Inflammation, Apoptosis, And Response To Danger Signals Flashcards
What type of stimulus might activate the intrinsic apoptotic pathway?
Abnormalities in DNA
Lack of O2
Lack of nutrients
Lack of survival signals (mitochondrial dysfunction)
What type of stimuli might activate the extrinsic apoptotic pathway?
Removal of survival factors
Proteins of TNF family
The intrinsic pathway is __________-dependent, and occurs in response to injury
Mitochondrial
Which apoptotic pathway is mitochondria-independent?
Extrinsic pathway
Caspases are first synthesized as an inactive precursor called ________, which must be activated by ________ cleavage at specific sites
Procaspases
Protease
Describe the general structure of a caspase after protease cleavage
Form a large and small subunit –> form a heterodimer
What are the initiator caspases?
Caspase 8
Caspase 9
What is the executioner caspase?
Caspase 3
Generation of many molecules of executioner caspases in the caspase cascade result in cleavage of _______ protein and nuclear _______
Cytosolic; lamin
The extrinsic pathway of apoptosis involves what two membrane receptor-ligand pairs?
FADD:Fas receptor binds Fas Ligand
TRADD:TNF-alpha receptor binds TNF-alpha
[occurs in CD8+ T cells only]
What is the first caspase made by the extrinsic pathway of apoptosis?
Caspase 8 (which then combines with caspases 3, 6, and 7)
CD8+ mediated death occurs in part because its expression of ____ increases upon antigenic activation as an anti-inflammatory response
FasL
Apoptosis of which cell type carries the risk of bystander damage?
CD8+ mediated cell death, due to perforin and granzyme release, even though these are directed at target cell by adhesion molecule binding
What is the difference between inflammation due to microbial attack vs. sterile attack?
Microbial attack due to PAMPs
Sterile attack due to DAMPs
Which type of inflammation leads to collateral damage?
Chronic inflammation
What are the cardinal signs of acute inflammation?
Pallor/Dolor (pain) Calor (heat) Rubor (redness) Tumor (swelling) Loss of function
Describe the onset, duration, and specificity of acute vs. chronic inflammation
Acute: rapid onset, short duration, non-specific
Chronic: insidious/delayed onset, long duration, specific (involves acquired immunity)
What are the cardinal signs of chronic inflammation?
Cardinal signs are absent in chronic inflammation
What are the causative agents of acute inflammation?
Physical and chemical damage
Pathogen invasion
Tissue necrosis
Immune response
What are the causative agents of chronic inflammation?
Persistent infection
Presence of foreign bodies
Autoimmunity
What are the fundamental cells involved in acute inflammation?
Neutrophils
Mast cells
Platelets
Basophils
[in addition to all their soluble mediators]
What are the fundamental cells involved with chronic inflammation?
B and T lymphocytes
Macrophages
Plasma cells
Antibodies
Inflammation is resolved by ___________, which clean up cellular debris utilizing a special type of PRR called _________ receptors.
Specialized anti-inflammatory cytokines include IL-10 and TGF-beta
M2 macrophages
Scavenger
How does necrosis compare to apoptosis in terms of cellular size and # of cells affected?
Necrosis: cell swelling, many cells affected
Apoptosis: cell shrinkage, one cell affected
How does necrosis compare to apoptosis in terms of cellular content uptake and inflammation?
Necrosis: cell contents ingested by macrophages, significant inflammation
Apoptosis: cell contents ingested by neighboring cells, no inflammation
How does necrosis compare to apoptosis in terms of membrane integrity?
Necrosis: loss of membrane integrity, cell lysis occurs
Apoptosis: membrane blebbing, but integrity maintained, apoptotic bodies form
How does necrosis compare to apoptosis in terms of organelles?
Necrosis: organelle swelling and lysosomal leakage, random degradation of DNA
Apoptosis: mitochondrial release of pro-apoptotic proteins, chromatin condensation and non-random DNA degradation
_________ are molecules released by stressed cells undergoing nerosis that act as endogenous danger signals to promote and exacerbate the inflammatory response
DAMPs
DAMPs are also called _______
Alarmins
Binding of DAMP ligands to _____ induces intracellular signaling in the phagocytes leading to their activation
PRRs
What are some examples of DAMPs due to cell necrosis?
dsRNA CpG Uric acid HMGB1 ATP HSP IL-1alpha
What are some DAMPs associated with ECM degradation?
Hyaluronan
Heparan sulphate
______ is a significant alarmin responsible for activating a cell by binding its receptor HMGB1 (high mobility box 1)
RAGE
True or false: DAMPs are non-infectious, associated with cell damage or necrosis, and may occur due to radiation, surgery, burns, UV light, etc.
True
The signaling system for detection of pathogens and stressors involves the assembly of a ________ sensor and adaptor, and the inactive caspase into the ________________ - which activates the caspase which in turn results in expression of IL-1
NLRP-3
Inflammasome
The inflammosome results in the production of what 2 potent inflammatory cytokines?
IL-1
IL-18
What is SIRS?
Systemic inflammatory response syndrome = pathogenic overstimulation of the immune response
What is the effect of non-infectious SIRS?
Caused by DAMPs, leads to shock
What is the effect of infectious SIRS?
Sepsis –> septic shock
What are the symptoms associated with systemic SIRS and sepsis?
Fever
Tachycardia
Tachypnea
Leukocytosis
What symptom is characteristic of severe SIRS or severe sepsis?
Organ failure (due to lack of perfusion)
What symptom is characteristic of shock or septic shock?
Hypotension
What is the typical cytokine profile of SIRS?
IL-1
IL-6
TNF-alpha
[these are the acute phase cytokines, which stimulate the liver to make more APPs including CRP and C’ –> cytokine storm]
Symptoms of SIRS appear during the hyper-inflammatory phase. The patient’s immune system will try to provide a ______
During this period, the patient is significantly _________
The immune system will rebound again with a hyperinflammatory reaction, leading to another compensatory response. Each one becomes less severe until _______ is reached
CARS (compensatory anti-inflammatory response)
Immunosuppressed
Homeostasis
______ is an inherited disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway
ALPS (autoimmune lymphoproliferative syndrome)
ALPs leads to an excess of what cell types?
TCR alpha/beta CD3+CD4-CD8- (double negative T cells)
These will accumulate in the LNs, spleen, and peripheral blood - results in lymphoproliferation, autoimmune disease, and malignancy
