Innate Immunity - Leitenberg Flashcards
defensins
a type of antimicrobial protein
- found in plants
- constitutively produced and induced upon infection
How do defensins disrupt microbial cell membranes
defensins are positively charged and insert into the negatively charged cell wall of the microbe and causes osmotic lysis
What are two sources of antimicrobial peptides
epithelial cells and neutrophils
What are the consequences of defects in antimicrobial production might be?
increased inflammation at barrier tissue sites
Complement
family of proteins produced by liver and present in high concentration in blood
What initiates the classical complement pathway?
antigen: antibody complexes
- adaptive immune response
What initiates the MB-lectin pathway?
initiated by complement binding to lectin
- mediated by protein mannose-binding lectin
What initiates the alternative pathway
negative microbial surface found on cell walls
- antibody independent
What are the three main activities of complement?
recruitment of additional inflammatory cells, opsonization of pathogens, and killing of pathogens
Opsonization
coated by complement component: C3b to make it more noticeable for destruction
What is c3b
important complement component that serves an opsonization function
What is an opsonin
a substance which promotes binding between a particle and phagocyte to facilitate phagocytosis
Recruitment of neutrophils to tissue
- proteolytic fragments of complement proteins
- attract immune cells to the site where complement fragments are being produced
- direct binding of complement mols will cause the cells to want to migrate
MAC complex
made up of C5B-C9
- forms hole through cell wall of microbe
- disrupts osmotic integrity
- causes lysis
C3a, C5a
a for cell attraction
c3b
b for binding to microbial cell walls
c5b-c9
membrane attack complex
what do macrophages and neutrophils do
stimulate phagocytosis of microbe
What are 4 innate immune cells
macrophages, dendritic cells, neutrophils, NK cells
What are receptor characteristics of innate immune cells
- specificity inherited in the genome
- expressed by all cells of a particular type
- triggers immediate response
- recognizes broad classes of pathogens
- interacts with a range of molecular structure of a given type
What are pattern recognition receptors
recognize PAMPS
- promotes phagocytosis of the microbes and triggers signal transduction pathways that regulate gene transcriptional program
What is the target of the complement proteins
microbial cell wall components
What is the target of mannose-binding lectin protein
mannose-containing microbial carbohydrates
Toll-like receptors
expressed on plasma membrane and recognize extracellular molecules as well as in endosomal compartments
What happens when TLR engage with ligands?
induces a cascade of signal transduction events
- activation of NF-kB
What happens when Nf-Kb is activated
triggers production of pro-inflammatory cytokines
- trigger cardinal signs of acute inflammation
What are pro-inflammatory cytokines
TNFalpha, IL-6, IL-1, IL-12, IFN
NOD-like receptors
- receptors that recognize microbial patterns
- triggers signal transduction cascade
- activates NF-kB and triggers production of pro-inflammatory cytokines
What mutations are associated with Crohn’s disease
loss of function mutations of NOD
Three examples of PAMPs
peptidoglycan, single stranded/double stranded RNA, mannose, lipopolysachardide
Two examples of pattern recognition receptors
TLR, NOD-like, glycan receptors
How is inflammation induced during sterile tissue injury?
receptor mediated recognition of DAMPs
- tissue damage that leads to cell necrosis
- release DAMPs that trigger inflammatory response
What are examples of DAMPs
uric acid, stress-induced proteins (heat shock proteins), nuclear proteins
What receptors can recognize DAMPs?
NOD-like receptors and TLR
Inflammasome complex
- NOD-like receptors
- can activate caspases (enzymes that cleave other proteins in the cell)
- cleaving of IL-1B
- caspase 1 cleaves IL-IB and is secreted as pro-inflammatory
What are the two regulatory points of the inflammasome
- activating caspases that cleave the proform
- pattern recognition receptors that promote increased transcription of the gene that codes for the proform of the inflammatory cytokine
Gout
inflammasome activation in response to uric acid crystals, produces inflammation
Periodic Fever Syndromes
associated with innapropriate activation of pyrin (NALP)
- familial mediterranean fever
macrophages/dendritic cells
- constitutively present in the tissues
- have receptors that recognize pathogens and danger
What is the role of macrophages
engulf pathogens and kill
- stay on site
- stimulate adaptive immunity
- make cytokines
What is the role of dendritic cells
engulf pathogens
- leave and migrate through tissues
- stimulate adaptive immunity
- make cytokines
What are monocytes derived from?
hemotapoetic progenitor cells in the adult bone marrow
- monocytes move to different tissues and differentiate to become macrophages
What is IL-8
chemokine = protein that has specific function where it can regulate the migration of other cells
- chemoattractant functions
What is the local effect of inflammatory cytokines
- mediate local response
- heat, redness, swelling, pain
- vasodilation and express adhesion molecules to recruit other cells to that site
- TNF-alpha and IL-1B
CXCL8
- chemokine
- recruits additional cells to the site
- recruits neutrophils
IL-12
promotes and activates NK cells
IL-6 local effects
regulates other cells that are in the microenvironment
What is local inflammation
- disrupt barrier integrity of skin epithelium
- tissue damage
- microbes in the local microenvironment in the subcutaneous
- trigger pattern recognition receptors on the cells to produce cytokines, prostaglandins to regulate the local inflammatory response
- regulate local vascular epithelium cells to vasodilate and to become leaky
- upregulate adhesion mols to allow WBC to recognize the active site
How does the local infection prevent induction of systemic inflammation
- contain inflammatory response to avoid sepsis and septic shock
What are systemic effects of inflammatory cytokines
- regulate cells in the hypothalamus by regulating body temperature
- regulate fat and muscle metabolism
- regulate neutrophil mobilization from bone marrow into blood stream
- regulation of gene transcription in the liver to increase production of proteins
IL-6
causes production of acute phase proteins from the liver = hallmark of inflammatory response
What are proteins that are upregulated by hepatocytes
- measure C-reactive protein, fibrinogen levels that are upregulated as a consequence of inflammation
What is CRP
complement activator
What does IL-6 do?
