Lec 1&2

Question 1

what can cytokines sometimes be known as

Answer 1

immune hormones, interleukins, TNF (tumour necrosis factor), IFN (interferons)

Question 2

how to cytokines form an interacting network

Answer 2

one cytokine can induce the production of other cytokines

Question 3

cytokine secretion

Answer 3

is for a brief period of time following stimulation such as pathogen recognition

Question 4

what mediates cytokine effects and what does it cause

Answer 4

mediated by high-affinity receptors which leads to change in gene expression

Question 5

what does the presence of high-affinity receptors indicate

Answer 5

that not all cytokines and cells are compatible

Question 6

what is an autocrine cytokine

Answer 6

bind to receptors on the same cell it is secreted by

Question 7

what is a paracrine cytokine

Answer 7

acts on cells in the immediate area of the cytokine

Question 8

what is an endocrine cytokine

Answer 8

acts like a typical hormone ie. enters bloodstream and is distributed in that fashion

Question 9

what are two potent pro-inflammatory mediators

Answer 9

TNFalpha (tumour necrosis factor alpha) and IL-1 (interleukin 1)

Question 10

what are the symptoms of inflammation

Answer 10

heat, swelling, redness, pain, loss of function

Question 11

what causes the symptoms of inflammation

Answer 11

effects on the vascular endothelium such as increased blood flow, increased vascular permeability, and recruitment of immune cells

Question 12

what is inflammation useful for

Answer 12

fighting infection and healing tissue damage

Question 13

what is inflammation harmful for

Answer 13

immunopathogenesis - excessive, deregulated, and systemic inflammation can cause more harm than good to the host, body must find a balance between enough immune response to treat the infection but not too much to cause further harm to the body

Question 14

what are some conditions where inflammation is harmful

Answer 14

1) autoinflammatory conditions where the immune system is accidentally triggered by something (fighting an infection that does not exist thus causing harm to the host) - rheumatoid arthritis, type 2 diabetes, hereditary autoimmune disorders, 2) immune response to treat an existent infection, successfully treats the infection but an excessive response happens which causes more harm to the body than the now treated infection - SIRS, sepsis, ARDS

Question 15

how is expression of pro inflammatory cytokines induced

Answer 15

activation of pattern recognition receptors (PTRs) by microbial products (PAMPs)or endogenous molecules (DAMPs)

Question 16

what is the workflow of the cytokine cascade in inflammation

Answer 16

infection causes lipopolysaccharide (LPS) to trigger the cytokine cascade which is LPS - TNFalpha - IL-1 - IL-6

Question 17

talk through the cytokine cascade

Answer 17

innate immune cells (monocytes, dendritic cells) recognise LPS which is an endotoxin via TLR4 and respond to it with the secretion of pro-inflammatory cytokines such as TNFalpha which then stimulates cells to produce more cytokines such as IL-1 and IL-6

Question 18

what is sepsis and what happens

Answer 18

sepsis is a systemic infection causing the production of inflammatory cytokines however a cytokine storm occurs which is the excessive systemic production of TNFalpha leading to vasodilation and blood clotting, loss of blood pressure, and organ failure with a high mortality rate of 25-80%

Question 19

what is the rationale behind anti-cytokine therapy for sepsis

Answer 19

to block TNFalpha and IL-1beta thus preventing the devastating systemic effects of these cytokines known as the cytokine storm

Question 20

how can you generally tell a monoclonal and a decoy antibody apart by name

Answer 20

monoclonal antibodies tend to end in ‘mab’ while decoys tend to end in ‘cept’

Question 21

what are the different therapeutic agents that block TNF

Answer 21

monoclonal antibodies (originally murine used but have since been humanised) eg. adalimumab, and decoy TNF receptors eg. immunex

Question 22

what are the three main antagonists that block TNF

Answer 22

Infliximab - chimeric anti-TNFalpha antibody, Adalimumab - fully human anti-TNFalpha antibody, Etanercept - TNFalpha decoy receptor

Question 23

why were TNFalpha and IL-1beta chosen as potential therapeutic targets in the context of sepsis

Answer 23

in sepsis there is excessive systemic inflammation that damages the body leading to multi organ failure, not very therapeutically successful for sepsis

Question 24

what diseases were TNFalpha and IL-1beta then used as therapeutic targets for and which cytokine was more successful

Answer 24

rheumatoid arthritis, TNFalpha was the more successful cytokine as it led the cytokine cascade (the production of TNFalpha triggers the production of other pro inflammatory cytokines so through blocking TNFalpha it blocks the production of all the subsequent pro inflammatory cytokines also)

Question 25

what are some drawbacks of anti-cytokine therapy

Answer 25

it is treating the symptoms not curing the disorders as lifelong consistent treatment is required for relief, patients are at higher risk of infections and malignancies, there is an increased risk when TNFalpha and IL-1 antagonists are given together so Etanrecept and Anakinra cannot be combined for treatment of rheumatoid arthritis, prescreening for latent TB before patients are put on TNF antagonists