

Answer 27

Via lymphatic vessels to regional lymph noded

Question 28

What do mature dendritic cells activate?

Answer 28

Naive T cells in lymphoid organs such as lymph nodes

Question 29

Name important cells in lung disease

Answer 29

- Airway Epithelial Cell and Dendritic Cell - Type 2 Helper T Cell (Th2 Cell) - Type 1 Helper T Cell (Th1 Cell) - Type 2 Innate Lymphoid Cell (ILC2) - Eosinophil - Neutrophil - Mast cell

Question 30

What can activate epthelial cells directly?

Answer 30

molecules such as allergens via pattern recognition receptors or protease activated receptors

Question 31

What can decrease barrier function?

Answer 31

Allergenic proteases by cleaving epithelial cell tight junction proteins and gain access to underlying cells like DCs

Question 32

What causes migration and activation of DCs to induce T cell immune responses

Answer 32

Cytokines produced by epithelial cells including IL-25 and IL-33

Question 33

What are the features of airborne allegens that may promote the primimg of Th2 cells that drive IgE responses?

Answer 33

- Protein, often with carbohydrate side chains - Low dose - Low molecular weight - Highly soluble - Stable - Contains peptides that bind host MHC class II

Question 34

What is the function of IL4?

Answer 34

promotes IgE production in B cells

Question 35

What is the function of IL5?

Answer 35

Drives eosinophil recruitment in lung tissue

Question 36

What is the function of IL-13?

Answer 36

Causes bronchial hyper-reactivity

Question 37

What does ILC2 secrete?

Answer 37

“large” amounts IL-5 and IL-13 and “small” amounts of IL-4

Question 38

What does IL-5 supports development of?

Answer 38

eosinophils in the bone marrow and recruitment to the circulation

Question 39

What supports recruitment of eosinophils to the lungs?

Answer 39

chemokines, eotaxin 1-3

Question 40

What do eosinophils synthesis?

Answer 40

Mediators such as cytokines and leukotrienes that amplify the inflammatory response

Question 41

What does Eosinophil peroxidase cause?

Answer 41

Bronchial hyper-reactivity and activation of DCs to drive Th2 polarisation

Question 42

What can damage structural cells of the lungs?

Answer 42

Eosinophil major basic protein

Question 43

What imparts characteristic orange colour in eosinophil stais?

Answer 43

eosin

Question 43

What imparts characteristic orange colour in eosinophil stais?

Answer 43

eosin

Question 44

What do mass cells express?

Answer 44

Express FceRI and so bind IgE with high affinity; cross-linking of IgE by allergens causes degranulation and release of inflammatory mediators

Question 45

What can infiltrate the bronchial smooth muscle layer and contribute to bronchial hyper-responsiveness?

Answer 45

Mast cells

Question 46

What leads to rapid release of inflammatory mediators?

Answer 46

IgE antibody cross-linking on mast-cell surfaces

Question 47

What does a resting mass cell contain?

Answer 47

Granules containing histamine and other inflammatory mediators

Question 48

What causes release of granule contents?

Answer 48

Multivalent antigen cross links bound IgE antibody

Question 49

Wha molecules are realeased by activated mast cells?

Answer 49

- enzymes - Toxic mediator - Cytokine - Chemokine - Lipid mediator

Question 50

Name enzymes released by acativated mast cells

Answer 50

- Tryptase - Chymase - Cathepsin G - Carboxypeptidase

Question 51

Name toxic mediators released by activated mast cells

Answer 51

- Histamine - Heparin

Question 52

Name cytokines released by acativated mast cells

Answer 52

- IL4 - IL13 - IL33 - IL3 - IL5 - GM-CSF - TNF-A

Question 53

Name chemokine released by activated mast cells

Answer 53

CCL3

Question 54

Name lipid mediator released by activated mast cells

Answer 54

- Prostaglandin D2, E2 - Leukotrienes C4, D4, E4 - Platelet activating factor

Question 55

What are the biological effects of enzymes produced by mast cells?

Answer 55

Remodel connective tissue matrix

Question 56

What are the biological effects of toxic mediators produced by mast cells?

Answer 56

- Toxic to parasites - Increase vascular permeability - Cause smooth muscle contraction - Anticoagulation

Question 57

What are the biological effects of cytokine IL4, IL13, IL33?

Answer 57

Stimulate and amplify Th2 cell response

Question 58

What are the biological effects of cytokine IL3, IL5, GM-CSF?

Answer 58

Promote eosinophil prodcution and activation

Question 59

What are the biological effects of cytokine TNF-a?

Answer 59

- Promotes inflammation - Stimulates cytokine production by many cell types - Activates endothelium

Question 60

What are the biological effects of chemokine CCL3?

Answer 60

Attracts monocytes, macrophages and neutrophils

Question 61

What are the biological effects of lipid mediators; Prostaglandin D2, E2 and leukotrienes C4, D4, E4?

Answer 61

- Smooth muscle contraction - chemotaxis of eosinophils, basophils and Th2 cells - Increase vascular permeability - Stimulate mucus secretion - Bronchoconstriction

Question 62

What are the biological effects of lipid mediator - platelet activating factor?

Answer 62

- Attracts leukocytes - Amplifies production of lipid mediators - Activates neutrophils, eosinophils and platelets

Question 63

What does IL17 do?

Answer 63

Increases airway remodelling by various methods, e.g., by promoting fibroblast proliferation

Question 64

Describe neutrophil predominant disease in asthma patients?

Answer 64

- Some asthma patients have neutrophil (and not eosinophil)-prominent disease with absence of Th2 cytokines - This is usually more severe with increased airway remodelling and is also late onset and associated with steroid resistance - Neutrophils/IL-17 important in pathogenesis of COPD

Question 65

What are Th1 cells induced by?

Answer 65

IL-12

Question 66

What do Th1 cells produce

Answer 66

IFNy

Question 67

What is the role of Th1 cells?

Answer 67

- Play a critical role in protection against mycobacterial disease - involved in protection against certain extracellular bacteria such as Klebsiella pneumoniae - involved in protection against respiratory viruses (e.g., influenza) and fungi (e.g., Aspergillus)