Innate Immunity - Leitenberg Flashcards
(93 cards)
1
Q
defensins
A
a type of antimicrobial protein
- found in plants
- constitutively produced and induced upon infection
2
Q
How do defensins disrupt microbial cell membranes
A
defensins are positively charged and insert into the negatively charged cell wall of the microbe and causes osmotic lysis
3
Q
What are two sources of antimicrobial peptides
A
epithelial cells and neutrophils
4
Q
What are the consequences of defects in antimicrobial production might be?
A
increased inflammation at barrier tissue sites
5
Q
Complement
A
family of proteins produced by liver and present in high concentration in blood
6
Q
What initiates the classical complement pathway?
A
antigen: antibody complexes
- adaptive immune response
7
Q
What initiates the MB-lectin pathway?
A
initiated by complement binding to lectin
- mediated by protein mannose-binding lectin
8
Q
What initiates the alternative pathway
A
negative microbial surface found on cell walls
- antibody independent
9
Q
What are the three main activities of complement?
A
recruitment of additional inflammatory cells, opsonization of pathogens, and killing of pathogens
10
Q
Opsonization
A
coated by complement component: C3b to make it more noticeable for destruction
11
Q
What is c3b
A
important complement component that serves an opsonization function
12
Q
What is an opsonin
A
a substance which promotes binding between a particle and phagocyte to facilitate phagocytosis
13
Q
Recruitment of neutrophils to tissue
A
- 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
14
Q
MAC complex
A
made up of C5B-C9
- forms hole through cell wall of microbe
- disrupts osmotic integrity
- causes lysis
15
Q
C3a, C5a
A
a for cell attraction
16
Q
c3b
A
b for binding to microbial cell walls
17
Q
c5b-c9
A
membrane attack complex
18
Q
what do macrophages and neutrophils do
A
stimulate phagocytosis of microbe
19
Q
What are 4 innate immune cells
A
macrophages, dendritic cells, neutrophils, NK cells
20
Q
What are receptor characteristics of innate immune cells
A
- 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
21
Q
What are pattern recognition receptors
A
recognize PAMPS
- promotes phagocytosis of the microbes and triggers signal transduction pathways that regulate gene transcriptional program
22
Q
What is the target of the complement proteins
A
microbial cell wall components
23
Q
What is the target of mannose-binding lectin protein
A
mannose-containing microbial carbohydrates
24
Q
Toll-like receptors
A
expressed on plasma membrane and recognize extracellular molecules as well as in endosomal compartments
25
What happens when TLR engage with ligands?
induces a cascade of signal transduction events
| - activation of NF-kB
26
What happens when Nf-Kb is activated
triggers production of pro-inflammatory cytokines
| - trigger cardinal signs of acute inflammation
27
What are pro-inflammatory cytokines
TNFalpha, IL-6, IL-1, IL-12, IFN
28
NOD-like receptors
- receptors that recognize microbial patterns
- triggers signal transduction cascade
- activates NF-kB and triggers production of pro-inflammatory cytokines
29
What mutations are associated with Crohn's disease
loss of function mutations of NOD
30
Three examples of PAMPs
peptidoglycan, single stranded/double stranded RNA, mannose, lipopolysachardide
31
Two examples of pattern recognition receptors
TLR, NOD-like, glycan receptors
32
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
33
What are examples of DAMPs
uric acid, stress-induced proteins (heat shock proteins), nuclear proteins
34
What receptors can recognize DAMPs?
NOD-like receptors and TLR
35
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
36
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
37
Gout
inflammasome activation in response to uric acid crystals, produces inflammation
38
Periodic Fever Syndromes
associated with innapropriate activation of pyrin (NALP)
| - familial mediterranean fever
39
macrophages/dendritic cells
- constitutively present in the tissues
| - have receptors that recognize pathogens and danger
40
What is the role of macrophages
engulf pathogens and kill
- stay on site
- stimulate adaptive immunity
- make cytokines
41
What is the role of dendritic cells
engulf pathogens
- leave and migrate through tissues
- stimulate adaptive immunity
- make cytokines
42
What are monocytes derived from?
