Chapter 2 Flashcards
(149 cards)
1
Q
What is the difference between innate and adaptive immunity in terms of time?
A
innate immunity happens immediately, whereas adaptive immunity happens late
2
Q
Pathogens are usually in 2 compartments. What are they?
A
1) Extracellular-can be taken care of by innate immune system/phagocytes
2) Intracellular-Innate cannot access the pathogens here. Need NK cells and the cytotoxic arm
3
Q
What are the 2 mechanisms of tissue damage by pathogens?
A
direct and indirect
4
Q
Viruses _________ the cells that they infect
A
damage
5
Q
T/F:
Most pathogens can overcome innate immune response and need adaptive response to prevent subsequent infection
A
true
6
Q
_________ surfaces of the body provide the first barrier against infection.
A
Epithelial
7
Q
Epithelial surfaces of the body provide the first barrier against infection. What is internal epithelia?
A
mucosal epithelia, secrete mucus made up of glycoprotein mucins * Cystic Fibrosis *
8
Q
The epidermis of the skin has multiple layers of ________________ in different layers of differentiation
A
keratinocytes
9
Q
___________ __________ have defensins and these are secreted into the waterproof lipid layer of the skin
A
Lamellar bodies
10
Q
The lungs have bronchial __________ epithelium. What does this have to do with immunity?
A
ciliated
Airways lined by cilia. Beating moves stream of mucus secreted by goblet cells
11
Q
The gut epithelium contains ______ cells that are deep in the epithelial crypts and produce antimicrobial defensins + the lectin RegIII
A
Paneth
12
Q
Reg III proteins belong to the family of ____-type lectin regenerating islet-derived proteins.
A
C
13
Q
The RegIII (regenerating gene family protein III) lectins belong to the antimicrobial proteins, and are expressed in epithelial cells of the…
A
stomach, small intestine and colon
14
Q
The RegIII (regenerating gene family protein III) lectins belong to the antimicrobial proteins, and are expressed in epithelial cells of stomach, small intestine and colon. Subsequently, they are secreted into the….
A
gut lumen
15
Q
RegIIIβ binds peptidoglycan and lipid A respectively, and thus can kill certain _________________ and ______________ bacteria, including the gut commensal microbiota and enteropathogenic bacteria.
A
Gram-positive and Gram-negative
16
Q
What does lysozyme do and where is it found?
A
contains a glycosidase enzyme that breaks down bonds in peptidoglycan
found in tears, saliva, and Paneth cells
17
Q
What are the 4 types of antimicrobial peptides?
A
1) defensins
2) cathelicidins
3) histatins
4) lectin
18
Q
Defensins are ________ conserved in eukaryotic organisms
A
highly
19
Q
What are defensins?
A
antimicrobial peptide
short cationic peptides w/ 3 disulfide bonds and a pos. charges region separated by hydrophobic areas
20
Q
Do cathelicidins contain disulfide bonds?
A
no
21
Q
Who carries cathelicidin genes?
A
mice and humans
22
Q
Who makes cathelicidins? For what purpose?
A
by neutrophils and macrophages
made in response to infection in keratinocytes and epithelial cells in lungs/intestine
23
Q
Histatins are constitutively produced in ________ ________ by parorid, sublingual, and submandibular glands.
A
oral cavity
24
Q
Histatins are _______ against pathogenic fungi and wound healing in oral cavity
A
active
25
What is lectin? What is an ex?
antimicrobial peptide
Bactericidal carbohydrate binding protein made by epithelial cells
Ex: Reg3 is made by Paneth cells and works better on G plus cells by making hole in membrane
26
Defensins, cathelicidins, and histatins are activated by _______________ to release an amphipathic antimicrobial peptide
proteolysis
27
Electrostatic attraction and the transmembrane electric field brings the defensins into the lipid bilayer. What does defensin do?
defensin peptides form a pore
28
What are the 2 types of bacteria?
