Innate Immunity: Cellular Mechanisms Flashcards
(130 cards)
1
Q
What are the granulocytes and where are they
A
Neutrophils, eosinophils and basophils
In blood and can migrate into tissue
2
Q
__ cells are resident in tissues, particularly at epithelial surfaces and is characterized by the presence of abundant intracellular granules
A
Mast
3
Q
NK cell
A
Circulating
Viral infections and tumor cells
4
Q
Neutrophils
A
Killing and removal of bacteria and fungi
5
Q
Eosinophils
A
Control infection with multicellular parasites
6
Q
Basophils and mast cells
A
Allergy (common debilitating immune disorder)
7
Q
Sequence of events for granulocyte
A
Resting. Signalling. Activation. Migration from blood and effector function
8
Q
Appearance of neutrophils
A
Polymorphic(multilobed) nucleus and neutral staining granules
Abundant in circulation
6 hour half life in blood and 1-2 days in tissue
Replaced from bone marrow
9
Q
In good health, _ neutrophils will be seen in tissue
A
Few
10
Q
What are the two main types of granules in neutrophils
A
Primary or azurophilic granules
Secondary of specific granules
11
Q
Primary/azurophilic granules
A
First appear during their development in bone marrow
12
Q
Secondary or specific granules
A
Appears later
3 times more common in the cytoplasm
13
Q
What stimuli mobilize the granules in neutrophils
A
Products of bacterial cell walls, complement proteins, the leukotreine group of lipid mediators and small bioactive peptides called cytokines
14
Q
N-formulated peptides (FMLP)
A
Bacterial derived and bind to receptors not he neutrophil surface
15
Q
The complement product, ___ binds to specific surface receptors on neutrophils
A
Ic3b
16
Q
Leukotreines
A
Products of the lipooxygenase pathway or arachidonate metabolism and some, such as LTB4 have potent stimulators effects on neutrophils
17
Q
Chemokine CXCL8 (IL-8) and TNF-a (a granulocyte-monocyte csf..gym-csf)
A
Potent effects on neutrophils
18
Q
What is in primary/azurophilic granules of neutrophils
A
Microbicidal things
Myeloperoxidasecathepsin G Proteinase-3 Elastase Lysozyme Defensins Bactericidal.permeability increasing protein (BPI)
19
Q
What is in secondary/specific granules
A
Microbicidal things
Cytochrome b558 and other respiratory burst components
Lysozyme
Lactoferin
And migration things
Collagenase
CD1 I b/CD18(CR3)
N formyl methionyl leucylphenylalanine receptor (FMLP-R)
20
Q
Following activation of what are lipids in the cell membrane concerted de novo into inflammatory mediators that have potent effects on vasculature and on inflammatory cells such as neutrophils
A
Mast cells, macrophages, granulocytes, and lymphocytes
21
Q
What are the 3 major classes of lipid mediators, converted from membrane phospholipids by phospholipase A2
A
Prostagladin D2
Leukotrines
Platelet activating factor
22
Q
Prostagladin D2 (PGD2)
A
From cyclooxygenase pathway of arachidonic acid metabolism
Binds receptors on smooth muscle in vascular endothelium leading to vasodilation
-increase blood supple and slows leukocytes passing through tissue allowing them to migrate fromt he blood
PGE2 and PGF2 made my macrophages also inflammatory
23
Q
Leukotreines
A
Formed when arachdonic acid is converted through the lipooxygenase pathway
Mast cell synthesis-LTB4, C4, D4, E4
Neutrophil synthesizes LTB4
Cause vasodilation and extravasation of fluid into the tissues
24
Q
PAF
A
Produced by mast cells and also has effect of relaxing vascular smooth muscle
25
NSAIDS
Asprin blocks cyclooxygenase so can control arthritis
