Block D - immune responses in the lungs

Question 1

why did the lungs evolve ?

Answer 1

Lungs evolved as efficient gas-exchanging apparatus, with a wide surface area that is covered with a single layer of epithelial cells.

Question 2

upper airways ?

Answer 2

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.

Question 3

lower airways ?

Answer 3

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.

Question 4

are the lungs sterile ?

Answer 4

Lungs are effectively sterile - suggesting very efficient protection.

Question 5

trachea ?

Answer 5

Trachea contains cartilage rings to keep it open, branches into bronchi then bronchioles and ending at the alveoli.

Question 6

bronchi and bronchioles ?

Answer 6

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

Question 7

alveoli ?

Answer 7

The alveoli are single layer of epithelial cells which are surrounded by smooth muscle and connective tissue.

Question 8

lung disease ?

Answer 8

Infection could be viral, bacteria and parasite.

Allergy I.e. asthma

Chronic obstructive pulmonary disease (COPD)

Cancer

Question 9

immune response to COVID ?

Answer 9

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.

Question 10

cytokine storm COVID ?

Answer 10

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.

Question 11

epithelial cell turnover ?

Answer 11

Epithelial cell turnover is quickly to prevent infections , if infection then apoptosis occurred to protect the infection from transmission

Question 12

epithelial tight junctions ?

Answer 12

Epithelial tight junctions that prevent pathogen gaining access to blood system underneath

Question 13

ciliated epithelium ?

Answer 13

Ciliated epithelium that are moving to transport anything inhaled to the bronchi and trachea then coughed out.

Question 14

goblet cell mucus ?

Answer 14

Goblet cell mucus trap particles and pathogens

Question 15

airway gyro dynamic shape ?

Answer 15

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

Question 16

coughs , sneexe reflexes ?

Answer 16

Cough, sneeze reflexes to expel anything inhaled

Question 17

alveolar macrophages and mast cells ?

Answer 17

Alveolar macrophages, mast cells to provide first line of defense against pathogens.

Question 18

Zona occludens ?

Answer 18

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.

Question 19

type one pneumocyte ?

Answer 19

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.

Question 20

Type two pneumocyte ?

Answer 20

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.

Question 21

defensins ?

Answer 21

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

Question 22

CF and defensins :

Answer 22

Patients with cystic fibrosis who have extra copies of defensin genes are more resistant to infection by Pseudomonas aeruginosa.

Question 23

surfactant proteins ?

Answer 23

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?].

Question 24

alveoli normally ?

Answer 24

Alveloli have thin membranes and thin type I overlying the capillary beds

Question 25

pneumonia alveoli ?

Answer 25

Not a lot of air space left , and struggle to take up oxygen and inflammatory responses.

Question 26

inflammatory response?

Answer 26

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

Question 27

BAL fluid immune cells ?

Answer 27

In the BAL fluid there are lots of macrophages and neutrophils

Question 28

sputum ?

Answer 28

Sptum is filled with macrophaes

Question 29

immuno responsive lungs ?

Answer 29

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.

Question 30

effects of smoking ?

Answer 30

Increase in infections, respiratory and general infections, lung tumors, asthma (esp. occupational asthma and in children), tissue remodeling.

Question 31

smoking – lymphocytes ?

Answer 31

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

Question 32

smoking - neutrophils ?

Answer 32

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.

Question 33

smokers less likely to have ?

Answer 33

Successful response to vaccination

Antibody to Hong Kong A2 Flu 1968 lower in smokers

Adverse effect of smoking on hepatitis B vaccination

Question 34

describe asthma ?

Answer 34

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).

Question 35

COPD ?

Answer 35

In COPD, there is a lot of fibrosis here and lost the structure of the airways.

Question 36

characterisics of COPD and asthma ?

Answer 36

COPD and asthma are characterised by a wheeze , cough and shortness of breath and both are treated with steroids.

Question 37

immune cause of asthma ?

Answer 37

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.

Question 38

most comon allergens ?

Answer 38

Most common allergens are house dust mites then pollen , cat hair and dog hair.

Question 39

functional unit of asthma ?

Answer 39

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.

Question 40

allergy and autoimmune disease ?

Answer 40

Incredibly rare as autoimmune is Th17/Th1 which supresses the Th2 associated with allergy.

Question 41

Th2 cytokines for allergy ?

Answer 41

Th2 cytokines

IL-5

Eosinophilia , mast cells and basophils

IL-4 and IL-13

Goblet cell metaplasia

Bronchial hyperreactivity (BHR)

Question 42

role of epithelial cells ?

Answer 42

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.

Question 43

fish factories and asthma ?

Answer 43

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.

Question 44

immunological therapies ?

Answer 44

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.

Question 45

Th2 response ?

Answer 45

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.

Question 46

COPD?

Answer 46

Emphysema – damage to the air sacs in the lungs

Chronic bronchitis – long-term inflammation of the airways.

Question 47

causes of COPD ?

Answer 47

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

Question 48

physiology of COPD ?

Answer 48

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.

Question 49

COPD and fibrosis ?

Answer 49

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.

Question 50

epithelial cells role in COPD ?

Answer 50

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.

Question 51

activation of Th17 in COPD ?

Answer 51

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

Question 52

phase one COPD ?

Answer 52

Phase one is the innate IL-17 immune response

Question 53

phase two COPD /

Answer 53

Phase two is the adaptive IL-17 immune response leading to changes in the extracellular matrix

Question 54

phase three ?

Answer 54

Phase three is the recruitment and proliferation of fibroblasts.

Question 55

phase four ?

Answer 55

Phase four is the epithelial mesenchymal transition and airway fibrosis occurs.

Question 56

COPD vs Asthma ?

Answer 56

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