Innate Immunity 8/27 Flashcards
Describe the principal components of innate immunity.
- The receptors of the innate immune system are encoded in the germline and are not produced by somatic recombination of genes.
- thus the receptors are identical on all cells of the same lineage (nonclonal) and recognize a variety of different microbes: Toll-like receptors, N-formyl methionyl receptor, mannose receptor.
- physical barrier (stratified squamous, tight junctions)
- chemical barrier on the skin (fatty acids and antiobiotics, ie. defensins)
- mucosal surfaces: removal of particles over turbinates, rapid pH changes, cilia, normal flora
Defensins
Very tiny chains of AA’s in Beta sheets
+ charged
found in granules and provide defense in innate immunity by targetting gram -/+ bacteria, fungi, parasites, and viruses
- they are produced by neutrophils and paneth cells maiinly
(cathelcidins are similar in nature to defensins)
- Cells of the immune system contain these peptides to assist in killing phagocytosed bacteria, for example in neutrophil granulocytes and almost all epithelial cells. Most defensins function by binding to the microbial cell membrane, and, once embedded, forming pore-like membrane defects that allow efflux of essential ions and nutrients.
Identify the mechanism(s) by which the innate immune system recognizes foreign substances.
Describe the mechanism(s) of acute inflammation. Include: cells, adhesion molecules, chemokines/cytokines, receptor expression, bioactive peptides and proteins. Relate all to an acute inflammatory response.
- At sites of infection, macrophages, dendritic cells, and other cells that have encountered microbes produce cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) that activate the endothelial cells of nearby venules to express selectins and ligands for integrins, and to secrete chemokines. Selectins mediate weak tethering and rolling of blood neutrophils on the endothelium, integrins mediate firm adhesion of neutrophils, and chemokines activate the neutrophils and stimulate their migration through the endothelium to the site of infection. Blood monocytes and activated T lymphocytes use the same mechanisms to migrate to sites of infection.
Inflammation
- Inflammation is a tissue reaction that rapidly delivers mediators of host defense—circulating cells and proteins—to the locations where they are needed, the sites of infection and tissue damage
- The process of inflammation consists of multiple steps, including recruitment of cells and leakage of plasma proteins through blood vessels, engulfment of microbes and dead material by phagocytes, and destruction of these potentially harmful substances.
LPS
LPS is a bacterial endotoxin (lipopolysaccharide) that phagocytes express a receptor for. Thus they recognize when bacteria has invaded local tissues.
PAMPs and PRR
PAMPs = The microbial molecules that stimulate innate immunity (pathogen-associated molecular patterns). They are shared by microbes of the same molecular patterns, and thus recognition of PAMPs results in an innate immune response.
PRR = pattern recognition receptors = receptors on leukocytes of innate immunity that recognize the PAMPs
- Recognize MAIs and danger signals along with LPS, mannose residues, dsRNA.
- Simple mutations are not evasive- thus the pathogen cannot easily evade this part of the immune response without killing the cells
DAMPs
- Damage associated molecular patterns - molecules released from damaged or nectrotic cells that act as an endogenous danger signal to promote and exacerbate the inflammator response i.e. alarmins and danger signals.
- increased serum level of DAMPs is associated with many inflammatory diseases (sepsis, arthritis, atherosclerosis, lupus crohn’s disease, cancer)
Toll-Like Receptors
TLR’s recognize PAMPs such as LPS and other bacterial particles on the outside of the cell. They are also located on the endosomes of the cells where they recognize foreign DNA/RNA
- activation of TLR’s leads to txn of NF-kB, which results in increased expression of cytokines and adhesion molecules
- ultimately this leads to acute inflammation and stimulation of adaptive immunity
NK’s
Natural killer (NK) cells are a class of lymphocytes that recognize infected and stressed cells and respond by killing these cells and by secreting the macrophage-activating cytokine IFN-γ
- NK cells have an inhibitory receptors that recognize the MHC I Complex (self-recognizing) - NK cell is not activated, and cell is not killed: if cell is virally infected the virus inhibits MHC I complex expression and the NK Cell is activated and kills the infected cell.
- NK cells respond to IL-12 produced by macrophages with microbes, and secrete IFN-gamma which activates the macrophage to kill phagocytosed microbes, and also recruits more macrophages to the area
- NK cells also respond to virus-infected cells and kill the cell.
- They secrete IFNgamma to activate macrophages and are activated by IL-12 secreted from macrophages
Mast Cells
- “sentinels”
- release histmaine and haparin to recruit neutrophils and macrophages
- reside in the connective tissue and mucosal membranes
- mast cells can be simulated to degranulate by direct injury and play a key role in the inflammatory process.
- Granules contain Histamin, proteases, heparin TNF
Eosinophils
- differentiate in response to IL-5
- Responsible for combatting multicellular parasites - they are “sister” to mast cells
- Can survive in tissue for a long time if not activated
Monocytes (Macrophages)
- “Rangers”- have ROS, iNOW produced for better killing cabaility
- induced from meyloid stem cell –> IL-3, CM-CSF –> GranulocyteMonocyte-CFU –> M-CSF–> macrophage
- don’t have any granules: largest phagocytic leukocytes
- Main responder to intracellular bacteria through IL-12 and IFNgamma
- less abundant than neutrophils: Monocytes that enter extravascular tissue differentiate into Macrophages, which surve longer in tissues.
- they produce cytokines that initiate and regulate inflammation
- injest and destroy microbes and clear dead tissues through activation through TLR’s
- resident macrophages live in the specific tissues (kupffer cells, osteoclasts, langerhans, microglia) whereas recruited macrophages are classically activated in terms of inflammation
Neutrophils
- “Kamikaze Pilot”
- Myeloid progenitor –> IL-3, GM-CSF –> granulocyte monocyte CSF –> G-CSF –> Neutrophil
- most abundant leukocytes in the blood: first and primary responders to acute inflammation: only live a few hours in tissues: migrate via chemotaxis
- main responder to Extracellular Bacteria (puss forming), through responding to TFN, IL1 chemokines
- They are the first on site - they phagocytose bacteria and if they get frustraited they throw out nets of containment until the next group of cells can come and clean up the mess.
Dendritic Cells (APCs)
- live within the tissues of epithelium
- respond to microbes by initiating inflammation and stimulating adaptive immune responses –> display of antigens
- have long dendrtic process that are at first phagocytic, but then are more antigen presenting
- bridge between innate and adaptive immunity
