Inflammation + Complement Flashcards
1
Q
What are the effector functions of NK cells?
A
- lysis of abnormal cells
- activation of macrophages through cytokine secretion
2
Q
What are NK cell cytotoxicity mechanisms?
A
- perforin-dependent mechanism
- CD95/CD95L (Fas/FasL) mechanism
- CD16 killing pathway (ADCC)
3
Q
During perforin-dependent mechanism the NK cell releases perforin from its granules which _______________ called perforin channels.
Later ___________, NK-lysis (granzymes), and __________ are released from cytotoxic granules and passed through the perforin channels, inducing apoptosis of the cell
A
- creates a lesion
- granulysin
- fragmentin (protease)
4
Q
NK cells normally express CD95L (FasL) on the cell surface, which binds to ______ expressed on target cells, inducing ________
A
- CD95 (Fas)
- apoptosis
5
Q
NK cells can recognize targets through a ____________ using CD16, a _________ receptor.
How does this pathway work? What is its other name?
A
- antibody dependent pathway
- Fc (FcyIII)
- antibodies bind to an antigen on infected cell, NK cells bind to antibodies via CD16 leading to NK cell cytotoxicity
- ADCC (antibody-dependent cellular cytotoxicty)
6
Q
T/F: NK cell target recognition through CD16 will only occur when antibodies are present
A
- true
7
Q
NK cells are activated by cytokines such as:
A
- IL-1, IL-2, IL-12, IL-15, IL-18, IL-21, type I + II IFNs
8
Q
Treatment of isolated NK cells in vitro turns them into __________ with increased cytotoxic ability, which have potential in immunotherapy of tumors
A
- lymphokine activated killer cells (LAK)
- some viruses inhibit NK cell cytotoxicity
9
Q
NKT cells are of _________ origin, with similar properties to NK cells and T lymphocytes. Their specificity is directed against ________ pathogens. They make up 0.5-1% of peripheral blood mononuclear cells
A
- thymic
- very few
10
Q
NKT cells express ____________ TCR, as well as NK1.1 and other KLR receptors.
Mostly they are _______, but can be double negative (CD4-/CD8-).
NKT cells recognize __________
A
- invariant a/B
- CD4+
- glycolipid antigens on bacteria
11
Q
NKT cells are activated by ______, do not develop into memory cells, and serve to link the T cell system and NK cells.
They play a role in allergies, ___________, autoimmunity,and antimicrobial immunity
A
- IL-15
- antitumor immunity
12
Q
T/F: NK DCs are NK cells with dendritic properties present in the spleen, liver, lymph nodes, and thymus
A
- false; DCs with NK cell properties
- NK DCs express NK1.1 and CD11c markers
13
Q
NK DCs spontaneously _______ tumor cells, present antigens to _________, and produce large amounts of ________ through TLR9 (CpG) stimulation.
A
- lyse
- naive T cells
- IFNy
- ** link innate and adaptive immunity
14
Q
Define inflammation
A
- defense reaction of living tissue against damage, aimed at removing the cause of injury and repairing the tissue.
- plays a integral role in both innate and adaptive immunity
15
Q
T/F: inflammation can be either acute or chronic
A
- true
16
Q
__________ inflammation fights the early stages of infection and prepares the process that leads to tissue repair
A
- acute
17
Q
Chronic inflammation is characterized by:
A
- dominating presence of macrophages in the injured tissue
18
Q
What are the exogenous causes of inflammation?
A
- physical agents
- mechanical: fractures, foreign objects, sand, etc.
- thermal: burns, freezing
- chemical agents: toxic gases, acids, bases
- **biological agents: bacteria, viruses, parasites, fungi
19
Q
What are the endogenous causes of inflammation?
A
- circulation disorders: thrombosis, infarction, hemorrhage
- metabolic products: uric acid, urea
20
Q
What are the hallmark signs of of acute inflammation?
A
- heat
- redness
- swelling
- pain
- loss of function
21
Q
The signs of inflammation develop as below:
- after injury, _________ occurs leading to rise in blood flow raising the temperature (heat)
- large volume of blood in the area causes __________
- vascular permeability increases leading to leakage of fluids resulting in ___________
- within hours leukocytes adhere to the endothelium in the injured area leading to ___________
- the leukocytes _________ invading pathogens and release mediators that further contribute to inflammation, and some induce pain
- injured tissue is eliminated from normal function
A
- vasodilation
- hyperaemia (redness)
- edema (swelling)
- phagocytose
22
Q
What are the mediators of inflammation?
A
- pro-inflammatory cytokines
- complement components
- prostaglandins
- leukotrienes
- vasoactive amines (histamine, serotonin)
- platelet-activating factor (PAF)
- plasma proteins
23
Q
__________ and _________ induce fever and stress hormone production (norepinephrine, vasopressin, activation of RAAS); as well as induce synthesis of IL-,IL-8,and interferon gamma (IFNy)
A
- tumor necrosis factor alpha (TNFa) + interleukin 1 (IL-1)
- (pro-inflammatory cytokines)
24
Q
________ stimulates release of acute-phase proteins such as C-reactive protein (CRP)
A
- IL-6
25
Pro-inflammatory cytokines activate the___________, release of nitric oxide, platelet-activating factor, ___________, and ____________.
