Block D - immune responses in the lungs Flashcards
why did the lungs evolve ?
Lungs evolved as efficient gas-exchanging apparatus, with a wide surface area that is covered with a single layer of epithelial cells.
upper airways ?
UPPER AIRWAYS are the conducting airways which allow air in and exchange air out (2cm2 cross-section) with up to 23 bifurcations, trachea, bronchi, bronchioles.
lower airways ?
LOWER AIRWAYS Gas exchange occurs (75m2 cross-section) this occurs in the respiratory bronchioles which lead to 300 million alveoli. Large mucosal surface and inhale 9000 L of air per 24hr at rest. Filtration of entire cardiac output so blood is in close proximity to air coming in , so pathogens can enter here.
are the lungs sterile ?
Lungs are effectively sterile - suggesting very efficient protection.
trachea ?
Trachea contains cartilage rings to keep it open, branches into bronchi then bronchioles and ending at the alveoli.
bronchi and bronchioles ?
Bronchi and bronchioles are associated with the heart as there is a network of exchange, deoxygenated blood comes from the vein and oxygenated blood goes into the arteries
alveoli ?
The alveoli are single layer of epithelial cells which are surrounded by smooth muscle and connective tissue.
lung disease ?
Infection could be viral, bacteria and parasite.
Allergy I.e. asthma
Chronic obstructive pulmonary disease (COPD)
Cancer
immune response to COVID ?
Covid infects epithelial cells through the receptor on these cells called ACE and this infection primes the normal immune response seen with infection in other pathogens such as activation of T cells, priming Th1 and Th17 responses which activate CD8+ T cells which kill infected cells by apoptosis and NK cells to release IFN gamma to kill by apoptosis. There is a mass destruction of epithelial cells.
cytokine storm COVID ?
In some cases of covid there is a cytokine storm , this is associated with a high viral load and the cytokines produced are out of control and not ra regulated immune response. This leads to recruitment of acute phase proteins and lymphopenia is a loss of lymphocytes and eosinophils. There is a micro inflamed endothelium and DIC. There is an increased risk of blot clots.
epithelial cell turnover ?
Epithelial cell turnover is quickly to prevent infections , if infection then apoptosis occurred to protect the infection from transmission
epithelial tight junctions ?
Epithelial tight junctions that prevent pathogen gaining access to blood system underneath
ciliated epithelium ?
Ciliated epithelium that are moving to transport anything inhaled to the bronchi and trachea then coughed out.
goblet cell mucus ?
Goblet cell mucus trap particles and pathogens
airway gyro dynamic shape ?
Airway gyro-dynamic shape to slow air down and deposit it in the upper airway rather than the lower airway, so easier to expel. This can be a challenge for inhaled drugs
coughs , sneexe reflexes ?
Cough, sneeze reflexes to expel anything inhaled
alveolar macrophages and mast cells ?
Alveolar macrophages, mast cells to provide first line of defense against pathogens.
Zona occludens ?
Tight junctions (zonula occludens) are variable impermeable barrier to fluid formed by CLAUDIN and OCCLUDIN proteins joining the cytoskeleton of adjacent cells. Prevents water loss and blocks entry of infectious and allergenic agents , there is an increased permeability of asthmatic epithelial cells.
type one pneumocyte ?
Type 1 pneumocyte participates in gas exchange which are Extremely thin (0.2 microns) and squamous cell, often below limit of detection. It provides minimal covering for capillaries as supported by reticular connective tissue and a basal lamina.
Type two pneumocyte ?
Type II pneumocyte are cuboidal cells , interspersed among Type 1 cells, located at the angular junctions of alveolar walls. Characterized by a reddish, foamy or vacuolated cytoplasm Secretory in nature and makes SURFACTANT to help to digest bacteria, divides into new Type 1 and 2 cells.
defensins ?
