What makes up the first line of defense?
surface barriers: skin, mucous membranes, and their secretions
stratum corneum is the outermost layer of the epidermis, made of dead cells
How do phagocytic cells recognize a microbial infection?
Pattern recognition receptors (PRRs) on host cells recognize the pathogen associated molecular patterns (PAMPs) on microbes and then can be engulfed by the phagocytic cells in areas called clatherin-coated pits. phagocytosis produces a vacuole filled with the ingested organism called a phagosome.
the phagosome fuses with granules or the lysosome and then granules are released into the phagosome.
What are two commonly seen phagocytic cell receptors and what microbial component do they recognize?
TLR-4 along with CD 14 recognizes LPS
TLR-2 recognizes peptidoglycan and lipotechoic acid
What oxygen dependent mechanism do neutrophils use to kill phagocytosed microbes?
- Generation of reactive oxygen intermediates
- neutrophils have myeloperoxidase that generates hypochlorite and a singlet oxygen
hypochlorite is an antimicrobial agent
What oxygen dependent mechanism do macrophages use to kill phagocytosed microbes?
macrophages can generate superoxide and hydrogen peroxide; however, they primarily use the development of nitric oxide (powerful antimicrobial agent and vasodilator) and reactive nitrogen intermediates.
macrophages do not have myeloperoxidase
What are the two oxygen independent mechanisms that neutrophils and macrophages use to kill phagocytosed microbes?
- Generation of antimicrobial peptides
-lysozyme degrades peptidoglycan
-lactoferrin sequesters iron to cause iron deficiency
in microbes.
-hydrolytic enzymes
-defensins
-DNAase
-RNAase - Fusion between phagosome containing microbes with lysosome
What cytokines induce NO production?
IFN-gamma is produced by CD4+ T cells (TH-1)
TNF-alpha is produced by macrophages
what effects does IFN-gamma have? in what type of cells?
in macrophages:
- increased levels of reactive oxygen intermediates in macrophages
- promotion of the fusion of the the phagosome and lysosomes
- activate the expression of inducible nitric oxide synthase which catalyses the conversion of L-arginine–> nitric oxide
What releases IFN-alpha and what does it cause?
IFN-alpha is released by virus-infected cells. it induces the neighboring uninfected cells to produce protein kinase R (PKR). PKR digests the RNA and DNA in infected cells, killing both the infected cells and the virus.
What are type I interferons? Type II?
Type I=INF-alpha and INF-beta
Type II=INF-gamma
describe the steps in a gram negative infection that can lead to inflammation
in a gram negative bacterial infection, LPS is released by the bacteria and bound to LPS binding protein
this complex then binds to TLR4 on monocytes and leads to the expression of transcription factor NFKB, which produces the synthesis of TNF-alpha.
TNF-alpha, in combination with IL-1 (causes increase in body temp) and IL-6 can lead to septic shock if produced in excess quantities
What are the three characteristics of septic shock and which cytokine mediates them?
- hypotension
- disseminated intravascular coagulation
- inflammation
all are mediated by the excess production of TNF-alpha
What effects does TNF-alpha cause in the cell?
- enhanced NO production through activation of Nitric oxide synthase in both endothelial cells and macrophages–> hypotension
- synthesis of bradykinins
- enhanced expression of tissue factor (TF) on monocytes and neutrophils –> triggers clotting
- induces expression of P-selectin and E-selectin–> facilitating binding g of leukocytes to endothelial cells–> this leads to enhanced expression of ICAM (intracellular adhesion molecules) causing increased binding of neutrophils and monocytes to endothelial cells through LFA (leukocyte function associated antigen)–> increased cells leaving the circulatory system to go to the site of infection (diapedesis) –> inflammation
overall, the three symptoms of septic shock if produced in excess
What chemotactic factor causes neutrophils to migrate to infection? What chemotactic factor causes monocytes and macrophages to migrate?
neutrophils: IL-8
monocytes and macrophages: GM-CSF, MIP, RANTES
During complement activation, what is the function of the C3a component? The C5a component?
C3a is a chemotactic agent–> increase blood cells to the site
C5a: anaphylotoxin: induces basophils and mast cells to release histamine –> increase vascular permeability
What is TNF alpha released in response to?
LPS released from gram negative bacterial infections
