Inflammatory Cells in the Airway Flashcards
Describe the structure of the respiratory tract
NALT
Trachea
BALT
Bronchiole
Alveoli
NALT = Nasal Associated Lymphoid Tissue; BALT = Bronchus Associated Lypmhoid Tissue
Describe the types of cells found in and around NALT
Epithelial cells
M Cells
Goble tcells
Intraepithelial Lymphocytes
What do mature B-cells predominantly express
IgA
Where is BALT usually found and what cells are involved?
Lower airways at bronchiole branches
Germinal centre consisting of B-cell follicle and T-cell area interspersed with macrophages and dendritic cells
Compare the overall structure of NALT and BALT
NALT are more defined areas whereas BALT are more diffused.
There is a school of thought that respiratory disease occurs due to disrupted lung _____ (ie immune response vs _____ _____). Some challenges to maintenance of homeostasis include:
- Air pressure
- Endogenous _____ flora in lower airways
- Inhaled _____, particulate matter and pollution
Key point: Lung immunity is a balance between maintaining homeostasis and mounting an appropriate immune response to threat
There is a school of thought that respiratory disease occurs due to disrupted lung homeostasis (ie immune response vs gas exchange). Some challenges to maintenance of homeostasis include:
- Air pressure
- Endogenous microbial flora in lower airways
- Inhaled antigens, particulate matter and pollution
Key point: Lung immunity is a balance between maintaining homeostasis and mounting an appropriate immune response to threat
Describe some features of the airway epithelium that are first-line in preventing an immune response (5)
- Ciliated epithelium
- Mucus and glycocalyx
- Tight Junctions
- Rapid epithelial cell turnover
- Microflora
Name some cells found in the large airways (conducting zone) (4)
- Ciliated epithelial cells
- Goblet Cells
- Basal Cells
- Neuoendocrine cells - samples for oxygen
Name some cells found in the small airways (3)
- Ciliated Epithelial Cells
- Club cells - secrete glycosaminoglycans and solution similar to surfactant
- Basal Cells
Name some cells found in the alveoli (lower airways)
Type I Alveolar Epithelial Cells
Type II Alveolar Epithelial Cells
Where is there more mucus secretion: upper or lower airways
Upper airways
Lower airways need less so that gas exchange is not hindered
Describe the function of cilia and mucus
Mucociliary Clearance
Ciliated epithelial cells transport mucus upwards and outwards to expell pathogens
What is the function of IgA when it is secreted into the mucosa
IgA can opsonise bacteria
Aggregation of bacteria
More phagocytosis and easier mucociliary clearance
Describe the structure of IgA
- Can form dimers
- J chain
- Secretory component
- J chain binds to IgA receptor on epithelial cells
How does IgA get from the lamina propria to the airway lumen
Trancytosis
IgA released by Plasma B cells
Dimerised with J chain
J Chain binds to IgA receptor
Endocytosis and movement of the endosome to the apical side
Secretion of IgA with a secretory component
Initial colonisation of airways by alveolar macrophages occurs in the first few days of birth and is dependent on fetal _____. These differentiate into macrophage subtypes depending on the environment they are in - they are referred to as _____-_____ macrophages.
Initial colonisation of airways by alveolar macrophages occurs in the first few days of birth and is dependent on fetal monocytes. These differentiate into macrophage subtypes depending on the environment they are in - they are referred to as tissue-resident macrophages.
Tissue resident macrophages are involved in normal physiology as well as pathology. Give some examples of pathology.
Microglia - neurodegeneration
Osteoclast/blast - osteoporosis
Atherosclerosis
Kupffer cells - fibrosis
Tissue resident macrophages are replenished throughout life through in situ _____ and self-renewal. Exposure to envrionmental factors (fibrosis, pollutants) lead to release of monocytes from the _____ _____ - these then differentiate into _____ (Ly6c+) and _____-_____ (Ly6c-). Ly6c+ differentiate into tissue resident macrophages. These cells are more _____ as they are dervied from cells produced in response to _____.
Tissue resident macrophages are replenished throughout life through in situ proliferation and self-renewal. Exposure to envrionmental factors (fibrosis, pollutants) lead to release of monocytes from the bone marrow - these then differentiate into circulatory (Ly6c+) and non-circulatory (Ly6c-) monocytes. Ly6c+ differentiate into tissue resident macrophages. These cells are more inflammatory as they are dervied from cells produced in response to stress.
As we age, there is depletion of our _____-derived tissue resident macrophages. These are replensihed by _____ _____-derived monocytes, which are pro-inflammatory.
As we age, there is depletion of our fetal-derived tissue resident macrophages. These are replensihed by bone marrow-derived monocytes, which are pro-inflammatory.