acts on hepatocytes to cause upregulation of proteins like CRP
What effect does IL-8 have?
chemokine that attracts neutrophils to the site of inflammation
- neutrophils express the receptor for IL-8
What cell type does IL-12 act on
NK cells
What effect does TNF-alpha have
acts on local blood vessel endothelial cells that upregulates adhesion molecules
What are the microbicidal actions of macrophages
phagocytosis and killing of bacteria and fungi by ROS, NO, lysosomal enzymes
What are functions of macrophages
- inflammatory response
- anti-inflammatory effects
- wound repair, fibrosis
TGF-beta
cytokine that is anti-inflammatory and promotes collagen deposition and activates fibroblast and increased VEGF
where are dendritic cells constitutively present
at barriers, constantly sampling their microenvironment and interprets sensory input signals and regulates the function of adaptive immune cells
Which cell is an important link between the innate and adaptive immune response?
dendritic cells
Where do dendritic cells migrate to?
migrate to lymph nodes from barrier sites where initiate adaptive immune response by interacting with T-lymphocytes
Plasmacytoid dendritic cells
- have alot of TLR that sense viral infection and produce type 1 interferons (IFN alpha and beta)
- more efficient at making interferons than any other cell
What do type 1 IFN cells do
protect against viral infection
- interferes with viral gene replication pathways
- regulates the function of MHC (adaptive immunity) and promotes t-lymphocyte adaptive immune response
- activate NK cells to kill virus-infected cells
What do prostaglandins and leukotrienes do
play a role in making local endothelial cells vasodilate and express adhesion molecules
TNF-alpha
regulates endothelial cell function and ability to recruit additional cells
IL 8
chemokine
IL 12
regulates activity of NK cells
What are two stimuli that regulate the movement of dendritic cells from tissue sites into lymph nodes
chemokines and PAMPs
Where are neutrophils made?
bone marrow and stored in the bone marrow
What is the role of neutrophils during inflammation
- leave the bone marrow to enter the blood
- enter the tissue to engulf and kill bacteria
How is leukocyte trafficking regulated
regulated by chemokines/chemoattractants and adhesion molecules
chemoattractants
migrate actual cell movement
- cells move from concentration of low chemoattractant to higher chemoattractant levels
Normal leukocyte trafficking when no inflammation
interact with endothelium weakly
- selectins are present and interact with ligands expressed on the WBC
- makes the neutrophil slow down a little bit but doesn’t stop to get out of blood stream into tissue
- rolls along the capillary endothelium
Leukocyte trafficking during inflammation
endothelial cells upregulate selectin molecules which slows down the rolling
- endothelial will upregulate other adhesion molecules that interact with integrins
- chemokines produced by tissue and cells will signal through chemokine receptor and promote higher affinity between WBC and endothelium and makes the WBC stop and respond to chemokines in the microenvironment and will enter through the endothelial cells through diapedesis where the chemokine is being produced
How do neutrophils kill microbes?
neutrophils will recognize microbes and trigger phagocytosis and take microbe in phagosomal vacuole and interact with other intracellular compartments to kill
What are the different mechanisms that the neutrophil uses to kill the microbe?
- neutrophil is phagocytosed
- pH of phagosome is adjusted
- increased acidity as you become deeper in the neutrophil to kill
- generation of reactive oxygen intermediates that are toxic to microbes
diapedesis
when leukocytes move out of the blood stream through the epithelial cells into the tissues
What would happen to a patient with a genetic mutation causing decreased expression of beta-2 integrin?
increased circulating neutrophils = leukocytosis
What cells release chemokines and cytokines?
macrophages for leukocyte recruitment and activation of antimicrobial responses
What is the role of DC in innate immunity
production of cytokines and chemokines and initiation of adaptive immunity
What lineage do NK cells belong it
large granular lymphocyte
What mediates the killing by NK cells
mediated by release of lytic granules
How do NK cells regulate the immune response
produce cytokines
How do NK cells get activated
KAR: Killer activating receptors and KIR: Killer inhibitory receptors
What happens to an NK cell that missing the inhibitory receptor ligand?
- NK cell should kill
- express activated receptor ligands that triggers the cell to kill the cell that it is interact with
perforin
protein released by NK cell
- forms a pore in the target membrane
granzymes
protein released by NK cells
- serine proteases that activate apoptosis once in cytoplasm of target cell
What happens when an NK cell interacts with a virus infected cell
- activate the activating receptor
- viruses interact with the host cell to downregulate the MHC class 1
- upregulate the activating receptor ligands
- granules released to kill viral cell
IFN gamma and IL 12
cytokines that NK cells make alot of to regulate the development of immune response
What do NK cells do to the viral replication?
NK cells control viral replication but don’t eliminate the virus
What happens when you get a splinter?
- disrupt the membrane integrity
- expose tissue residue to PAMPs
- trigger expression of chemokines and cytokines
- leads to swelling, leaking of blood vessels
- recruitment of additional cells
- activation of complement
- trigger dendritic cells to migrate
- trigger immune response
