Lecture 4 - the lungs - immunology and inflammation Flashcards
explain how epithelial surfaces are the first line of defence against infection?
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
explain what epithelium penetration results in and activated macrophages do?
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
what do activated macrophages secrete and what effect does this have on local vs systemic effects?
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
how to infectious agents induce adaptive immunity?
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
what are important cell types?
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
how are epithelial cells activated ?
Epithelial cells can be activated directly by molecules such as allergens via pattern recognition receptors or protease activated receptors
what do allergenic proteases do?
Allergenic proteases can also decrease barrier function by cleaving epithelial cell tight junction proteins and gain access to underlying cells like DCs
what do cytokines produced by epithelial cells include and cause?
Cytokines produced by epithelial cells include IL-25 and IL-33, which cause migration and activation of DCs to induce T cell immune responses
when can there be high levels of igE ?
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.
how are TH2 antigen delivered?
Th2-inducing antigen delivered trans-mucosally and at low dosage is taken up and processed by Dendritic cells in the respiratory mucosa
where do dendritic cells migrate to?
DCs migrate to regional lymph nodes and mature into cells that favour Th2 differentiation
what do Th2 cells secrete?
Th2 cells secrete IL-4, IL-5 and IL-13
what does IL-4 promote, Il-5 drive and il-3 cause ?
IL-4 promotes IgE production in B cells, IL-5 drives eosinophil recruitment in lung tissue, IL-13 causes bronchial hyper-reactivity
what does ILC2 cells secrete and what do they represent?
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
wat does IL5 support development of?
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
what are eosinophil synthesis mediators and what effect do they have?
Eosinophils synthesis mediators such as cytokines and leukotrienes that amplify the inflammatory response
what does eosinophil peroxidase cause?
Eosinophil peroxidase causes bronchial hyper-reactivity and activation of DCs to drive Th2 polarisation
what can eosinophil do do lungs?
Eosinophil major basic protein can damage structural cells of the lungs
describe mast cells
Express FceRI and so bind IgE with high affinity; cross-linking of IgE by allergens causes degranulation and release of inflammatory mediators
what are molecules released by activated mast cells?
enzymes, toxic mediator, cytokien, chemokinase and lipid mediators
describe neutrophils in asthmatic patients
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
