Midterm Flashcards
(211 cards)
1
Q
Anatomic barriers
A
skin, oral mucosa, respiratory epi, intestine
2
Q
Chemical barrier
A
Complement/antimicrobial proteins
- C3, defensins, RegIIIy
3
Q
Lysozyme
A
-Digests cell walls of Gram-positive and Gram-negative bacteria
-More effective against gram positive bc greater accessibility
-Expose cell membrane to antimicrobrial agents
4
Q
Defensins
A
-amphipathic peptides that disrupt cell mem of microbes
-Positively charged defensins, interact with negatively charged bacterial cell wall
-forms pores, loss of membrane integrity
“punch hole in wall, bacteria dies”
5
Q
Granulocytes
A
-Neutrophils
-Basophils
-Eosinopils
-Mast cells
6
Q
Myeloid antigen-presenting cells
A
-Monocytes
-Macrophages
-Dendritic cells
7
Q
Innate lymphocytes
A
-NK cells
-ILCs
8
Q
Phagocytes
A
-Macrophage
-Granulocytes
Dendritic cells
9
Q
Myeloid lineage
A
MOST innate cells
10
Q
Lymphoid lineage
A
MOST adaptive cells + ILC and NK
11
Q
Neutrophil
A
phagocytosis and activation of bactericidal mechanisms
12
Q
Eosinophil
A
Killing of antibody-coated parasites
ANTIPARASITIC
13
Q
Basophil
A
Promotion of allergic responses and augmentation of anti-parasitic immunity
ANTIPARASITIC AND ALLERGIC
14
Q
Most important APC
A
Dendritic cells, present antigens
15
Q
Mast cell
A
Release of granules containing histamine and active agents
ALLERGIC RXNS
16
Q
Macrophage
A
Phagocytosis and activation of bactericidal mechanisms, antigen presentation, cytokine production
17
Q
Dendritic cells
A
-Antigen uptake in peripheral sites, antigen presentation and cytokine production
18
Q
NK cells
A
Recognize and destroy virus-infected and tumor cells
19
Q
General principle of innate
A
- Inflammatory inducers (lipopolysaccharides, ATP, urate crystals)
- Sensor cells
(macrophage, neutrophils, dendritic cells) - Mediators
(cytokines, cytotoxicity) - Target tissues
(production of antimicrobial proteins, induction of intracell antiviral proteins, killing of infected cells)
20
Q
ILC
A
-secrete cytokines to activate innate immune cells
21
Q
Interstitial spaces, blood, lymph protective immunity
A
complement, phagocytosis, antibodies
22
Q
Epithelial surfaces
A
antimicrobial peptides, antibodies (especially IgA)
23
Q
cytoplasmic protective immunity
A
NK cells
Cytotoxic T cells
24
Q
vesicular protective immunity
A
T-cell dependant and NK cell dependant macrophage activation
25
PAMPS
PGN, LPS, CpG DNA
26
PRRs
TLRs, NLR
27
macrophage receptors ex.
mannose
TLR1-TLR2 dimer
NOD1
TLR-4
glucan
scavenger
28
sensor cell inflam response
1. bacteria triggers macrophage to release cytokines and chemokines
2. vasodilation and increased vascular perm causes redness, heat and swelling
3. Inflam cells migrate into tissue, release inflam mediators that cause pain
29
Cytokines
increase blood vessel permeability, allow fluid and proteins to pass into tissues
30
Chemokines
direct migration of neutrophils to infection site
31
Families of PRR
1. TLR
2. lectin
3. scavenger receptor
4. cytosolic
5.opsonin
32
Lectin
-e.g. mannose receptor
-binds to carbs (sulfated sugars and polysaccharides)
-prompts phagocytosis
33
scavenger receptor
-e.g. SR-A and SR-B
-binds to negatively charged ligands (sulfated polysaccharides and LTA( G+), LPS (G-))
-prompts phagocytosis
34
cytosolic innate receptor
-binds intracellular PAMPs (cytosolic nucleic acids (DNA, dsRNA), cytosolic bacterial signalling molecules (cyclic dinucleotides)
eg. RIG-1 binds viral RNA, cGAS binds DNA
-Inhibits pathogen growth
-Prompts WBC recruitment to kill infected cells
35
opsonin rec
e.g. complement receptors CR3 and CR4
e.g. Fc receptor
-binds pathogens or foreign molecules tagged with opsonins
36
Anti-viral (intracell) TLRs
3,7,8,9
37
Bacterial or fungal (extracell) TLRs
1, 2, 5, 10
38
TLR 4
LPS (Gram negative)
39
Features shared between TLRs
-Leucine-rich repeat.s (LRRs)
-Overall C form
-Toll-IL-1 receptor (ITRs) (initiates signalling)
40
TLR-4 signaling pathway
1. dimerized TLRs recruit IRAK1 and IRAK4, activating E3 ubiquitin ligase TRAF6
--> MyD88 forms scaffold for IRAK1 which recruits TRAF6, without it no signalling
2. TRAF6 is polyubiuitinated, creating scaffold for activation of TAK1
3. TAK1 associated with IKK and phosphorylates IKKB which phosphorylates IkB
4. IkB is degraded, releasing NFkB into nucleus to induce expression of cytokine genes
41
