Acute Phase Response And Inflammasome Flashcards
Do pathogens vary in size and lifespans?
Yes
When is innate immune protection needed?
When the barriers have failed
Where do worms usually go?
Extracellular e.g. interstitial space, lymph nodes and epithelial surfaces
What are intracellular pathogens and where can these be found?
Things like viruses, protozoa and mycobacterium, they can be found in the cytoplasm of cells and the vesicular area of cells.
What can help protect the body against pathogenes?
Recognition of PAMPs and response of complement, antimicrobial proteins, innate immune cells, adaptive immune system.
What are the cell mediated immunity steps after invasion by pathogens?
Inflammatory inducers, sensor cells (macrophages, neutrophils and dendritic cells), mediators to the target tissue
What cytokines do activated macrophages secrete?
IL-1beta, TNF-alpha, IL-6, CXCL8 and IL-12
What is the local affects of IL-1beta?
Activates vascular endothelium, lymphocytes and increases access to effector cells
What does IL-1beta produce?
IL-6
What does TNF-alpha do?
Activate vascular endothelium and increase vascular permeability which leads to increased entry of IgG, complement and cells to tissues and increases fluid drainage to lymph nodes.
What are the effects of IL-6?
Lymphocyte activation and increased antibody production. It also causes fevers and induces acute phase responses.
What does CXCL8 do?
Recruits neutrophils, basophils and T cells to site of infection
What does IL-12 cells do?
Activates NK cells and induces differentiation of CD4 T cells into T helper cells
What three things stimulate the accute phase response?
TNF-alpha, IL-1beta and IL-6
What do TNF and IL-1 do in the acute phase reaction?
Act of leucocytes and endothelium to induce acute inflammation which induces the expression of IL-6 from leukocytes and other cells types
What does IL-6 do in the acute phase?
Goes to the liver and bind to its receptor to make it produce CRP, SAP, fibrinogen, MBL and MBP and complement. These protiens/peptides rolls are to defend and protect.
What molecules are decreased after a trauma or shock?
Transferrin, albumin and fibronectin
What is an example of a pattern recognition molecules?
These include CRP’s which is composed of 5 subunits and are detectable on the surface of about 4% of normal peripheral blood lymphocytes.
What does the PAMP CRP do?
It binds to phosphocholine which is found on bacterial and fungal cell walls and not on mammalian phosphocholine.
What is the native form of CRP and what can it turn into
Homodimer and can turn into mCRP.
What does native CRP do?
Activates the classical complement pathway, induces phagocytosis, increases IL-6 and TNF-alpha and promotes apoptosis
What does monomeric CRP (mCRP) do?
Recruits circulating leucocytes to areas of inflammation
What does C-reactive protein (CRP) act as?
An opsonin which allows it to be phagocytosed
Apart from CRP what is another PAMP?
Mannose binding lectins
Where is Mannon-binding leptin (MBL) found and what does it bind?
Primarily bound in the liver and binds mannose-containing strcutures (lectin) on micro-organisms and dying host cells
What does MBL function as and what does this activate?
An opsonin so is phagocytoses and this activates the lectin complement pathway
What does the genetically determined variations in MBL serum concentrations influence?
People are more susceptable to infections if they do not have this
Another class of accute phase proteins is complement (C3, C4, C5) - what does this consist of?
Lots of small protiens found in the blood normally functioning as inactive zymogens
What are the steps of the complement system?
3 triggers cause proteases to cleave specific proteins amplifying the cascade/C3 convertase which will cause inflammtion, phagocytosis and trigger the membrane attack complex.
what are the 3 different pathways of complement?
Lectin, Classical and alternative
What does the lectin complement pathway involve?
MBL and ficolins recognise and bind carbohydrates on pathogen surface
What does the classical complement pathway involve?
C1q (activated by CRP) interacts with pathogen surface or with antibodies to surface
What does the alternative complement pathway involve?
C3 undergoes spontaneous hydrolysis to C3(H2)) to initiate eventual deposition of C3 convertase on microbial surfaces.
What is the result of all three complement pathways?
They generate C3 convertase which cleaves C3 leaving C3B bound to the microbial surface and releasing C3A
What does C3a and C5a cause?
inflammation
What does C3b bound to pathogen cause?
Opsonisation
What are C4a and C3a and what does this do?
Anaphylotoxins which causes the smooth muscles to contract, vasodilation and histamine release.
After C3 is cleaved how does C3A and C5A cause inflammation?
They recruit phagocytic cells to the site of infection and promote inflammation
How does the cleaving of C3 cause phagocytosis?
C3B is left bound to the surface of the invading cells and phagocytes with receptors for this engulf and destroy the pathogen
How does completion of the complement cascade lead to lysis?
The membrane attack complex is formed which disrupts cell membrane and causes cell lysis
Coagulation factors as acute phase proteins - what does fibrinogen do?