1) gram-positive bacteria
2) gram-negative bacteria
29
What is the difference between gram pos and gram neg bacteria?
gram pos has a much thicker peptidoglycan wall
gram neg contains LPS and an additional outer membrane, peptidoglycan is thinner than gram pos
30
______________ or ______________ have to get through the peptidoglycan wall to expose the lipid bilayer
Lysosomes or defensins
31
The complement system is made up of 30+ proteins produced by the _________
liver
32
complement proteins circulate around the body in their _______ form
inactive
33
In the presence of pathogens or Ab bound to pathogen, the ____________ system will be activated
complement
34
What are the final outcomes of the complement system?
kill pathogen, phagocytose it, inflammation to fight off
infection
35
What are the stages of complement action?
36
What complement proteins are there (C___-C____)?
C1-C9
37
Simplest terms, what does C1q do?
bind Ab
38
Simplest terms, what does C4b and C3b do?
bind surface
39
What are the inflammatory mediator complement proteins?
C5a, C3a, C4a
40
What are the MAC complement proteins?
C5b, C6-C9
41
What do the regulator complement proteins do?
they regulate immune system and don't activate the complement system/inflammatory response unless they absolutely have to
42
The complement system recognizes features of microbial surfaces and marks them for destruction by coating them with _____
C3b
43
Complement activation is largely confined to the
surface on which it is ________
initiated
44
What are the 3 pathways in innate immunity?
1) classical
2) alternative
3) mannose binding lectin (MBL) pathway
45
The lectin pathway, or mannose-binding lectin (MBL) and ficolins recognize and bind ________ on pathogen surface
carbohydrates
46
Classical pathway has _____ that interacts with pathogen surface or with antibodies bound to the surface
C1q
47
Alternative pathway has ____ that undergoes spontaneous hydrolysis to C3(H2) to initiate eventual deposition of C3 convertase on microbial surfaces
C3
48
All 3 pathways generate a _____ convertase, which cleaves C3, leaving C3b bound to the microbial surfaces and releasing C3a
C3
this is a crucial step!! no turning back now
49
What is the goal of all 3 pathways?
make C3 convertase and have it split to C3a and C3b
50
After all 3 pathways generate a C3 convertase, C3a and C__a recruit phagocytic cells to the site of infection and promote inflammation
C5a
51
After all 3 pathways generate a C3 convertase, phagocytes with receptors for ____ engulf and destroy the pathogen
C3b
52
After all 3 pathways generate a C3 convertase, completion of the complement cascade leads to the formation of a ________________, which disrupts cell membrane and causes cell lysis
membrane attack complex (MAC)
53
C3b forms a covalent bond with the microbial surface. Covalent bond is possible due to a....
thioester domain (TED) hidden inside folded C3 protein
54
When C3 is cleaved (opening up the bond), the thioester domain can react with nearby ________ or ________ group on microbial surface
hydroxyl or amino
55
The newly synthesized C3 protein is cleaved to generate a _______ chain and an ________ chain held together by disulfide bonds
beta, alpha
56
Before cleavage of C3 convertase, the ____________ bond within TED is protected from reacting.
thioester
57
Cleavage of C3 releases ____ and a change in conformation of ______ allows the thioester bond to react with a chemical group on the pathogen surface
C3a, C3b
58
The reactive thioester group of C3b is in TED. What happens now?
C3b is bound to pathogen surface (tags the pathogen)
or
C3b can be inactivated by hydrolysis
59
The classical pathway is initiated by activation of the ______________
C1 complex
60
C1 is a pathogen sensor and interacts directly with
pathogen and with __________ that are bound to
pathogens.
antibodies
61
Can C1 work in both innate and adaptive immune system?
YES
62
What is the function of C1q in the classical pathway?
binds directly to pathogen surfaces or indirectly to antibody bound to pathogens, thus allowing autoactivation of C1r
63
What is the function of C1r in the classical pathway?
cleaves C1s to active protease
64
What is the function of C1s in the classical pathway?
cleaves C4 and C2
65
What is the function of C4b in the classical pathway?
covalently binds to pathogen and opsonizes it. Binds C2 for cleavage by C1s
66
What is the function of C2a in the classical pathway?
active enzyme of classical pathway C3/C5 convertase and also cleaves C3 and C5
67
What are the functions of C3b in the classical pathway?