TLR signaling to produce interferons (antiviral cytokins) --> 2 different pathways
1. TLR 3 in endosome binds dsRNA and signals via TRIF to induce IFN gene expression
2. TLR-7 in endosome binds ssRNA and signals via MyD88 to induce IFN gene expression
42
Cytosolic innate immune receptors and recognition strategies
RIG-1: triphosphate dsRNA
MDA-5: dsRNA
cGAS: DNA
NOD1: y-glutamyl diaminopimelic acid (iE DAP)
Nod2: muramyl dipeptide (MDP)
43
Inflammatory cytokines
TNFa: secreted by macrophages, inflammation
IL-1: secreted by macrophages, DCs, inflammation
44
Signaling cytokines (secreted by/ function)
IL-2: by T cells, T-cell activation
IL-4: by DCs, B-cell activation
IL-10: by monocytes, anto-inflam
IL-12: by DCs, Th1 helper T-cell activation
IL-17: by T cells, neutrophil activation
IFNy: by T cells, macrophage, and NK cells, macrophage activation
IFN-a/IFN-B: by macrophages, virally infected cells, NK activation, prevention of viral replication
TGF-B: by regulatory T cells, peripheral tolerance
45
Chemokines
CXCL8 (IL8): by monocytes, macrophages, mobilizes and activates neutrophils
46
Many receptor signals use rapid pathway called
JAK-STAT pathway
47
IL-1B local and systemic effects
Local:
- activates vascular endothelium
-activates lymphocytes
-increases access of effector cells
INCREASED VASCULAR PERM
Systemic
- fever
-production of IL-6
48
TNF-a local and systemic
Local:
- activates vascular endothelium and increases vascular perm: increased entry of IgG, complement, and cells to tissues, increased fluid drainage in lymph nodes
Systemic:
-fever
-mobilization of metabolites
-shock
49
IL-6
Local:
-lymphocyte activation
-increased antibody production (!!!!!)
Systemic
-fever
-induced acute-phase protein production
50
CXCL8 (IL8) (local and systemic)
Local:
- chemotactic factor recruits neutrophils (!!!) , basophils and T. cells to infection site
51
IL-12 local and systemic
Local:
- activates NK cells (!!!!)
-induces differentiation of CD4 T cells into TH1 cells
52
Leukocyte recruitment
1.Tethering
2.Rolling
3.Activation
- neutrophils stop rolling
4.Firm adhesion
53
4 types of cell adhesion molecules
*one present on neutrophil, other is on tissue
1. Selectin: bind to carb groups present on neutrophils
2. Glycoproteins: bind to complementary selectin
3. Integrins: bind to other proteins
4. ICAMS: bind to integrins
54
What molecule causes rolling of leukcyte and stopping
Selectin: weak interaction, can continue to roll
Integrin: causes complete stop
55
Selectins
- binds to carbs, initiates leukoctye, endothelial interaction
-P-selectin (activated endothelium and platelets, PSGL-1 and sialyl-lewis is ligands)
-E-selectin (activates endothelium, Sialyl-Lewis is ligand)
56
Integrins
aLb2:
- LFA-1 binds to ICAM-1 and ICAM-2
aNB2
-Mac-1 binds to ICAM-1, iC3b, fibrinogen
a5B1
-VLA-5 binds to fibronectin
57
Integrin-mediated adhesion is
non-reversible, tight binding
leads to diapedesis
58
SUMMARY: leukocyte-vessel wall interactions
1. rolling adhesion
- tethering, rolling
-by selectins and mucins
2. Tight binding
-activation and firm adhesion
-activation by chemokines, firm adhesion by integrins and Ig superfam members)
3. Diapedesis
-transmigration
-by integrins and IgAsuperfam members and chemokines
4. Migration
- chemotaxis
-by chemokines
59
What is the complement system
system of soluble plasma protiens (complement) that opsonizwe and lyse pathogens
60
Complement proteins produced mainly by _____, activated how
liver, circulate in inactive form and are activated in presence of pathogens or antibodies bound to pathogen
61
Many of complement proteins are _______
proteases. synthesized as inactive proteases or zymogens
62
Complement activates
inflammation, phagocytosis, membrane attack
63
Effector pathways of complement system
1. Pathogen recognition
- self vs non-self
2. Inflammation
3. Pathogen destruction
64
C3 cleaves to produce
C3a (smaller) and C3b (larger)
65
Proteins of alternative pathway
factor B and factor D
-factor B cleaves into Ba (smaller) and Bb (larger)
66
Exceptions with complement protein naming
1. C2 produces C2a (LARGER)
2. C1q, C1r and C1s not cleavage proteins of C1 but distinct proteins that compose C1
67
Order of discovery complement proteins
C1, C4, C2, C3 ....... (classical)
68
Lectin pathway initiation
- by soluble carb-binding proteins: mannose-binding lectin (MBL) and ficolins