- coagulation cascade
- prostaglandins
- leukotrienes
26
IL-1, IL-6, and IL-8 promote ________, induce _________ of granulocytes, and ____________ of neutrophils
- chemotaxis
- extravasation
- degranulation
27
The complement components of inflammation C3a andC5a increase ______________ and stimulate __________ of neutrophils, eosinophils, and monocytes
- vascular permeability
- chemotaxis
28
_________ contribute to vasodilation, capillary permeability, pain and fever during inflammation.
- prostaglandins
- can lower blood pressure
29
Stable prostaglandins (PGE1 + PGE2) support the effects of _________ and other inflammatory mediators
Prostaglandin _____________ promotes platelet aggregation and vasoconstriction
- histamine
- thromboxane A2
30
Leukotrienes are eicosanoid inflammatory mediators produced in leukocytes by oxidation of arachidonic acid.
LTC4, LTD4, and LTE4 are slow-acting substances of anaphylaxis (SRS-A) that induce ___________
LTB4 is a ______________
- smooth muscle contraction
- chemoattractant of neutrophils
31
______________ are found in platelets, basophils, and mast cells, and cause dilation + increased permeability of capillaries
- vasoactive amines (histamine, serotonin)
- act through HI (histamine) and 5-HT (serotonin) receptors
32
Platelet-activating factor (PAF) is generated from a lipid complex stored in cell membranes. It induces _________, activates neutrophils, is a _____________ chemoattractant, and contributes t efflux of plasma proteins leading to _________.
- platelet aggregation
- eosinophil
- edema
33
Plasma proteases, like __________, increase capillary permeability and pain, as well as produce fibrin peptides
- kinins
34
What are the 2 stages of inflammation?
- vascular + cellular
35
T/: the phases of the vascular stage are 1. vasoconstriction, 2. passive vasodilation, and 3. active vasodilation
- false; vasoconstriction, active, passive
- vasoconstriction: 30s after injury, lasts only a couple minutes
- active vasodilation: increase in blood flow, active hypermedia, increased cellular metabolism
- passive vasodilation: vessels stop reacting to stimuli,increase in permeability causes swelling, pain, impaired function
36
The cellular stage of inflammation is marked by movement of _________ into the area of injury, the sequence of events includes chemotaxis, ________, migration, and phagocytosis.
- leukocytes (mainly granulocytes + monocytes)
- rolling (leukocytes slow down/express adhesion molecules)
37
T/F: the first cells to arrive at the site of infection are cells of adaptive immunity
- false; innate immunity (granulocytes, neutrophils, NK)
38
In order for cells of the immune system to participate in inflammatory response they must use ___________ to migrate
- cell adhesion molecules (CAM)
39
T/F: both the endothelium and leukocytes express CAM, allowing extravasation of leukocytes rom blood vessels into tissues or lymph nodes via adhesion to the endothelium
- true.
- most CAM are constitutively expressed, some are expressed depending on local conditions.
- some allow leukocyte-leukocyte interaction
40
What are the 4 families of proteins that make up CAMs?
- selectins, mucins, integrins, Ig-superfamily CAM
41
Selectins are membrane glycoproteins containing extracellular lectin domains that bind _________ on mucin-like molecules.
The most important selectins are selectin ____, _____, ____
- carbohydrate moieties
- selectin E, L, and P (CD62E, CD62L, CD62P)
42
T/F: selectin P is expressed on leukocytes, selectin L and E are expressed on the endothelium during inflammation
- false; L: leukocytes, P+E: endothelium
- P: contained in granules in endothelial cells, released when granules fuse with cell membrane
- E: synthesized de novo following stimulation
43
T/F: mucins are responsible for leukocyte interaction with the endothelium during the initial vascular phase of inflammation
- false; selectins
44
A group of heavily glycosylated, serine- and threonine-rich proteins that bind to selectins:
- mucins
- ex: CD34 or GlyCAM-1 on endothelial cells binds to CD62Lon leukocytes
- ex: PSGL-1 on neutrophils binds to selectin E + P on endothelial cells
45
_________ are heterodimeric proteins consisting of a and B chains that are covalently joined at the cell surface, forming a binding site to which the Ig superfamily domains bind
- integrins
- divided into subgroups according to type of B chain expressed (B1 - B7)
46
Leukocyte express integrins with ______ chain.
Deficiency in this integrin leads to immunodeficiency called leukocyte adhesion deficiency (LAD), an autosomal recessive disorder manifested by _______________ because neutrophils are unable to extravasate
- B2 (CD18)
- recurrent bacteria infections
47
Ig-superfamily CAMs contain ________________ domains and __________ domains. Important representatives are:
- immunoglobulin-like domains
- fibronectin domains
- ICAM-1 (CD154), ICAM-2 (CD102), ICAM-3 (CD50) and VCAM (CD106)
48
T/F; usually selectins bind to integrins and me in-like cams band to Ig-superfamily cams
- false: selectins to mucin-like cams, Ig-superfamily CAMs to integrins
49
Other CAMs have structures with features of both mucins and Ig-superfamily, allowing binding to both ___________________.