-binds to pathogen surface and acts as opsonin
-initiates amplification via the alternative pathway
-peptide mediator of inflammation (immediate activity)
68
What is the first step of the complement system classical (antibody dependent) pathway?
soluble antibody binds to a soluble antigen or to an antigen associated w/ a bacterial cell (IgG or IgM primarily)
69
What is the 2nd step of the complement system classical (antibody dependent) pathway?
binding induces changes in the antibody Fc portion
-exposes a binding site for the C1 protein
>C1 is a complex of 1q, 2r, and 2s subunits (C1= C1qr2s2)
>q forms a stalk w/ branches, r/s binds to branches
-binding of C1 to antibody requires multiple Fc to be in close proximity (IgM)
70
What is the 3rd step of the complement system classical (antibody dependent) pathway?
binding to the antibody activates C1r to cleave C1s (now have active C1s)
(Ab on pathogen, C1 binds to it)
71
What is the 4th step of the complement system classical (antibody dependent) pathway?
C4 binds to C1s and is converted into an active C4b fragment and smaller C4a fragment
-C4b attaches to target surface near the Ab
72
What is the 5th step of the complement system classical (antibody dependent) pathway?
at the same time as step 4, C2 is cleaved by C1s into a larger C2a and smaller C2b
73
In the complement system classical (antibody dependent) pathway, C1 binds and will be converted to an active fragment and then cleave C4. What does this generate/what happens?
-generates C4a and C4b
-C4b will land on surface of agent
-C4 cleavage will also bring out cleavage of C2
74
What is the 6th step of the complement system classical (antibody dependent) pathway?
the C4b and C2a form a complex (C4b2a is also called C3 CONVERTASE)
75
What is the 7th step of the complement system classical (antibody dependent) pathway?
C3 convertase converts a large number of C3 into C3a (small) and C3b (large enzyme)
76
What is the 8th step of the complement system classical (antibody dependent) pathway?
some of the C3b produced combines w/ C4b2a ro form C4b2a3b (called C5 convertase)
-some of the C3b does other things
77
What is the 9th step of the complement system classical (antibody dependent) pathway?
C5 convertase binds to C5 and cuts it into C5b (large) and C5a (small)
-C5b produced will initiate later steps!
78
The lectin pathway uses soluble receptors that recognize microbial surfaces (_____________________________) to activate the complement cascade.
LPS, glycans on yeast surface
79
What sugar is more abundant in foreign agents like bacteria and yeast, as opposed to humans? What do humans have that is more abundant?
mannose sugar
humans are abundant w/ sialic acid
80
Mannose binding lectins (MBL) is made in the ________
liver
81
MBL assembles into _________ that float in blood. What happens in this form?
trimers
When in trimer form have high affinity for glycans on bacteria. Low affinity for sialic acid ends
82
Ficolins are found in various tissues and are a group of proteins containing both a __________-like and a __________-like domain.
collagen, fibrinogen
83
Where are ficolins secreted?
in the liver
84
What does ficolins have a high and low affinity for?
High affinity for oligosaccharides with acetylated
sugars on bacteria.
Low affinity for mannose containing sugars
85
MBL monomers form trimeric clusters of ______________ domains. MBL binds w/ high affinity to mannose and fucose residues
carbohydrate-recognition
86
Ficolins are similar in structure to MBL but have a different carbohydrate-binding domain. What do they bind to?
oligosaccharides containing acetylated sugars
87
MBL forms complex with MBL associated _________ _____________ (MASP) which are inactive
serine proteases
88
When MBL binds to pathogen surface, conformational change in MASP 1 allows it to activate _______
MASP 2.
89
MASP 2 cleaves C2 and C4. C4 also has buried ________ bond. C4a is released and C4b has a conformational change. The ________ bond is accessible to bind to the microbial surface. It bind with C2 on surface. Now this cleaves C3 into C3a and b. C3a is released and inflammatory response begins. C3b on the surface can be opsonized
thioester, thioester
90
Activated MASP-2 associated w/ MBL or ficolin cleaves C4 to C4a and C4b, which binds to the microbial surface. What happens next?