Defensins - small [18-45αα, 6-8 cysteine ] cationic detergent proteins, highly conserved
And active against bacteria, fungi and viruses. Bind to microbial cell membrane to form pore-like membrane defects. Inactivate enveloped virus particles by disrupting viral envelopes or by interacting with viral glycoproteins, such as HIV gp120
CF and defensins :
Patients with cystic fibrosis who have extra copies of defensin genes are more resistant to infection by Pseudomonas aeruginosa.
surfactant proteins ?
Surfactant proteins -SP-A and SP-D (and C1q, Mannan Binding Lectin) , they are Ca++ dependent, collagenous, carbohydrate (lectin) binding proteins- collectins. Bind and agglutinate pathogens , this promotes phagocytosis by macrophages and modulates inflammatory response [complement?].
alveoli normally ?
Alveloli have thin membranes and thin type I overlying the capillary beds
pneumonia alveoli ?
Not a lot of air space left , and struggle to take up oxygen and inflammatory responses.
inflammatory response?
The inflammatory response is made up of neutrophils, macrophages and monocytes. The first stage of inflammation is swelling ( odema) and filling up with fluid. The first cells recruited are neutrophils , then monocytes and macrophages. Then the adaptive response is activated and recruiting CD4+ and CD8+ T cells to provide the specific immune response against the infection, and antibodies are produced
BAL fluid immune cells ?
In the BAL fluid there are lots of macrophages and neutrophils
sputum ?
Sptum is filled with macrophaes
immuno responsive lungs ?
The lung is an immuno-responsive organ , locally produced IgA/IgE in the upper airways , transuded serum IgG- lower airways is leaked into airways from damaged epithelial integrity.local autonomous CMI and like the gut has it’s own lung associated lymphoid tissue.Hilar lymph nodes (branch of main bronchi) ,
Inducible Bronchus-Associated Lymphoid Tissue (BALT) , para-bronchial and para-tracheal nodes. Like the gut there are lots of nodules / aggregates / lymphocytes.
effects of smoking ?
Increase in infections, respiratory and general infections, lung tumors, asthma (esp. occupational asthma and in children), tissue remodeling.
smoking – lymphocytes ?
Lymphocytes
decreased IgG, IgM, IgA and sIgA, increased IgE , more likely to make allergic responses and less likely to make protective immune responses.
decreased functional antibody e.g. anti-flu and anti-Hep B
reduced NK function, decreased antigen and mitogen stimulation
smoking - neutrophils ?
Neutrophils
increase in neutrophil numbers
Less able to respond as reduced chemotaxis, phagocytosis and respiratory burst
increased peroxidase and elastase activity so increased tissue remodelling.
smokers less likely to have ?
Successful response to vaccination
Antibody to Hong Kong A2 Flu 1968 lower in smokers
Adverse effect of smoking on hepatitis B vaccination
describe asthma ?
In asthma there is a massive infiltration of inflammatory cells and associated with an increase in goblet cells producing mucus. The epithelial layer is disrupted and there’s an increase in fibrosis (green is staining for collagen).
COPD ?
In COPD, there is a lot of fibrosis here and lost the structure of the airways.
characterisics of COPD and asthma ?
COPD and asthma are characterised by a wheeze , cough and shortness of breath and both are treated with steroids.
immune cause of asthma ?
Usually an ALLERGIC Th2 mediated response to an inhaled allergen such as pollen , house dust mite.Can also be induced by:
Exercise
Cold Air
Air pollution
Viral infection
Bacterial Infection
Aspirin
Obesity
Mast cells will produce mediators which will cause smooth muscle contraction.
most comon allergens ?
Most common allergens are house dust mites then pollen , cat hair and dog hair.
functional unit of asthma ?
Blood smear shows the mast cells, they are described as mastcellen which are fattened cells that stain well and the granules are what are stained. These granules contain different mediators such as heparin, enzymes, leukotrienes and prostaglandins. When these are produced, they have physiological such as production of mucus, induce secretion of fluid into airways and constriction of sooth mucus and immunological effects.
Mast cells are activated by IgE binding to receptors on mast cells called FCeR1. Mast cells bind antibodies and find in mucous membranes but won’t activate and degranulate until antigen binding occurs.
allergy and autoimmune disease ?