26
Side effect nsaid
Increasing stomach inflammation —fatal hemorrhage
| Cox-2 selective for pain and inflammation and spares stomach problems
27
The lipid mediators are released as a result of ___ reactions and have profound effects on smooth muscle in lung, causing bronchial constriction ...manifests as ___
Inflammation
| Asthma (tightness in chest, wheezing,
28
Leukotreines and prostaglandins are made from ___ ____. PAF is made from _____
Arachidonic acid
Lysoglyceryl platelet activating factor
29
Prostagladin are made through what pathway. Leukotreines are made through what pathway. PAF is made through what pathway
P-cyclooxygenase
L-lipooxygenase
PAF_acetyl transferase
30
What is a cytokine
Polypeptide released by a cell in order to change the function of the same or another cell. Important chemical messengers
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Pleitropy
Cytokine with many different effects
32
Autocrine
Act on cell that releases it
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Paracrine
Act on cells immediately around
34
Endocrine
Cytokines act like hormones
35
Chemokine
Natural chemical mediators
Act as chemotactic molecules
Trafficking of cells
36
CXCr5 and CCR4
Coreceptors used by HIV to get into target cell
37
CXC
Two cysteine residues separated by any aa
38
CC
Two cysteine next to each other
39
CX3C
Two cysteines separated by any 3 aa residue
40
C
One cysteine
41
Chemokine receptors
G protein receptors with 7 transmembrane spanning domains
More chemokine than receptors-they are shared
42
CXCL12
Development of secondary lymphoid organs
43
MPO
Major microbicidal system
44
Cathepsin G and related serprocidins, proteinase-3 and elastase
Deadly to a range of gram positive and negative organisms and some candida
45
Cathespins B D E
Bactericidal
46
Defensins
Cysteine rich antibacterial and antifungal polypeptides
47
Three defensins make up 5% of all protein in a neutrophil and act by insertion into pathogen membranes to disrupt ion fluxes. Name them.
HNP1-3
48
BPI
Toxic ot gram negative bacteria
49
What’s in secondary granules
Preformed receptors and an assortment of proteins
50
Cytochrome b558 and its associated proteins
Major bactericidal mechanism
51
Presynthesized receptors for some molecules capable of activating them (FMLP, complement)
Ok
52
Collagenase and elastase
Break down fibrous structures int he extracellular matrix , facilitating progress of the neutrophil through the tissues
53
What activates neutrophils and when are they released
C5a, LTB4, FMLP, CXCL8 (IL8)
At site of inflammation
54
How does a neutrophil get to tissue
Signal, bind, adhere, cross into tissue
55
What are the 3 basic steps of neutrophil crossing into tissue
Rolling, adhesion and transmigration (specialized adhesion molecules)
56
The interface between tissue and blood is formed by ___ cells
Endothelial
57
Tissue signals are given out by endothelial cells lining the post capillary venues. Why
Flow is at its slowest here
58
Tissue damage, results in release of mediators from _____
Mast cells, such as histamine
59
What does histamine do
Dilation of vessels to increase leafiness and reduce rate of blood flow facilitate neutrophil access to site
60
Rolling /marination
Neutrophils adhere very lightly to endothelium and let go...slowing down.
61
What molecules are responsible for rolling
Selectins, on endothelium
62
What effect does CXL8, FMLP, TNFa have on endothelium
Express stronger adhesion molecules...