-C4b then binds to C2, which can then be cleaved by MASP2 to C2a, with which it forms the C4b2a complex and C2b
-C4b2a is an active C3 convertase cleaving C3 to C3a and C3b, which binds to the microbial surface or to the convertase itself
-one molecule of C4b2a can cleave up to 1000 molecules of C3 to C3b. Many C3b molecules bind to the microbial surface
91
What is the first step of the complement system alternative (antibody independent, no antibody required) pathway?
activation=
-occurs when C3b (produced as a result of slow constant hydrolysis) binds to a foreign surface Ag
92
What is the 2nd step of the complement system alternative (antibody independent, no antibody required) pathway?
C3b bound to the surface binds to another serum protein Factor B (floating around in blood)
-binding alters structure B and makes it accessible to be cut by the protein Factor D
93
What is the 3rd step of the complement system alternative (antibody independent, no antibody required) pathway?
the resulting complex C3bBb acts as a C3 convertase and produces a lot more C3b
-some of that binds to C3bBb and forms C3bBbC3b
94
What is the 4th step of the complement system alternative (antibody independent, no antibody required) pathway?
C3bBbC3b acts as a C5 convertase --> C5b is produced
95
The alternative pathway is an amplification loop for C3b
formation that is accelerated by ___________ in the presence of pathogens.
properdin
96
C3b is deposited by the classical pathway or lectin pathway C3 convertase. What happens next for alternative pathway?
-C3b binds to Factor B
-Bound factor B is cleaved by plasma protease Factor D into Ba and Bb
-C3bBb complex is a C3 convertase, cleaving many C3 molecules to C3a and C3b
97
Factor B contains a serine protease (SP) domain, and when activated it provides the catalytic activity of the _______________ pathway C3 and C5 convertases. Factor B circulates as an inactive proenzyme (i.e., a zymogen), and only becomes activated after cleavage by the protein factor D. However, factor D can only cleave factor B when it is bound to the active forms of C3:
C3(H2O) and C3b. Factor B is generated as a single-chain protein, and cleavage by factor D generates two peptide fragments (Ba and Bb).
alternative
98
Factor D is a serine protease (SP) consisting of a single polypeptide of 228 amino acids. Unlike other SPs in the complement system, factor D circulates in the plasma as a mature but ‘resting-state’ form at a very low concentration and is produced mainly
in _________________
adipocytes.
99
In the alternative pathway, C3 undergoes spontaneous hydrolysis to C3(h2O), which binds to factor B, allowing it to be cleaved by factor D into Ba and Bb. What happens next?
-the C3(h2O)Bb complex is a C3 convertase, cleaving more C3 into C3a and C3b. C3b is rapidly inactivated unless it binds to a cell surface
-Factor B binds noncovalently to C3b on a cell surface and is cleaved to Bb by factor D
100
What is the function of C3b in the alternative pathway?
-binds to pathogen surface
-binds factor B for cleavage by factor D
-C3bBb is a C3 convertase and C3b2Bb is a C5 convertase
101
What is the function of Bb in the alternative pathway?
Bb is the active enzyme of the C3 convertase C3bBb and the C5 convertase C3b2Bb
102
What is the function of Factor D in the alternative pathway?
plasma serine protease, cleaves Factor B when it is bound to C3b to Ba and Bb
103
What is the function of properdin (P) in the alternative pathway?
plasma protein that binds to bacterial surfaces and stabilizes the C3bBb convertase
104
C3 convertase is unstable, why?
bc you want it to cleave quickly
105
Is C3 convertase short lived or long lived?
short lived
106
What is C3 convertase stabilized with?
stabilized by binding the plasma protein Properdin
(Factor P)
107
______________ is made by neutrophils and
stored in granules
Factor P
108
Factor P may do _____________ ____________
on pathogens and is released
pattern recognition
109
Properdin (Factor P) binds to bacterial surface and helps bring about _____________ activity
complement
110
Pathogens lack _________________ proteins. Binding of properdin (factor P) stabilizes the C3bBb complex. What happens next?