-bind to particular carb structures on microbial servics
-MASPs (MBL-associated proteases) trigger cleabage of complement routines and activation of the pathway
69
Classical pathway initiation
-initiated when C1 either recognizes microbial surface directly or bind to antibodies already bound to a pathogen
70
Alternative pathway
-initiated by spontaneous hydrolysis and activation of C3, which can bind directly to a microbial surface
71
All complement pathways generate
a C3 convertase that cleaves C3, leaves C3b bound to microbial surface and releases C3a
71
3 results from cleavage of C3
1. C3a and C5a recruit phagocytic cells to site of infection and promote inflammation
2. Phagocytes with receptors for C3b engulf and destroy the pathogen
3.All pathogens generate a C5 convertase that leads to formation of a membrane-attack complex (MAC) which disrupts cell membrane
72
C3a
anaphylatoxin
--> capable of activating an inflammatory response by triggering degranulation of cells capable of inducing inflam
73
C3b
opsonin
--> covalently attaches (complement fixation) to pathogen surface, marks for destruction - renders pathogen more susceptble to phagocytosis
74
C3 cleavage process
1. newly synthesized C3 protein proteolytically processed to generate B chain and a chain held together by disulfide bonds
2, Before cleavage by C3 convertase, the thioester bond within TED (thioester-containing domain) is protected from reacting
3. Cleavage of C3 releases C3a, changes conformation of C3b allows thioester bond to react with chemical group on pathogen surface
4. C3b bound to pathogen surface, C3b thioester bond inactivated by hydrolysis
75
Order of when each pathway acts
1. alternative
2. lectin
3. classical
76
Lectin (complement)
-MBLs and ficolins associated with 3 proteases (MASPs)
-bind carb on surface of pathogen, does not bind WHOLE cell (cant bind sialic acid)
-MBL binds to high avidity mannose and fucose residues
-Ficolins bind oligosaccharides containing acetylated sugars
*sialic acid found on healthy cell
*ficolins more prominant
77
Classical C3 convertase
C4bc2a
78
Alternative C3 convertase
C4bBb
79
Lectin C3 convertase
C4bc2a
80
how does c3b tag fr phagocytosis
macrophages have CR1, binds to C3b
81
c3b recognition by different receptors
1. C3b bound to pathogen surface
2.cleavage of bound C3b by factor I and MCP cofactor release C3f fragment and leaves iC3b on surface
3.cleavage of iC3b by factor I and CR1 released C3c and leaves C3 dg bound to surface
82
Factor I
serine protease, inactivates C3b through cleavage into smaller fragments known as iCb, which cannot function as a component of C3 convertase
83
2 plasma proteins that regulate complement
-factor H
-->enhances cleavage of C3b into iC3b by factor I
-->inhibits complement activation
-bind to cell mem by interacting with sialic acid
-factor I
84
2 membrane proteins that regulate complement
-DAF (decay-accelerating factor)
--> breakdown of alternative C3 conertase
-MCP (membrane cofactor protein)
--> binds to C3b and enhances its cleavage to inactivate iC3b by factor I
85
Membrane attack complex
C5, C6, C7, C8, C9
-work to form holes in bacterial and eukaryotic membranes
-C5b an initiating factor in formation of MAC
86
What plasma proteins regulate MAC
s protein, clusterin, factor J
87
What human cell-surface proteins regulate MAC
CD59, HRF
88
Extracell regonition
By TLR and Lectin
-bacteria to TLR, fungal to Lectin
89
Intracell recognition: cytosolic
By NLR (nod-like) and RLR (RIG-like)
-bacterial PGNs to NLR, viral RNA to RLR
90
Intracell recognition: endosomal
TLR (3,7,8,9,= viral)
91
Integrin binds _______ to initiate neutrophil recruitment
iCAM
- neutrophil stops, squeezes out, goes to chemokine signal
92
4 basic principles of clonal secretion
1. each lymphocyte bears a single type of receptor with unique specificity
2. interaction between a foreign molecule nd a lymphocyte rec capable of binding that molecule with high affinity leads to lymphocyte activation
3.the differentiated effector cells derived from activated lymphocyte will bear rec of identical specificity to those of parental cell from which lymphocyte was derived
4. lymphocytes bearing receptors specific for ubiquitous self molecules are deleted at an early stage in lymphoid cell development and are therefore absent from repertoire of mature lymphocutes
93
process of clonal selection
