Flashcards in Sepsis Deck (56):
What are the possible causes of meningitus?
Also comment on how common and severity
Viral (most common, least severe)
Bacterial (least common, most severe)
What is meningitus?
Inflammation of the meninges as the result of an infection that has spread into the subarachnoid space
Which two meninges is the subarachnoid space in between?
Arachnoid and pia mater
Mechanism of bacterial meningitus
Bacterial infection spreads into the bloodstream through a mucous surface e.g. nasal cavity
Infection enters the subarachnoid space
The immune response is triggered - astrocytes and microglia release cytokines
The BBB becomes permeable allowing WBCs into the CSF
Entry of WBCs triggers large scale inflammation and cerebral oedema
Increased intracranial pressure makes it harder for blood to enter the brain, cells apoptose
Which type of cells cause initial T cell activation and how?
Phagocytose pathogen and migrate to lymph node
3 things needed for T cell activation
1. APC cell presents antigen on MHC II, binds to toll-like receptor
2. Co activation by B7 (or CD80/86) binding to CD28 receptor
3. Presence of IL-2 for proliferation
What do activated CD4+ T helper cells do?
Release more IL-2 and other cytokines to help proliferation of CD8 cytotoxic T cells
What do activated CD8+ cytotoxic T cells do?
Kill cells expressing the antigen on MHC I
What general things would you expect to see in CSF of a patient with meningitus?
Cloudy (due to leukocytes)
Increased intracranial pressure
What would you expect to see in a CSF sample taken from a patient with bacterial meningitus?
What would you expect to see in a CSF sample taken from a patient with viral meningitus?
High lymphocytes (T and B cells)
What would you expect to see in a CSF sample taken from a patient with parasitic meningitus?
If viral meningitus is suspected, what further tests could be done?
If bacterial meningitus is suspected, what further tests could be done?
Purple = gram pos bacteria
Pink = gram neg bacteria
Or a blood culture to see if any bacterial cultures grow
What are the ligands of JAK/STAT receptors?
Cytokines (IFNy, IFN-a, IFN-b, IL-2)
What does JAK/STAT signalling initate?
Processes such as immunity (iNOS, APPs)
Tumour formation (Myc)
Process of JAK/STAT receptor signalling
Ligand binds to receptor
Two receptors dimerise which activates JAK
JAK phosphorylates tyrosine residues on receptors
Phosphorylated receptors attract SH2 domain on STAT
JAK phosphorylates STAT
Two STATs dimerise
Translocate to nucleus to transcribe genes
How is JAK/STAT signalling regulated?
STAT transcribes gene for SOCS
'Suppressor of cytokine signalling'
Causes negative feedback
What is sepsis?
An infection triggers the body's immune response, which starts to damage the body's own tissues
What is septic shock?
Sepsis causes extremely low blood pressure, that does not improve with IV fluids
What is severe sepsis?
Insufficient blood supply to organs, which can lead to organ failure
What are PAMPs?
Pathogen Associated Molecular Patterns
Exogenous molecules present on all pathogens
Recognised by PRRs (Pathogen recognition receptors)
What is the PAMP/PRR combination for gram negative bacteria?
PAMP = lipopolysaccharides
PRR = toll like receptor 4
What is the PAMP/PRR combination for gram positive bacteria?
PAMP = lipoteichoic acid (LTA)
PRR = toll like receptor 2
What PAMP can be present on both gram pos and neg bacteria, and what is its PRR?
PAMP = Peptidoglycans
PRR = toll like receptor 2
What does PRR activation lead to?
Which immune cells have PRRs?
What is NFkB signalling?
NFkB is a transcription factor
Normally inhibited by the IkB inhibitor
IkB inhibitor can be removed by the IkB Kinase (IKK)
IKK phosphorylates IkB, marking it for ubiquitylation
What initiates activation of the IKK?
What 4 things initiate the arachidonic acid pathway by activation of phospholipase A?
What are the products of NFkB signalling?
Adhesion proteins (ICAM-1)
Coagulation factors (e.g. tissue factor)
An example of an antioxidant and how it works
SOD - Superoxide Dismutases
Catalyses conversion of the superoxide ion (O2-) into hydrogen peroxide (H2O2)
Examples of pro-oxidants
iNOS, NADPH Oxidase, COX-2
How is NFkB signalling regulated?
NFkB transcription factors transcribes gene for IkB inhibitor, for negative feedback
How do phagocytes kill pathogens using ROS?
Phagocytosis of pathogen into phagosome
Phagosome fuses with lyososome
Fusion activates myeloperoxidase (MPO)
MPO catalyses formation of hypochlorus acid (HOCl) from hydrogen peroxide (H2O2) and chloride ions
What are APPs?
Acute phase proteins
Produced by liver
Plasma concentration increases in response to inflammation
Examples of APPs
Complement protein C3
Serum Amyloid protein (opsonin)
Mannose binding lectin (opsonin)
What is c-reactive protein and what does it do?
Non-specific biomarker of inflammation
Binds to phosphorylcholine on bacteria to fix complement and promote phagocytosis
Challenges of vaccine production
Pathogens can frequently mutate and become resistant to the vaccine
Animal models cannot be used to develop vaccines for diseases that only occur in humans
What are the 5 groups of cytokines?
TNF (tumour necrosis factors)
What are monokines?
Cytokines released from mononucleus cells, such as macrophages and monocytes
What are defensins?
Cationic (positively charged) proteins that can form ion pores in cell membranes
What is the difference between COX-1 and COX-2?
COX-2 is specifically produced during inflammation
COX-1 is constitutively produced, causes production of gastric mucous
Specific COX-2 inhibits have fewer GI effects
Where is MHC I and MHC II present?
MHC I on cell surface of all nucleated cells
MHC II on APC
Which is the only anti-inflammatory cytokine?
What is the missing self hypothesis?
NK cells kills cells that aren't expressing MHC I
Kill cells using perforin and granzymes
How does NO kill pathogens?
Inhibits viral replication
Binds to iron, preventing bacteria from using it
What are alarmins?
Endogenous molecules released after tissue damage
Perpetuate non-infectious inflammatory responses
Also known as DAMPs (Damage associated molecular patterns)
What are commensal microorganisms?
Doesn't cause harm to health or benefit
Cover epithelial surfaces such as respiratory tract and GI tract
Which commensal microorganism can be the cause of bacterial meningitis?
Diplococcus (round, forms pairs)
Causes meningitus B and C, and septicaemia
Also staphylococcus aureus
Through which G-protein subunit do prostaglandins signal through?
What is an attenuated vaccine? And example
Pathogen is alive but attenuated so not as pathogenic
What is a conjugate vaccine? And example
Bacterial polysaccharide conjugated to a toxoid
e.g. Men C, HPV
What is a subunit vaccine? And example and a disadvantage
Just contains antigen subunits
e.g. Men B
Can be time consuming and expensive to identify best subunits to use
What is a disadvantage of an inactivated vaccine? And example
Tend to require boosters