Lecture 4 - the lungs - immunology and inflammation

Question 1

explain how epithelial surfaces are the first line of defence against infection?

Answer 1

Successful infection normally involves adhering to cells via specific receptors > prevents dislodgement/allows invasion

Epithelial cells secrete mucus > interferes with adhesion and results in expulsion resulting from beating of cilia

Epithelial cells produce antimicrobial peptides such as b-defensins that damage bacterial cell membranes and surfactant proteins A and D that facilitate phagocytosis

Question 2

explain what epithelium penetration results in and activated macrophages do?

Answer 2

Epithelium penetration results in recognition of pathogen surface molecules by macrophages and subsequent phagocytosis

Activated macrophages secrete cytokines (affect behaviour of other cells) and chemokines (attract other cells)

Cytokines and chemokines therefore initiate inflammation

Question 3

what do activated macrophages secrete and what effect does this have on local vs systemic effects?

Answer 3

activated macrophages secrete a range of cytokines such as TNF-a, IL-6, IL-1b, cxcl8 AND il-12.

TNF-a, IL-6, IL-1b have local effects and help to fight infection. also have systemic effects that can be harmful - fever

Question 4

how to infectious agents induce adaptive immunity?

Answer 4

activating DCs:

Pathogens are ingested by immature dendritic cells (DCs) in infected tissues

This is dependent on Pathogen Recognition Receptors (PPRs) or macropinocytosis

DCs mature and migrate to peripheral lymphoid organs and present pathogen antigens to T cells

T cells become activated and contribute to adaptive immunity

Question 5

what are important cell types?

Answer 5

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 6

how are epithelial cells activated ?

Answer 6

Epithelial cells can be activated directly by molecules such as allergens via pattern recognition receptors or protease activated receptors

Question 7

what do allergenic proteases do?

Answer 7

Allergenic proteases can also decrease barrier function by cleaving epithelial cell tight junction proteins and gain access to underlying cells like DCs

Question 8

what do cytokines produced by epithelial cells include and cause?

Answer 8

Cytokines produced by epithelial cells include IL-25 and IL-33, which cause migration and activation of DCs to induce T cell immune responses

Question 9

when can there be high levels of igE ?

Answer 9

Higher amounts can be a sign that the body overreacts to allergens, which can lead to an allergic reaction.

when the body is fighting an infection from a parasite and from some immune system conditions.

Question 10

how are TH2 antigen delivered?

Answer 10

Th2-inducing antigen delivered trans-mucosally and at low dosage is taken up and processed by Dendritic cells in the respiratory mucosa

Question 11

where do dendritic cells migrate to?

Answer 11

DCs migrate to regional lymph nodes and mature into cells that favour Th2 differentiation

Question 12

what do Th2 cells secrete?

Answer 12

Th2 cells secrete IL-4, IL-5 and IL-13

Question 13

what does IL-4 promote, Il-5 drive and il-3 cause ?

Answer 13

IL-4 promotes IgE production in B cells, IL-5 drives eosinophil recruitment in lung tissue, IL-13 causes bronchial hyper-reactivity

Question 14

what does ILC2 cells secrete and what do they represent?

Answer 14

ILC2 cells secrete “large” amounts IL-5 and IL-13 and “small” amounts of IL-4

ILC2s may represent early source of cytokines like IL-4 for Th2 polarisation

Question 15

wat does IL5 support development of?

Answer 15

IL-5 supports development of eosinophils in the bone marrow and recruitment to the circulation

Recruitment to the lungs is supported by the chemokines, eotaxin 1-3

Question 16

what are eosinophil synthesis mediators and what effect do they have?

Answer 16

Eosinophils synthesis mediators such as cytokines and leukotrienes that amplify the inflammatory response

Question 17

what does eosinophil peroxidase cause?

Answer 17

Eosinophil peroxidase causes bronchial hyper-reactivity and activation of DCs to drive Th2 polarisation

Question 18

what can eosinophil do do lungs?

Answer 18

Eosinophil major basic protein can damage structural cells of the lungs

Question 19

describe mast cells

Answer 19

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

Question 20

what are molecules released by activated mast cells?

Answer 20

enzymes, toxic mediator, cytokien, chemokinase and lipid mediators

Question 21

describe neutrophils in asthmatic patients

Answer 21

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

IL-17 plays a role, but where in the asthmatic lung it is produced and by what cell type is currently not entirely clear

IL-17 increases airway remodelling by various methods, e.g., by promoting fibroblast proliferation

Neutrophils/IL-17 important in pathogenesis of COPD