What are the two ‘general’ phenotypes of macrophages
M1 - pro-inflammatory
M2 - Tissue-healing
In reality, macrophages express same receptors but in different ratios - no distinct receptor expression
Name some proteins produced by M2 macrophages which are involved in tissue healing
IL-4
IL-10
TGF-B
IGF-1
MMP-9
Arginase -> polyamines and collagen
Name some proteins produced by M1 macrophages that are involved in inflammation
TNF-a
IL-6
IL-1
IFN
CXCL 9, 10, 11
Name surface markers found on alveolar macrophages (4)
CD11c+
CD200R
CD206
SIGLEC-F
SIGLEC-F = Sialic Acid-Binding Immunoglobulin-like Lectin F
Describe the process of macrophage phagocytosis
- Phagocytosis of pathogen
- Formation of phagosome
- Lysosome and phagosome fuse to make phagolysosome
- Pathogen degraded into fragments
- Antigens presented on APC surface (MHC)
- Leftover fragment exocytosed
Alveolar macrophages have poor _____ _____ ability and produce _____ levels of ROS. They are naturally _____ under steady state.
Alveolar macrophages have poor antigen presenting ability and produce low levels of ROS. They are naturally hyporesponsive under steady state.
Neutrophils are continuously generated in the bone marrow from myeloid precursors. Name the upstream signalling that leads to neutrophil release from bone marrow
Macrophage release IL-23
Th17 matures and releases IL-17A
Stimulates fibroblasts to release G-CSF
Causes release of neutrophils from bone marrow
What two transcription factors control maturation of neutrophils
PU.1
C/EBP
CCAAT-enhancer-binding proteins
Name the 6 stages of neutrophil development
Myeloblast
Promyelocyte
Myelocyte
Metamyelocyte
Band
Neutrophil
Outline the process of neutrophil recruitment from the blood stream (5)
- Free circulating Neutrophil
- Rolling
- Tethering
- Slow Rolling
- Adhesion
- Full Arrest
- Firm Adhesion
- Crawling
- Transmigration
- Paracellular
- Transcellular
Describe the process of tethering and rolling with regards to adhesion molecules involved
Tethers bind to endothelial P-selectin via its ligand PSGL1
PSGL1 forms patches along the whole projection that attach and pull apart sequentially - step-wise peeling of slings
Deceleration from neutrophil LFA1 to endothelial ICAM2
PSGL1 = P-selectin glycoprotein ligand 1; LFA1 = Lymphocyte function-associated antigen 1; ICAM2 = intercellular adhesion molecule 2
Neutrophils can be short- and ‘longer’-lived. Explain the relevance as to why neutrophils can be both.
Short-lived
- Limit potential to cause damage
- Secondary necrosis
- Die through apoptosis to protect surrounding tissue
Long-lived
- Extended life span to ensure pathogens are cleared
- Enables orchestration/regulation of other aspects of inflammatory response
How can neutrophils kill pathogens (bacteria)
- ROS
- NADPH oxygenase-dependent mechanism (NOX)
- Anti-bacterial proteins
- Cathepsins
- Defensins
- Lactoferrin
- Lysosyme
- NETs
- Genetic material trapping pathogens
NETs are composed of _____ and granule proteins (serine proteases, neutrophil elastase). They trap and kill extracellular pathogens. The neutrophils sense the _____ of the pathogen and release NETs if they are too big.
NETs are composed of chromatin and granule proteins (serine proteases, neutrophil elastase). They trap and kill extracellular pathogens. The neutrophils sense the size of the pathogen and release NETs if they are too big.
Neutrophils don’t just kill pathogens, they also have _____ activity, producing pro-inflmmatory, anti-inflammatory, immunoregulatory, angiogenic and fibrogenic cytokines
Neutrophils don’t just kill pathogens, they also have biosynthetic activity, producing pro-inflmmatory, anti-inflammatory, immunoregulatory, angiogenic and fibrogenic cytokines
What do neutrophils produce to activate NK cells during infection
IL-12 (DC), IL-18 (neutrophils)
Stimulates NK cell IFN-γ produciton
Neutrophils can present antigens to _____ cells, promoting their maturation and capacity to mediate T cell proliferation and polarisation. Neutrophils also release chemokines to promote T cell (_____ and _____) recruitment. Neutrophils can also facilitate T cell-independent anitbody response by marginal zone B cells
Neutrophils can present antigens to dendritic cells, promoting their maturation and capacity to mediate T cell proliferation and polarisation. Neutrophils also release chemokines to promote T cell (Th1 and Th17) recruitment. Neutrophils can also facilitate T cell-independent anitbody response by marginal zone B cells
Neutrophils are also _____-_____, producing _____ and pro-resolving lipid mediators. They can also negatigvely regulate T cell function.
Neutrophils are also anti-inflammatory, producing IL-10 and pro-resolving lipid mediators. They can also negatigvely regulate T cell function.