complement-regulatory
-C3bBb complex is a C3 convertase and deposits many molecules of C3b on the pathogen surface
-opsonization, activation of terminal components
111
Surface-bound C3 convertase deposits large
numbers of C3b fragments on pathogen surfaces and
generates _____ __________ activity. Some of the C3b produced combines with C4b2a to form C4b2a3b (called C5 convertase) in the alternative pathway
C5 convertase
112
C5 convertase binds to C5 and cuts it into C5b (_______)
and C5a (_______)
large, small
113
C3b binds to both C4b2a and C3bBb, forming the active C5 convertases C4b2a3b and C3b2Bb. What happens next?
-C5 binds to the C3b component of the C5 convertase enzyme
-C5 is cleaved by C2a or Bb to form C5b and C5a
114
End result of activating all three complement pathways is the formation of _______
C5b
115
End result of activating all three pathways is the formation of C5b. So what happens now?
-After being produced, C5b (acts like a recruiter) binds to the surface of the target
>It will serve as a docking site for the rest of the components of the MAC
-C5b on the surface is unstable
>Must be stabilized by the binding of C6
-When C7 binds to C5bC6, the trimeric complex undergoes a conformational change which exposes a hydrophobic region of the protein
>Allows it to insert itself into the phospholipid bilayer
-C8 binds to C5bC6C7 and together form a small pore in the membrane
-The C5bC6C7C8 complex serves as docking site for binding of a perforin-like protein called C9 (polymerizes and increases size of the pore--> cell dies)
116
Membrane and plasma proteins that regulate the formation and stability of C3 convertases
determine the extent of...
complement activation.
117
Many reg. proteins present in plasma to protect host cells. These proteins interact with C3b and prevent the convertase from forming or cause its rapid _____________
disassociation
118
Inactivation can happen from cleaving C3b. Plasma protein ___________ can do this by binding to C3b. Factor H also binds C3b (preferentially on sialic acid which is in vertebrates) and inactivates it.
Factor I
119
What 2 plasma proteins ensure that C3 does not get activated?
Factor I and Factor H
120
T/F:
Complement can attack both the pathogen and the infected host under the right conditions
true!
this must be strictly regulated to minimize abnormal activation
121
What are the 2 main mechanisms of complement regulation?
1) Overall instability of complement intermediates
2) Inhibitory proteins
122
One of the mechanism of complement regulation is overall instability of complement intermediates. What does this mean?
-Most components degrade quickly if not stabilized by other components
-If one gets activated abnormally, it typically gets degraded within a few min
-Example: C3b produced must bind to C3 convertase immediately or be degraded
123
One of the mechanisms of complement regulation is inhibitory proteins. List the inhibitory proteins
(Wide variety – can affect different steps in different pathways)
A) Inhibitor of C1 (only classical affected)
B) Inhibitors of C3 convertase
C) Inhibitors of the MAC
124
Who is the inhibitor of C1? What pathway is affected and what does it do?
Called C1 inhibitor (C1inh)
only affects classical pathway
binds to C1 and causes C1r2s2 to come off of C1q
125
Why are the inhibitors of C3 convertase important?
C3 convertase is the major point of amplification in all 3 pathways
Tons of C3b is made by this enzyme --> can create great damage
126
Talk about the inhibitors that block the classical/lectin C3 convertase
-Some bind to C4b and prevents its association with C2a and others (DAF) actively dissociate it when it forms
-Another (Factor I) binds to C4b and destroys it
127
Talk about the inhibitors that block the alternative C3 convertase
-Bind to C3b and prevent association with Factor B
-Some also cut C3b, destroying it (Factor I)
128
Talk about the inhibitors of the MAC
-Some block C5b67 from inserting into the membrane (S protein)
>Prevents it from coming out from 1 cell and inserting into an innocent bystander cell
-Others block C9 from associating with C5b678 (blocks self cell destruction)
129
Pathogens produce several types of proteins that can __________ complement activation
inhibit
130
Complement activation can lead to cell lysis, inflammation, opsonization, and _____________ of immune complexes
clearance
131
What happens with the lysis of cells by the MAC?