hemotapoetic progenitor cells in the adult bone marrow
| - monocytes move to different tissues and differentiate to become macrophages
43
What is IL-8
chemokine = protein that has specific function where it can regulate the migration of other cells
- chemoattractant functions
44
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
45
CXCL8
- chemokine
- recruits additional cells to the site
- recruits neutrophils
46
IL-12
promotes and activates NK cells
47
IL-6 local effects
regulates other cells that are in the microenvironment
48
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
49
How does the local infection prevent induction of systemic inflammation
- contain inflammatory response to avoid sepsis and septic shock
50
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
51
IL-6
causes production of acute phase proteins from the liver = hallmark of inflammatory response
52
What are proteins that are upregulated by hepatocytes
- measure C-reactive protein, fibrinogen levels that are upregulated as a consequence of inflammation
53
What is CRP
complement activator
54
What does IL-6 do?
acts on hepatocytes to cause upregulation of proteins like CRP
55
What effect does IL-8 have?
chemokine that attracts neutrophils to the site of inflammation
- neutrophils express the receptor for IL-8
56
What cell type does IL-12 act on
NK cells
57
What effect does TNF-alpha have
acts on local blood vessel endothelial cells that upregulates adhesion molecules
58
What are the microbicidal actions of macrophages
phagocytosis and killing of bacteria and fungi by ROS, NO, lysosomal enzymes
59
What are functions of macrophages
- inflammatory response
- anti-inflammatory effects
- wound repair, fibrosis
60
TGF-beta
cytokine that is anti-inflammatory and promotes collagen deposition and activates fibroblast and increased VEGF
61
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
62
Which cell is an important link between the innate and adaptive immune response?
dendritic cells
63
Where do dendritic cells migrate to?
migrate to lymph nodes from barrier sites where initiate adaptive immune response by interacting with T-lymphocytes
64
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
65
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
66
What do prostaglandins and leukotrienes do
play a role in making local endothelial cells vasodilate and express adhesion molecules
67
TNF-alpha
regulates endothelial cell function and ability to recruit additional cells
68
IL 8
chemokine
69
IL 12
regulates activity of NK cells
70
What are two stimuli that regulate the movement of dendritic cells from tissue sites into lymph nodes
chemokines and PAMPs
71
Where are neutrophils made?
bone marrow and stored in the bone marrow
72
What is the role of neutrophils during inflammation
- leave the bone marrow to enter the blood
| - enter the tissue to engulf and kill bacteria
73
How is leukocyte trafficking regulated
regulated by chemokines/chemoattractants and adhesion molecules
74
chemoattractants
migrate actual cell movement
| - cells move from concentration of low chemoattractant to higher chemoattractant levels
75
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
76
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
77
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
78
What are the different mechanisms that the neutrophil uses to kill the microbe?
1. neutrophil is phagocytosed
2. pH of phagosome is adjusted
3. increased acidity as you become deeper in the neutrophil to kill
- generation of reactive oxygen intermediates that are toxic to microbes
79
diapedesis
when leukocytes move out of the blood stream through the epithelial cells into the tissues
80
What would happen to a patient with a genetic mutation causing decreased expression of beta-2 integrin?
increased circulating neutrophils = leukocytosis
81
What cells release chemokines and cytokines?
macrophages for leukocyte recruitment and activation of antimicrobial responses
82
What is the role of DC in innate immunity
production of cytokines and chemokines and initiation of adaptive immunity
83
What lineage do NK cells belong it
large granular lymphocyte
84
What mediates the killing by NK cells
mediated by release of lytic granules
85
How do NK cells regulate the immune response
produce cytokines
86
How do NK cells get activated
KAR: Killer activating receptors and KIR: Killer inhibitory receptors
87
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
88
perforin
protein released by NK cell
| - forms a pore in the target membrane
89
granzymes
protein released by NK cells
| - serine proteases that activate apoptosis once in cytoplasm of target cell
90
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
91
IFN gamma and IL 12
cytokines that NK cells make alot of to regulate the development of immune response
92
What do NK cells do to the viral replication?
NK cells control viral replication but don't eliminate the virus
93
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
