Lecture 4: The lungs- immunology and inflammation Flashcards
What is the single largest infectious cause of death in children worldwide?
Pnuemonia
What are the stages in infection?
- Pathogens adhere to epithelium
- Local infection, penetration of epithelium
- Local infection of tissue
- Adaptive immunity
What protects pathogens from adhering to the epithelium?
- Normal flora
- Local chemical factors
- Phagocytes (especially in lung)
What protects against local infection, penetration of epithelium?
- Wound healing induced
- Antimicrobial proteins and peptides, phagocytes and complement destroy invading microorganisms
What protects against local infections of tissues?
- 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
What protects against adaptive immunity?
- Infection cleared by specific antibody
- T-cell dependanct macrophage activation and cytotoxic T cells
What is the first line of defence against infection?
Epithelial surface - epithelial cells held together by tight junctions form a seal against external environment
What do epithelial cells secrete?
Mucus - interferes with adhesion and results in expulsion resultin from beating of cilia
What do epithelial cells produce?
Antimicrobial peptides such as b-defensins that damage bacterial cell membranes and surfactant proteins A and D that facilitate phagocytosis
What does epitheliam penetration result in?
Recognition of pathogen surface molecules by macrophages and subsequent phagocytosis
What do activated macrophages secrete?
Cytokines and Chemokines
What do cytokines do?
Affect behaviour of other cells
What do chemokines do?
Attract other cells
Define inflammation
Heat, pain, redness and swelling due to effects of cytokines/other mediators on local blood vessels
Name the cytokines
- Il-1B
- TNF-a
- IL-6
- CXCL8
- IL-12
What are the local effects of IL-1B
- Activates vascular endothelium
- Activates lymphocytes
- Local tissue destruction increases access of effe tor cells
What are the local effects of TNF-a?
- 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
What are the local effects of IL6
- Lymphocyte activation
- Increased antibody production
What are the local effects of CXCL8?
Chemitactic factor recruits neutrophils, basophils and T cells to site of infection
What are the local effects of IL12?
- Activates NK cells
- Induces the differentiation of CD4 T cells into Th 1 cells
What are the systemic effects of IL-1B?
Fewer production of IL6
What are the systemic effects of TNF-a?
- Fever
- Mobilization of metabolites
- Shock
What are the systemic effects of IL6?
- Fever
- Induces acute phase protein prodcution
What ingests pathogens in infected tissues?
Immature dendritic cells - this is dependant on Pathogen Recognition Receptors (PPRs) or macropinocytosis
What do dendritic cells mature and migrate to?
Peripheral lymphoid organs and present pathogen antigens to T cells
Where do immature dendritic cells reside?
In peripheral tissues
How do dedritic cells migrate?
Via lymphatic vessels to regional lymph noded
What do mature dendritic cells activate?
Naive T cells in lymphoid organs such as lymph nodes
Name important cells in lung disease
- 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
What can activate epthelial cells directly?
molecules such as allergens via pattern recognition receptors or protease activated receptors
What can decrease barrier function?
Allergenic proteases by cleaving epithelial cell tight junction proteins and gain access to underlying cells like DCs
What causes migration and activation of DCs to induce T cell immune responses
Cytokines produced by epithelial cells including IL-25 and IL-33
What are the features of airborne allegens that may promote the primimg of Th2 cells that drive IgE responses?
- Protein, often with carbohydrate side chains
- Low dose
- Low molecular weight
- Highly soluble
- Stable
- Contains peptides that bind host MHC class II
What is the function of IL4?
promotes IgE production in B cells
What is the function of IL5?
Drives eosinophil recruitment in lung tissue
What is the function of IL-13?
Causes bronchial hyper-reactivity
What does ILC2 secrete?
“large” amounts IL-5 and IL-13 and “small” amounts of IL-4
What does IL-5 supports development of?
eosinophils in the bone marrow and recruitment to the circulation
What supports recruitment of eosinophils to the lungs?
chemokines, eotaxin 1-3
What do eosinophils synthesis?
Mediators such as cytokines and leukotrienes that amplify the inflammatory response
What does Eosinophil peroxidase cause?
Bronchial hyper-reactivity and activation of DCs to drive Th2 polarisation
What can damage structural cells of the lungs?
Eosinophil major basic protein
What imparts characteristic orange colour in eosinophil stais?
eosin
What imparts characteristic orange colour in eosinophil stais?
eosin
What do mass cells express?
Express FceRI and so bind IgE with high affinity; cross-linking of IgE by allergens causes degranulation and release of inflammatory mediators
What can infiltrate the bronchial smooth muscle layer and contribute to bronchial hyper-responsiveness?
Mast cells
What leads to rapid release of inflammatory mediators?
IgE antibody cross-linking on mast-cell surfaces
What does a resting mass cell contain?
Granules containing histamine and other inflammatory mediators
What causes release of granule contents?
Multivalent antigen cross links bound IgE antibody
Wha molecules are realeased by activated mast cells?
- enzymes
- Toxic mediator
- Cytokine
- Chemokine
- Lipid mediator
Name enzymes released by acativated mast cells
- Tryptase
- Chymase
- Cathepsin G
- Carboxypeptidase
Name toxic mediators released by activated mast cells
- Histamine
- Heparin
Name cytokines released by acativated mast cells
- IL4
- IL13
- IL33
- IL3
- IL5
- GM-CSF
- TNF-A
Name chemokine released by activated mast cells
CCL3
Name lipid mediator released by activated mast cells
- Prostaglandin D2, E2
- Leukotrienes C4, D4, E4
- Platelet activating factor
What are the biological effects of enzymes produced by mast cells?
Remodel connective tissue matrix
What are the biological effects of toxic mediators produced by mast cells?
- Toxic to parasites
- Increase vascular permeability
- Cause smooth muscle contraction
- Anticoagulation
What are the biological effects of cytokine IL4, IL13, IL33?
Stimulate and amplify Th2 cell response
What are the biological effects of cytokine IL3, IL5, GM-CSF?
Promote eosinophil prodcution and activation
What are the biological effects of cytokine TNF-a?
- Promotes inflammation
- Stimulates cytokine production by many cell types
- Activates endothelium
What are the biological effects of chemokine CCL3?
Attracts monocytes, macrophages and neutrophils
What are the biological effects of lipid mediators; Prostaglandin D2, E2 and leukotrienes C4, D4, E4?
- Smooth muscle contraction
- chemotaxis of eosinophils, basophils and Th2 cells
- Increase vascular permeability
- Stimulate mucus secretion
- Bronchoconstriction
What are the biological effects of lipid mediator - platelet activating factor?
- Attracts leukocytes
- Amplifies production of lipid mediators
- Activates neutrophils, eosinophils and platelets
What does IL17 do?
Increases airway remodelling by various methods, e.g., by promoting fibroblast proliferation
Describe neutrophil predominant disease in asthma 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
- Neutrophils/IL-17 important in pathogenesis of COPD
What are Th1 cells induced by?
IL-12
What do Th1 cells produce
IFNy
What is the role of Th1 cells?
- 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)
