Lec 1&2 Flashcards
what can cytokines sometimes be known as
immune hormones, interleukins, TNF (tumour necrosis factor), IFN (interferons)
how to cytokines form an interacting network
one cytokine can induce the production of other cytokines
cytokine secretion
is for a brief period of time following stimulation such as pathogen recognition
what mediates cytokine effects and what does it cause
mediated by high-affinity receptors which leads to change in gene expression
what does the presence of high-affinity receptors indicate
that not all cytokines and cells are compatible
what is an autocrine cytokine
bind to receptors on the same cell it is secreted by
what is a paracrine cytokine
acts on cells in the immediate area of the cytokine
what is an endocrine cytokine
acts like a typical hormone ie. enters bloodstream and is distributed in that fashion
what are two potent pro-inflammatory mediators
TNFalpha (tumour necrosis factor alpha) and IL-1 (interleukin 1)
what are the symptoms of inflammation
heat, swelling, redness, pain, loss of function
what causes the symptoms of inflammation
effects on the vascular endothelium such as increased blood flow, increased vascular permeability, and recruitment of immune cells
what is inflammation useful for
fighting infection and healing tissue damage
what is inflammation harmful for
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
what are some conditions where inflammation is harmful
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
how is expression of pro inflammatory cytokines induced
activation of pattern recognition receptors (PTRs) by microbial products (PAMPs)or endogenous molecules (DAMPs)
what is the workflow of the cytokine cascade in inflammation
infection causes lipopolysaccharide (LPS) to trigger the cytokine cascade which is LPS - TNFalpha - IL-1 - IL-6
talk through the cytokine cascade
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
what is sepsis and what happens
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%
what is the rationale behind anti-cytokine therapy for sepsis
to block TNFalpha and IL-1beta thus preventing the devastating systemic effects of these cytokines known as the cytokine storm
how can you generally tell a monoclonal and a decoy antibody apart by name
monoclonal antibodies tend to end in ‘mab’ while decoys tend to end in ‘cept’
what are the different therapeutic agents that block TNF
monoclonal antibodies (originally murine used but have since been humanised) eg. adalimumab, and decoy TNF receptors eg. immunex
what are the three main antagonists that block TNF
Infliximab - chimeric anti-TNFalpha antibody, Adalimumab - fully human anti-TNFalpha antibody, Etanercept - TNFalpha decoy receptor
why were TNFalpha and IL-1beta chosen as potential therapeutic targets in the context of sepsis
in sepsis there is excessive systemic inflammation that damages the body leading to multi organ failure, not very therapeutically successful for sepsis
what diseases were TNFalpha and IL-1beta then used as therapeutic targets for and which cytokine was more successful
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)
what are some drawbacks of anti-cytokine therapy
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