Incredibly rare as autoimmune is Th17/Th1 which supresses the Th2 associated with allergy.
Th2 cytokines for allergy ?
Th2 cytokines
IL-5
Eosinophilia , mast cells and basophils
IL-4 and IL-13
Goblet cell metaplasia
Bronchial hyperreactivity (BHR)
role of epithelial cells ?
TLR, NOD bind to PAMP’s on pathogens
Induces production of cytokines
IL-25 (IL-17E) - Amplifies Th2 cytokine production and eosinophilia
IL-33 (IL-1 family member)- Synergizes with stem cell factor (SCF) and IgER to activate mast cells, basophils and eosinophils and enhance their survival.
TSLP -Activates DC to promote Th2
IL-22 - Induces EC proliferation and production of anti-microbial peptides to protect against pathogens.
Protects against extracellular bacteria.
fish factories and asthma ?
People who work in fish factories are exposed to an aerosol of antigen from the prawn. If you smoke and work here, then the levels of antibody increase a large amount. Smoking disrupts the epithelial integrity and exposes the smoker to an inflammatory response.
immunological therapies ?
Anti-IgE (Omalizumab) - used widely and prevents IgE binding to mast cells.
Anti-CD4
Anti-IL-5
Anti-TNF - mast cells release this and by blocking can reduce tissue remodelling.
Corticosteroids suppress the T helper response and can make you more susceptible to infections.
Th2 response ?
Th2 response is directed against allergen will produce cytokines on epithelial and goblet cells. An indirect effect is the recruitment of immune cells such as eosinophils and basophils which will release mediators to effect on smooth muscle cells, and airways for tissue remodelling.
COPD?
Emphysema – damage to the air sacs in the lungs
Chronic bronchitis – long-term inflammation of the airways.
causes of COPD ?
Smoking – 90% of cases
Occupational exposure causing inflammation in lungs.
cadmium dust and fumes
grain and flour dust
silica dust
welding fumes
isocyanates
coal dust
Air pollution
Genetics
1% of COPD patents have alpha-1-antitrypsin deficiency
physiology of COPD ?
In COPD there’s destruction of alveoli and production of excess mucus leading to blockage of airway. The airway wall has thickened to prevent effective gas exchange, there is also disrupted alveolar attachments called emphysema).
In COPD this is fibro proliferation condition where the fibroblasts are proliferating which alters the cell architecture and a build-up of collagen.
COPD and fibrosis ?
Inflammatory response leads to proliferation of fibroblast which deposits collagen, this causes a loss of function. If there is recurrent injury this will build up over years.
epithelial cells role in COPD ?
Epithelial cells play a role in the immune response , when insulted by smoking , allergen , infection they damage the airway epithelium , this will provide alerts to resident immune cells and recruitment of other immune cells occur.
Growth factors and MMP will alter the architecture of the airways.
activation of Th17 in COPD ?
Activation of Th17 cells leads to:
Production of defensins by epithelial cells
Production of inflammatory cytokines by epithelial cells to release defensins and these cytokines, TNF, IL-1, IL-6)
This leads to:
Recruitment of neutrophils and macrophages
Alteration in mucus production
Epithelial cell denudation
Fibroblast proliferation
Collagen deposition
phase one COPD ?
Phase one is the innate IL-17 immune response
phase two COPD /
Phase two is the adaptive IL-17 immune response leading to changes in the extracellular matrix
phase three ?
Phase three is the recruitment and proliferation of fibroblasts.
phase four ?
Phase four is the epithelial mesenchymal transition and airway fibrosis occurs.
COPD vs Asthma ?
COPD
airways have become narrowed permanently , no fix.
inhaled medication has limited benefit as change to the tissue cannot be resolved.
Asthma
narrowing of airways comes and goes, when exposed to a trigger.
dust, pollen or tobacco smoke.
Inhaled bronchodilators open airways fully.
Both treated with corticosteroids