| ICAMS on endothelium
63
What effect does CXCL1-3,5,6,8 and C5a and FMLP have on neutrophils
Express LFA1
64
What are the three main families of surface proteins for adhesion
Selectin, integrity, ICAM (intracellular adhesion molecules)
65
Selectins
P-selectin platelet
E-selectin-endothelium
L-selectin leukocyte
66
Where is P selectin also found
On activated endothelium
67
What do P and E selectin bind to
Sialylated carbohydrate residue which is constituitively expressed on circulating immune cells -
for rolling
68
What do L selectins bind to
Glycoproteins cell adhesion molecule (GlyCAM-1) found on the high endothelial venues of lymph nodes
For homing to lymph nodes
Or a glycoproteins cell adhesion molecule on mucosal endothelium, called MAdCAM-1
69
GlyCAM-1 and MAdCAM-1 guide leukocytes to particular tissues and have been termed ___
Addressins
70
P selectin
CD62
On endothelium and platelet
Bind sialyl lewis(CD15) on neutrophils
71
E selectin
CD62E
On endothelium
Bind sialyl Lewis (CD15s) on neutrophils
72
L selectin
CD62L
On neutrophils
Binds GlyCAM-1 on peripheral lymph node endothelium and MAdCAM-1 on mucosal endothelium
73
Integrins
Heterodimer ( a and b chain) on leukocytes
| Interact with ICAM
74
B2 integrins
Adhesion in all leukocytes including lymphocytes
75
B1 integrins
T and B cell function
76
Leukocyte function associated antigen-1 (LFA-1)
CD11a/CD18
On neutrophils, lymphocytes and monocytes
Binds ICAM-1 and ICAM-2 on endothelium
77
Macrophage-1 (Mac-1) and complement receptor-3 (CR3)
CD11b/CD18
On neutrophils, monocytes, and some lymphocytes
Bind ICAM1 on endothelium and iC3b following complement activation
78
P 150/95, and complement receptor 4 (CR-4)
```
CD11c/CD18
Tissue macrophages (to a lesser extend neutrophils and monocytes)
```
Bind to iC3b and C4b
79
ICAM1 is also the receptor for ___
Rhinovirus
80
ICAMS are expressed one esting endothelium but are up regulated by inflammatory mediators such as __
TNFa
81
Note. What else are cd11/CD18 used for
Adhesion that are used during other forms of cell to cell contract such as when antigen presenting cells interact with T cells
82
Chemotaxis
Direct movement of a cell along a gradient of increasing concentration of the attracting molecule (termed chemoattractant) used by neutrophils
83
What are the most potent chemotactic agents for neutrophils
C5a, FMLP, CXCL8 and LTB4
84
Brownian movement
Neutrophils have a constant process of random movement akin to gaseous molecules
85
What happens a chemotactic factos binds at one pole of the cell, two processes take place. What are they
Granule release, to upregulate receptors for the chemotactic factors at that pole
Neutrophil extends its membrane and cytoplasm into thin, footlike processes known as pseudopodia
86
Pseudopodia
Rich in microtubles, actin, myosin and actin binding protein
After extending it anchors itself and the remainder of the cytoplasm is drawn up. A new pseudopodia achors itself and the process is repeated
Like a caterpillar
87
Can neutrophils only phagocytosis one thing at a time
No can ingest more than one bacterium or fungus at a time
88
What do you get when large numbers of phagocytes are involved in an infective process
Abscess filled with pus (dying neutrophils)
89
Phagocytosis is ineffective in the absence of __
Opsonins
90
Common opsonins used by neutrophils
C3b and CRP and antibody (specific immune system giving direction to innnate)
91
Reverse phagocytosis
Granule contents discharged into external milieu...granule proteins and chromatin combine ot form extracellular fibers that bind gram neg and pos bacteria NET
92
Neutrophils Extracellular traps (NET
Form of innate response that binds microorganisms, prevents them from spreading and ensures a high local concentration of antimicrobila agents to degrade virulence factors and kill bacteria
93
What are the two routes that neutrophils use to kill
Oxygen dependent and oxygen independent
94
Oxygen independent mechanism of neutrophil killing
Lysozyme and cathespins
95
Oxygen dependent mechanisms of neutrophil killing
Respiratory burst
| H202-myeloperoxidase-halide system
96
What is generated in respiratory burst
Superoxide anion 02-
Hydrogen peroxide h202
Singlet oxygen 102
Hydroxyl radical OH
97
Genetic abnormality in which neutrophil working is impaired
Recurrent bacterial, fungal infections
Failure to thrive
Organ damage and premature death
98
Some conditions have no secondary granules...
