Neutrophils in health and disease Flashcards
What are the two fathers of immunology?
Metchnikoff
Ehrlich
What aspect of immunology was Metchnikoff interested in?
Cells
What aspect of immunology was Ehrlich interested in?
Soluble factors
What is phagocytosis?
The process by which a cell binds to the molecule it wants to engulf on the cell surface
Draws the molecule inwards whilst engulfind around it
Describe the steps of phagocytosis
- The microbe and phagocyte come into contact with each other
- The microbe binds to the phagocytic receptor
- The phagocyte membrane starts to zip up around the microbe
- The surrounded microbe becomes completely enclosed in a bubble-like structure called the phagosome within the cytoplasm
- The phagosome fuses with a lysosome, becoming a phagolysosome
- Degradation of microbe by lysosomal enzymes, including ROS and NO
- Once the contents have been neutralized the phagolysosome forms a residual body that contains the waste products left over
What chemicals in the phagolysosome help destroy the cell?
Oxygen radicals
Nitric oxide
Antimicrobial proteins
Antimicrobial peptides
Binding proteins
Are macrophages or neutrophils more efficient at phagocytosis?
Neutrophils
How do neutrophils phagocytose bacteria?
Become polarised
Hunt the bacteria that try to escape
Which part of the immunity do neutrophils belong to?
Innate immunity
What is the defining feature of neutrophils?
Lobed nuclei
What proportion of the white blood cell population are composed of neutrophils?
60%
Are neutrophils smaller or larger that macrophages?
Smaller
What causes granulomatous disease?
Dysfunction of neutrophils
What condition arises following the dysfunction of neutrophils?
Chronic granulomatous disease
Why does chronic granulomatous disease appear?
Skin lesions develop s a result of poor bacterial clearance
Patient becomes susceptible to pneumonia and bacteria
How are neutrophils defective in chronic granulomatous disease?
Defect in the NADPH oxidase system
Causes the neutrophils to become unable to make superoxides
What other conditions are caused by neutrophil deficiencies?
Cyclic neutropenia
Severe congenital neutropenia
Kostmann syndrome
MPO deficiency
Lymphocyte adhesion deficiency
What do neutrophils require in order to migrate to sites of inflammation?
Chemokines
CXCL8
IL-8
IL-1b
What steps allow neutrophils to moe from the blood into tissues?
Rolling
Adhesion
Tight binding
Diapedesis
Migration
What are the 3 ways by which neutrophils kill pathogens?
Phagocytosis
Degranulation
NETs
What are the 3 main destructive molecules that allow neutrophils to kill pathogens?
ROS
NO
Hydrochlorus acid
How are ROS made?
Reduction of oxygen
How is NO made?
Derived from arginine
How is hydrochlorus acid made?
Reduction of water to make superoxide
Combines with hydrogen and chloride ions to make acid
What important protein is involved in the ROS killing mechanism?
Phagocyte oxidase
What important proteins is involved in the NO killing mechanism?
iNOS
What important protein is involved in the Hydrochlorus acid killing mechanism?
NADPH oxidase complex
Protein channel
MPO
How does neutrophil degranulation kill bacteria?
Granules contain a lot of important enzymes responsible for direct and indirect microbe killing
Causes a destruction of microbes whilst stimulating the migration of immune cells by the release of pro-inflammatory molecules
What important enzymes are involved in neutrophil degranulation killing mechanisms?
MMPs
MPO
Lactoferrin
Lysozyme
Cathepsin
HOCl
H2O2
How do neutrophils form NETs in order to kill bacteria?
Undergo a process of NETosis
Characterised by chromatin decodensation and nuclear membrane disintegration
These NETs are released into the extracellular space to trap microbes
What are the negative effects of NET formation by neutrophils?
Thrombosis
Sepsis
SLE
Why is mucus green?
The myeloperoxidase in neutrophils
What is ARDS?
Acute respiratory distress syndrome
Condition affecting the alveoli of the lungs
What is the cause of ARDS?
Direct and indirect insults to the lungs
What is the prevalence of ARDS?
220 000 cases in the USA
33 000 cases in the UK
What is the mortality of people suffering with ARDS?
25-40%
What is the therapy of ARDS?
Supportive ventilator therapy
What leads to ARDS?
Disruption of the endothelium
Leads to activation of neutrophils
Neutrophils release chemokines, which favours leukocyte migration, and protease, inducing epithelial injury and bacterial killing
Edema develops as a result
What is characteristic in blood tests of ARDS patients?
Complete infiltration by neutrophils
How do neutrophils cause epithelial and endothelial damage?
By the same mechanism they use to kill microbes
ROS Proteases Cytokines MMPs NETs
What are therapeutic agents in ARDS?
Blocking chemokines
Leads to a reduction in neutrophil accumulation and a subsequent reduction in inflammation
