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Flashcards in Sepsis Deck (56):
1

What are the possible causes of meningitus?
Also comment on how common and severity

Viral (most common, least severe)
Bacterial (least common, most severe)
Parasitic
Fungal

2

What is meningitus?

Inflammation of the meninges as the result of an infection that has spread into the subarachnoid space

3

Which two meninges is the subarachnoid space in between?

Arachnoid and pia mater

4

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

5

Which type of cells cause initial T cell activation and how?

Dendritic cells
Phagocytose pathogen and migrate to lymph node

6

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

7

What do activated CD4+ T helper cells do?

Release more IL-2 and other cytokines to help proliferation of CD8 cytotoxic T cells

8

What do activated CD8+ cytotoxic T cells do?

Kill cells expressing the antigen on MHC I

9

What general things would you expect to see in CSF of a patient with meningitus?

Decreased glucose
Cloudy (due to leukocytes)
Increased intracranial pressure

10

What would you expect to see in a CSF sample taken from a patient with bacterial meningitus?

High neutrophils
High protein

11

What would you expect to see in a CSF sample taken from a patient with viral meningitus?

High lymphocytes (T and B cells)
Low protein

12

What would you expect to see in a CSF sample taken from a patient with parasitic meningitus?

High eosinophils

13

If viral meningitus is suspected, what further tests could be done?

PCR

14

If bacterial meningitus is suspected, what further tests could be done?

Gram stain
Purple = gram pos bacteria
Pink = gram neg bacteria

Or a blood culture to see if any bacterial cultures grow

15

What are the ligands of JAK/STAT receptors?

Cytokines (IFNy, IFN-a, IFN-b, IL-2)
EPO
Growth hormone
Prolactin
Leptin

16

What does JAK/STAT signalling initate?

Processes such as immunity (iNOS, APPs)
Cell division
Cell death
Tumour formation (Myc)

17

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

18

How is JAK/STAT signalling regulated?

STAT transcribes gene for SOCS
'Suppressor of cytokine signalling'
Inactivates JAK
Causes negative feedback

19

What is sepsis?

An infection triggers the body's immune response, which starts to damage the body's own tissues

20

What is septic shock?

Sepsis causes extremely low blood pressure, that does not improve with IV fluids

21

What is severe sepsis?

Insufficient blood supply to organs, which can lead to organ failure

22

What are PAMPs?

Pathogen Associated Molecular Patterns
Exogenous molecules present on all pathogens
Recognised by PRRs (Pathogen recognition receptors)

23

What is the PAMP/PRR combination for gram negative bacteria?

PAMP = lipopolysaccharides
PRR = toll like receptor 4

24

What is the PAMP/PRR combination for gram positive bacteria?

PAMP = lipoteichoic acid (LTA)
PRR = toll like receptor 2

25

What PAMP can be present on both gram pos and neg bacteria, and what is its PRR?

PAMP = Peptidoglycans
PRR = toll like receptor 2

26

What does PRR activation lead to?

NFkB signalling

27

Which immune cells have PRRs?

Macrophages
Neutrophils
NK cells

28

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

29

What initiates activation of the IKK?

PRR activation
JAK/STAT receptors
Cytokine receptors

30

What 4 things initiate the arachidonic acid pathway by activation of phospholipase A?

Kinin
C5a
Thrombin
Cell damage

31

What are the products of NFkB signalling?

Proinflammatory cytokines
Pro-oxidants
Antioxidants
Adhesion proteins (ICAM-1)
Coagulation factors (e.g. tissue factor)

32

An example of an antioxidant and how it works

SOD - Superoxide Dismutases
Catalyses conversion of the superoxide ion (O2-) into hydrogen peroxide (H2O2)

33

Examples of pro-oxidants

iNOS, NADPH Oxidase, COX-2

34

How is NFkB signalling regulated?

NFkB transcription factors transcribes gene for IkB inhibitor, for negative feedback

35

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

36

What are APPs?

Acute phase proteins
Produced by liver
Plasma concentration increases in response to inflammation

37

Examples of APPs

C-reactive protein
Fibrinogen
Complement protein C3
Serum Amyloid protein (opsonin)
Mannose binding lectin (opsonin)
Haptoglobulin

38

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

39

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

40

What are the 5 groups of cytokines?

Interleukins
Interferons
TNF (tumour necrosis factors)
Lymphokines
Chemokines

41

What are monokines?

Cytokines released from mononucleus cells, such as macrophages and monocytes

42

What are defensins?

Cationic (positively charged) proteins that can form ion pores in cell membranes

43

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

44

Where is MHC I and MHC II present?

MHC I on cell surface of all nucleated cells
MHC II on APC

45

Which is the only anti-inflammatory cytokine?

IL-10

46

What is the missing self hypothesis?

NK cells kills cells that aren't expressing MHC I
Kill cells using perforin and granzymes

47

How does NO kill pathogens?

Inhibits viral replication
Binds to iron, preventing bacteria from using it

48

What are alarmins?

Endogenous molecules released after tissue damage
Perpetuate non-infectious inflammatory responses
Also known as DAMPs (Damage associated molecular patterns)

49

What are commensal microorganisms?

Doesn't cause harm to health or benefit
Cover epithelial surfaces such as respiratory tract and GI tract

50

Which commensal microorganism can be the cause of bacterial meningitis?

Neisseria Meningitidis
Gram negative
Diplococcus (round, forms pairs)
Causes meningitus B and C, and septicaemia

Also staphylococcus aureus
Gram positive

51

Through which G-protein subunit do prostaglandins signal through?

Gq

52

What is an attenuated vaccine? And example

Pathogen is alive but attenuated so not as pathogenic
e.g. MMR

53

What is a conjugate vaccine? And example

Bacterial polysaccharide conjugated to a toxoid
e.g. Men C, HPV

54

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

55

What is a disadvantage of an inactivated vaccine? And example

Tend to require boosters
e.g. Polio

56

What is a toxoid vaccine?
Give an example of one and a disadvantage

Contains toxins that have been detoxified
e.g. Tetanus
Only useful when toxins are cause of the disease