Lung and skin nfecitons with staph a and candida
99
Sometimes can’t do respiratory burst
Plus forming organisms and fungi cause prolonged infections of bone skin and lungs
100
Sometimes common B chain of integrins is not synthesized
LAD
Leukocyte adhesion defiency
Failure of leukocyte adhesion
| Repeated infection
101
Superoxide dismutase
HO2+O2-+H—-> O2+ H2O
102
Myeloperoxidase
H2O2-+2Cl-+H+——> H2O2+Cl2+OH-
103
Describe the hydrogen peroxide-myeloperoxidase-halide system
H2O2 is generated by the respiratory burst, MPO from the primary granules and a halide such as Cl combine to give chlorine and hydroxyl ions, both of which are toxic to microorganisms
104
Eosinophils comprise _% of granulocytes in circulation
3-5
105
NOTE: this statistic hides the amount of eosinophils in tissue. How many there
Several hundred times more in the tissues, they collect at epithelial surfaces and may survive for several weeks
106
How identify eosinophils
Staining is a result of granule contents, mainly cationic proteins with affinity for acid aniline dyes such as eosin
107
Main role of eosinophils
Multicellular parasites
| Releases toxic, cationic proteins
108
Eosinophils in allergic disease
Asthma
109
What are the two types of eosinophils granules
Specific (95%)
| Primary (5%)
110
Specific granules
Cationic proteins
Major Basic protein (MBP_
Eosinophil cationic protein (ECP, also bactercidal)
Eosinophil neurotoxin
Eosinophil peroxidase-similar to MPO generating toxic metabolites
111
Primary granule
LTC4, LTD4, LTC4 PAF
| Produces changes in airway smooth muscle and vasculature...allergic responses
112
What are there specific receptors for on eosinophils
C3b/C4b (CR-1), iC3b (CR3), C5a and LTB4
IL3, IL5-development and differentiation
GM-CSF-acts on other cells
113
What are highly selective in eosinophil recruitment
Eotaxin 1(CCL11) and eotaxin-2 (CCL24)
114
Il-_ is a sufficient growth factor and essential for eosinophils and may also be produced by them
IL-5
115
What are the most important factors in neutrophil recruitment and activation
I’ll-5 and eotaxins
116
What are the two main features of mast cells and basophils
Histamine containing granules
| Possession of a high affinity receptor for IgE
117
Half life of histamine
5 minutes
118
What is the triple response of histamine
Erythema of skin , arterioles dilate, post capillary venues contract
Increased vascular permeability
Histmine acts directly on local axons to induce more widespread vascular changes distant to the injection site
119
What does histamine do
Vasodilation
Increase vascular permeability
Smooth muscle contraction in airways
120
What do the protease enzymes do
Mainly tryptic enzymes (cf. pancreatic trypsin)
Digestion of basement membrane causes increased vascular permeability
Digestion of CT to increase cell migration
Cleavage of C3->C3a
121
What do proteoglycans do
Mainly heparin in mast cells
Mainly chondroitin sulphate in basophils
Responsible for distinctive blue stain
Anticoagulant activity
122
What do chemotactic factors do
Eosinophil chemotactic factor for anaphylaxis
| Neutrophil chemotactic factos
123
PAF-synthesized de novo
Vasodilator
124
LTB-D4-synthesized de novo
```
Eosinophil activators
Neutrophil chemoattractants
Platelet activators
Vascular permeability increased
Bronchoconstrictors
```
125
Prostagladins (PGD2)-synthesized de novo
Increase vascular perm
Bronchoconstrictors
Vasodilator
126
What are the two receptors for histamine
H1 and H2
127
H1 receptors
Mediate the vascular and bronchial smooth muscle effects and is blocked by drugs such as mepyramine and terfenadine, which form the basis of many proprietary antihistamines used for allergic reactions such as hay fever
128
H2 receptors
Mediate gastric acid secretion and is blocked by the now famous drugs cimetidine and ranitidine, which treat gastric and duodenal ulceration
129
Consequence of mast cell and basophils degranulation
Histamine-smooth muscle contraction-airway obstruction tear formation, nasal discharge(coryza), conjunctival redness, gritty eyes and itching
Anaphylaxis-syndrome of circulatory shock and collapse with low blood pressure and chest tightness leading to arrrested breathing and death unless treated
130
How are mast cells and basophils activated
IgE-both
C3a, C4a and C5a -activate basophils and lung mast cells
FMLP-basophils