Crosslinks with fibrin mech and links protofibril D domain to make a clot. Can also coat pathogen and prevent entry into blood (CONTAINMENT) and induce clots in vessels which localises the infection.
What is ESR?
Erythrocyte sedimentation rate
What is ESR?
Is a non-specific measure of inflammation - rate at which red blood cells sediment in a period of one hour
What is the results of an ERS?
If there is more fibrinogen the blood cells form stacks and settle faster indicating an inflammation.
What induces the acute phase reponse?
Trauma, neoplasia, infection and stress
Can TNF-alpha induce shock?
Yes
Why systemic infection bad?
Causes the increase of TNF-alpha which can cause sepsis
What happens in normal, healthy reaction of TNF-alpha to a stimulus?
Plasma proteins out of tissue
Phagocytes and lymphocyte migration into tissues
Increased platelets adhesion to blood vessel wall.
Bacteria is then phagocytosed, local vessel occlusion
Plasma and cells drain to the lymph nodes
Remove infection by adaptive immune system.
What happens in systemic infections?
Blood volume decrease, hypoproteinemia, neutropenia and later neutrophilia occurs and collapse of vessels. Disseminated intravascular coagulation leading to wasting and multiple organ failure and then death.
How can TNF-alpha cause damage if produced systemically?
TNF inhibits MI contractibility which causes reduced BP and shock.
It also causes intravascular thrombosis, activates neutrophils causing influx and vascular plugging, also DIC (disseminated intravascular coagulation).
What does prolonged TNF cause?
Wasting of muscles and fat cells (cachexia)
Appetite supression
Organ failure.
Do people survive mild sepsis?
Normally yes if mild however there is a 40% mortality rate for septic shock
What is the treatment for sepsis?
Early antibiotics (this is usually caused by gram negative bacteria)
Intesive monitoring and aggressive management of haemodynamics,
Rapid source identification and control.
Support of major organ dysfunction.
Have previous experiments and clinical intervention trials been effective and some examples of this?
No they have not been effective,
Examples include Anti-TNF antibodies, soluble TNF receptors, Anti-IL-1 antibodies, soluble IL-1 receptors and Il-1 receptor antagonist protein.
What is an autoimmune disease?
When the adaptive immune system has mistakenly identified something specific in the body as harmful and attackes it e.g. MS, RA is common.
What is an autoinflammatory disease?
The innate part of the immune system reacts often without cause and without control e.g. gout, periodic fever sydromes - this is rare.
What are the three different diseases that are auto-inflammatory cryopyrin-associated periodic syndromes (CAPS)?
Muckle-Wells syndrome (MWS), Familial cold autoinflammatory syndrome (FCAS) and neonatal onset multisystem inflammatory disease (NOMID).
What gene was mutated in MWS, NOMID and FCAS?
Autosommal dominant NLRP3
What is the symptoms of NOMID?
Diagnosis occurs shortly after birth and is the most severe. This has symptoms of rashes, fever/chills, optic nerve abnormalities, deafness, chronic aseptic meningitis, mental impairement and facial malformations.
When do FACS symptoms develop?
When patients are exposed to even a mild degree of cold and this causes a systemic inflammatory response.
Symptoms of FCAS?
Rash, fever/chills, arthralgia, conjunctivitis and fatigue.
Why do MWS symptoms occur?
The same reasons as FCAS but this is more chronic. Stress, exercise and cool temperatures might be the trigger.
Symptoms of MWS?
Rash, fever/chills, arthralgia, conjunctivitis and fatigue.
How has autoinflammatory diseases been treated successfully?
The put a 70 day old with NOMID on canakinumab (inhibits interleukin-1 beta receptor binding) which caused his white blood cells, CRP and IL-6 levels to decrease. The patients is now older with good mental development, and no recurrance of the disease but was given anti-IL-1b monoclonal antibody treatment for 2 years.
Do you need to diagnose NOMID fast?
Yes
What is the inflammasome?
Multiprotein complexes that form in the cytosol in response to cytosolic PAMPS and DAMPS whose function is to generate acŧive forms of IL-1beta and IL-18
What happens when the inflammosome is triggered?
The cell lyses and pyropotosis occurs (the insides of the cell leaves via pores).
What are the steps of the inflammosome? Steps 1 -4
1) Priming (TLR stimulation induces expression of the pro-forms of IL-1beta and IL-18).
2) NLRs respond to PAMPs or pathogen activities and oligomerize into an inflammosome. The caspase becomes active.
3 )The assembled inflammasome recruits and activates caspase-1, which cleaves pro-IL-18 and pro-IL-1b and gasdermin D.
4) Formation of a gasdermin D prote allows release of IL-1beta and IL-18 and induces pyroptotic cells death.
What are the two triggers of the inflammosome?
Priming to produce Pro-IL-1beta and IL-18
Trigger - one of :ATP, crystals, ROS, less potassium and also caspase 1
What two cells undergo programmed cell death in the form of pyropotosis?
Macrophages and dendritic cells.
