Lecture 6: Innate Responses to Infection Flashcards
Describe the characteristics of macrophages.
- Derived from the myeloid progenitor
- Round nucleus, agranular
- First cells to encounter pathogens
- Detects pathogens using PRRs (membrane-associated or cytosolic)
- Carry out phagocytosis and inflammatory response dignalling
- Long lifespan, important role in adapative immunity
Describe the ways in which the macrophages recognise, engulf, and destroy microorganisms
Pathogens become bound to the PRRs on the cell surface (e.g. bacteria to mannose receptors). Pathogen is then engulfed into the cell by the process of endocytosis into a phagosome. It then fuses with a lysosome to form a phagolysosome and the bacterium is completely degraded. Macrophages will then present peptide fragments of these pathogens to the adaptive immune cells.
Mention the bactericidal substances produced or released by macrophages.
Describe the mechanism of respiratory burst.
When phagosome fuses with lysosome, NADPH-dependent oxidases generate toxic oxygen radicals and hydrogen peroxide. This is then accompanied by transient increase in O2 consumption known as respiratory burst.
NADPH oxidase and superoxide dismutase as two key enzymes in radical production, producing super oxide and hydrogen peroxide respectively. Activated phagocytes also produce nitric oxide, which reacts with oxygen radicals (mediated by NO Synthase) to produces peroxynitrite (ONOO-).
Why aren’t host cells damaged during respiratory burst?
It is accompanied by the synthesis of enzymes to inactivate damaging molecules. Catalase converts hydrogen peroxide to water and oxygen.
Describe the overview of cytokines.
- small glycoproteins that mediate immune cell communication
- affect the behaviour of cells (autocrine, paracrine, or endocrine)
- act by binding to specific receptors on cells
- Potent and pleiotropic (multiple functions) => hence tightly regulated
- defects in cytokine production, signalling, or regulation => lead to autoimmunity
Mention the six major cytokine families.
IL-1, hematopoietin, IFN, TNF, IL-17, chemokines
Grouped based on structure and function
What are chemokines?
CHemokines (chemotactic cytokines) regulate movement of cells.
Describe the main inflammatory cytokines produced from macrophages and explain their roles.
- IL-12: Activate NK cells - induces the differentiation of CD4 T cells intoTH1 cells
- CXCL8 (IL-8): Chemotactic factor recruits neutrophils, basophils, and T cells to site of infection
- IL-6: Lymphocyte activation and increase antibody production
- Systemic effect: Fever, induces acute-phase protein production
- IL-1ß: Activates vascular endothelium; activate lymphocytes; local tissue destruction
- Systemic effect: fever; production of IL-6
- TNF-α: activates vascular endothelium and increases vascular permeability - leads to increased IgG, complement, and cell entry
Recall the systemic effects of pro-inflammatory cytokines.
What are acute-phase proteins?
They are proteins produced by the liver and released into the circulation. In the absence of infection, the concentration in the plasma is very low. Within a day or two of infection, plasma concentration rises very quickly. Synthesis and release is stimulated by inflammatory cytokines(such as IL-6) and their levels rise 2-200 fold.
Mention examples of acute phase proteins.
MBL and CRP enhance the fixation of complement at pathogen surface.
Recall the function of MBL and CRP.
CRP binds to phosphorylcholine of certain bacterial and fungal cell wall LPS.
MBL binds to carbohydrates on bacterial surfaces, acting as an opsonin and complement activator.
Describe the characteristics of neutrophils.
- Derived from myeloid progenitor
- Granular, lobular nucleus
- Terminally differentiated in bone marrow
- Stored in bone marrow, released progressively in steady-state
- Detects pathogens using PRRs
- Carry out phagocytosis and forms NET
Describe how cytokines direct neutrophil migration.
- Vascular endothelium is activated (IL-1beta and TNF-alpha)
- Induces higher expression of adhesion molecules and leads to stronger interaction with neutrophils
- Neutrophils bind to the endothelium and squeeze between cells
- Neutrophils enter infected tissue and make up first wave of cells that cross the BV wall to enter the inflamed tissue
Describe the mechanism of neutrophil migration rolling adhesion.
Summarise the neutrophil migration into infected tissue.
sialyl-Lewisx ligand of the neutrophil undergoes weak binding with the E-selectin receptor in the endothelial cells, slowing down the neutrophil. As the neutrophil gets closer to the infection site, IL-8 chemokines attract the neutrophil towards it. Due to the interaction of LFA-1 and ICAM-1 receptor, the neutrophil then undergoes diapedesis through the cell junction to the infection site.
Recall some information regarding adhesion molecules.
Describe the rolling adhesion phase of neutrophil migration.
Describe the tight-binding phase of neutrophil migration.
Describe the diapedesis phase of neutrophil migration.
Describe the migration phase of neutrophil migration.
Describe the ways in which the neutrophils recognise, engulf, and destroy microorganisms
In addition to killing microbes engulfed by phagocytosis, neutrophils use a novel mechanism of destruction that is directed at extracellular pathogens.
When they undergo cell death (NETosis), they release nuclear chromatin into extracellular space and forms a fibril matrix known as neutrophil extracellular traps (NETs). The captured microorganism can then be more efficiently phagocytosed by neutrophils or macrophages.
Just recall neutrophil phagocyte process.
fMet-Leu-Phe is a bacterial tri-peptide released by bacteria. This peptide acts as a chemotactic factor and activate Rac2, which initiates the endocytosis of the bacteria. Phagosomes then fuse with primary and secondary granules, after which Rac2 would induce the assembly of functional NADPH oxidases in the phagolysosome membrane, leading to the generation of toxic oxygen radicals.
Recall the bactericidal substances produced or released by neutrophils.