A example of this is __________, responsible for migration of leukocytes to mucosa
- Ig-like and mucin domains
- MAdCAM-1 (binds a4B7 (L-PAM) through Ig-like domain and CD62L through mucin domain)
50
During initiation of inflammation, cytokines and other mediators of inflammation stimulate endothelial cells leading to increased CAM expression. This is called _________________.
- endothelial cell activation
51
What are the 4 phases of extravasation of leukocytes?
- rolling: leukocytes loosely bind to selectin E +P on endothelial cells, slowing down and rolling on endothelium
- activation: increase in cytokine, specifically chemokine secretion, increases chemokine receptor expression on leukocytes leading to activation
- adhesion (strict):citi action produces conformational changes allowing integrins on leukocytes to bind firmly to endothelium
- transendothelial migration: leukocytes squeeze between neighboring endothelial cells and pass into inflamed tissue, using homotypic bonding of platelet-endothelial-cell adhesion molecule 1 (PECAM-11 (CD131)) on the endothelium (self-to-self binding)
52
T/F: Neutrophils are among the first cells to arrive at the site of inflammation and cannot bind to endothelial cells under normal circumstances
- true; without inflammation there is no expression of selectin E, P,and other CAMs n endothelium
53
___________ and mucin PSGL-1 are responsible for rolling of neutrophils
- selectin L
54
IL-8 and IP-1B are responsible for ___________ of neutrophils, which also leads to increased expression of ICAM on the endothelium and __________ on neutrophils, leading to firm adhesion and finally ___________
- activation
- CD11a/CD18, C11b/CD18 (LFA-1 and MAC-1)
-diapedesis
-chemokine gradient then leads neutrophils to focal point of inflammation
55
Monocytes arrive slightly late a site of inflammation because high expression of _______________ is only possible after activation stage
- VCAM-1 and ICAM-1
- only a small subset of monocytes can extravasate under normal circumstances to replenish tissue macrophages and DCs, homeostatic migration regulated by CXCL14
56
In monocyte migration: ______ is responsible for rolling, ______ for activation, _______ for diapedesis, and complement receptors such as CR3/CR4, bacterial peptides participate in extravasation into inflamed tissue
- CD62L
- MCP-1
- PECAM-1
57
T/F: lymphocytes are continually circulating between blood and lymphatic tissues
- true, similar extravasation mechanism to neutrophils, pass through post capillary venules (high endothelial venules - HEV)
58
Activation of lymphocytes in HEVs prior to extravasation is mediated by chemokines __________
- CCL19, CCL21, and CXCL12
59
Under optimal conditions, inflammatory response remains localized, but some cases can result in systemic manifestations such as:
- acute phase response
- alterations in WBC count (leukocytosis or leukopenia)
- high fever
- sepsis and septic shock (systemic inflammatory response)
60
Acute phase response refers to ____________ , most of which are synthesized in liver after induction by pro-inflammatory cytokines
- changes in serum proteins
- acute phase response proteins (APP) - concentrations that change
- ex: complement system proteins, C-reactive proteins (CRP) - part of innate response
61
T/F: C-reactive proteins belong to pentraxins (pentameric proteins), and are a APP that promote uptake by phagocytes and activate complement mediated attack when bound to microbes
- true;
- ligands are pneumococcal polysaccharides and phosphorylcholine
62
T/F: mannose-binding lectin is a APRP that recognizes mannose on vertebrate cells and not microbes
- false; microbes and not vertebrate cells
63
What are secondary systemic effects of inflammation?
- loss of appetite
- altered sleep patterns
- lethargy
- muscular wasting (cachexia)
- metabolic acidosis (lowered blood pH)
64
T/F: when no longer needed, inflammatory response passively ends
- false; must be actively terminated to prevent damages
65
What are inflammation termination mechanisms?
- short half-life of inflammatory mediators in vivo
- production/release of transforming growth factor (TGF) beta from macrophages
- IL-4 + IL-10 induce down-regulation of TNFa,IL-1,IL-6, and IL-8
- downregulation of pro-inflammatory molecules like leukotrienes
- up-regulation of anti-inflammatory molecules (ex: interleukin 1 receptor agonist or soluble tumor necrosis factor receptor)
- apoptosis of pro-inflammatory cells
- down-regulation of receptor activity by high concentration of ligands
66
At end stages of inflammation, granulocytes promote _______________, which initiate the termination sequence. This cease neutrophil recruitment an apoptosis is engaged.
_______ and ________ synthesized from omega-3 polyunsaturated fatty aids shorten neutrophil infiltration by initiating apoptosis
Anti inflammatory process ends with___________
- arachidonic acid-derived lipotoxins
- resolvins + protectins
- departure of macrophages through lymphatics
67
What are outcomes of inflammation?
- resolution: complete restoration
- fibrosis: formation of scar tissue, functional impairment
- abscess formation
- chronic inflammation: dominating presence of macrophages, tissue destruction