The MAC is capable of destroying Gram-negative bacteria, enveloped viruses, parasites, RBCs, and nucleated cells (can be activated by antibody or microbial products)
132
What are some examples of resistance mechanisms?
1) Gram neg bacteria--> some produce extra polysacc in their LPS, this prevents MAC from inserting into the inner membrane
2) Gram pos bacteria --> almost always totally resistant bc of their thick peptidoglycan layer prevents MAC from insertion into the membrane
3) many pathogens produce inhibitors to complement proteins
4) cancer cells can engulf the MAC before it can kill
133
Many of the smaller _____ fragments produced by complement protein cleavage help to induce an inflammatory response. These proteins are called anaphylatoxins. What are the 3 main ones?
(a)
C3a, 4a, and 5a
134
What are the 5 functions of anaphylatoxins?
1) Bind to receptors on basophils and mast cells and trigger degranulation (release of pro-inflammatory chemicals)
2) Induce smooth muscle contraction and increased vascular permeability
3) Promote increased leukocyte adhesion (to vessel walls) and extravasation
4) Serve as a chemoattractant for movement of immune cells through the tissue
5) Stimulate respiratory burst in neutrophils
135
What is respiratory burst?
increase in oxygen consumption to increase energy in cells
136
___ is a great opsonin. What does it do?
C3b
binds to the surface of the Ag and tags it for destruction by phagocytes
137
Most phagocytes have ______________ receptors
complement
138
The repeating nature of most viral structural components (e.g. capsids) stimulates complement activation.....
w/ or w/o antibody
139
Complement proteins can neutralize virions in several different ways. What are they?
1) C3b coats the surface (w/ Ab) and causes them to aggregate
-Instead of having 1,000 individual infectious particles, have 1 large aggregate
2) Prevents viral particles from binding to receptors on target cells
3) They are opsonized and targeted for destruction by phagocytes (CR1)
4) MAC can punch holes in the membrane of enveloped viruses
140
Some viruses have developed mechanisms of evading the complement system. Give an example
1) Herpesviruses produce a fake FC receptor (locks up all the Ab)
2) Vaccinia virus produces proteins that directly inhibit complement proteins
141
How does the immune system dispose of complexes containing antibodies and small, soluble antigens from our blood?
-Fc receptors on phagocytes play some role
-Complement plays a more important role
142
What are the general steps for the clearance of immune complexes via complement?
1) C3b can bind to antibodies that have bound soluble antigen into a complex
2) The C3b then binds to CR1 on the surface of a RBC
3) RBC circulates and ends up at the liver and spleen
-Complexes are stripped off their surface and immediately get degraded by local phagocytes
Note: tons of RBCs in our blood, few phagocytes
143
_____________ of complement-tagged pathogens by phagocytes is mediated by receptors for the bound complement proteins.
Ingestion
144
Bacterium is coated w/ C3b. What now?
-when only C3b binds to CR1, bacteria will not be able to undergo phagocytosis
-C5a needs to also bind to activate macrophages to phagocytize via CR1 (C5a binds to a GPCR on the surface)
145
What are some defects in regulators?
-Factor I deficiency leads to uncontrolled complement activation, complement proteins become depleted
and people suffer from repeated bacterial infections.
-Single nucleotide polymorphisms in factor H gene, is related age-related macular degeneration; leading
cause of blindness in the elderly in developed countries.
146
Mutations in central players such as ______ and ______ can lead to more severe problems
C3 and C5
147
Diseases can be subdivided into 4 groups. What are they?
1) Those that result from inefficient cell lysis
2) Those that result from poor opsonization
3) Those that result from poor clearance of immune complexes
4) Those that result from inefficient regulation of inflammation
148
Recurrent bacterial and fungal infections can lead to what?
major increases in Staph, Strep, and Neisseria infections
149
What can a hyperactive inflammatory response lead to?
-Too many immune complexes floating around (or too many anaphylatoxins) can lead to the continual activation of the inflammatory response
-Can lead to lupus, chronic kidney inflammation, vasculitis