1. single progenitor cell gives rise to large number of lymphocytes, each with different specificity
2. removal of self-reactive immature lymphocytes by clonal deletion
3. pool of mature naive lymphocytes
4. proliferation and differentiation of activated specific lymphocyes to form a clone of effector cells
94
T cells and B cells develop where
T: start developing in bone marrow, complete in thymus
B: start developing in bone marrow, complete in bone marrow
95
Activation of T cells location (and where do dendritic cells go)
1. immature dendritic cells reside in peripheral tissues
2. dendritic cells migrate via lymphatic vessel to regional lymph nodes
3. mature dendritic cells activate t cells in lymphoid organs such as lymph nodes
96
Where do circulating lymphocytes encounter antigens
Peripheral lymphoid organs
97
Inner and outer cortex of lymphnodes, what is found
inner; T cells
outer: B cells
98
Helper T cell and Cytotoxic T cell
Helper: CD4
Cytotoxic: CD8
99
Epitope
region or sites of antigen recognized by immune system
100
Immunoglobins also known as
antibodies
101
Membrane bound vs secreted form of Igs
Membrane bound: BCR
Secreted form: Igs
102
Heavy/light and heavy/heavy chains are joined by
disulphide bonds
103
Avidity
the total strength of interaction between antibody and antigen
104
Affinity
the strength of the interaction between a single antigen-binding site and antigen
105
L chain has _____ Ig domains
2
106
H chain has ______ Ig domains
4 or 5
107
Variable region
-made up of VH and VL chains
-on amino (N) terminus
-determines antigen binding specificity
108
Constant domains
distinguishes different classes
109
Antibody molecule cleaves into distinct fragments:
Hinge region
- lies within C region
- allows flexibility in binding to multiple antigens
- differs between isotype
-(polypeptide chains that join arms to trunk)
Fab (fragment antigen binding) region
-heavy and light chain variable reg
-antigen-binding activity
Fc (fragment crystallizable)
-does not interact with antigen
-biological activity
-differs between H chain isotypes
110
5 main heavy chain isotypes
IgM, IgD, IgG, IgE, IgA
111
Subclasses of Ig isotypes
IgG: 4 subclasses
IgA: 2 subclasses
112
Which antibody (Ig) isotype is most abundant in serum
IgG
113
what antibody (Ig) isotype is the first produced after B cell activation
IgM
-secreted as a pentamer, present in bloodstrem, not tissues
-pentamer increases avidity
114
Which isotypes interact with C1/activate complement
IgM IgG
115
Which Ig acts at mucosal surfaces
IgA
116
Which Ig works in parasite immunity and allergic rxns
IgE
117
Which Ig has the highest molecular mass
IgM
118
Which Ig has high affinity binding to mast cells and basophils
IgE
119
Which Ig molecules can form polymers and how
IgM and IgA form polymers by interacting with J chain
120
Which Ig found as pentamers in plasma (10 antigen bind sites)
IgM
121
IgA molecules found as
dimers in mucous secretions and monomers in plasma
122
Hypervariable regions
CDRs, in H and L chains (variable reg) make up antigen-binding site
123
Antibodies composed of
repeating 110 aa unites referred to as domains or folds
124
TCR
-transmembrane protein with almost entirely extracell structure
-each T cell has 1 type of TCR with protection against only 1 pathogen
-no soluble T cells: recognizes antigens associated with cell
125
TCR Structure
2 chains: a and B
-each chain has C and V reg
-V reg makes up antigen bindi site
-hypervariable reg on variable (6)
-carbohydrates (4)
126
MHC restriction
each T-cell receptor specific for particular peptide bound to particular MHC molecule
127
MHC I
2 subunits:
1. a chain (a1, a2, a3)
-a1 and a2 form peptide-binding groove)
2. B2 macroglobulin
-soluble
-provides structural support
-Binds small peptides of 8-10aa in length, generated from intracell proteins
128
MHC II
2 subunits:
1. a chain
-a1, a2
2.B chain
-B1, B2
-both chains transmembrane
-a1, B1 forms peptide-bind groove
-binds larger peptides of 13-25aa in length, generated from extracell proteins
129
CD4
-binds to MHC II
-targets extracell pathogens
130
CD8
-binds to MHC I
-targets intracell pathogens
131
TCR is not expressed without
CD3
132
CD3
brings TCR to surface, recruits signal molecules activated upon TCR engagement
-6 subunits
133
what gene segments form the hypervariable regions
CDR1 and CDR2 loops: V gene segment
CDR3: sequences from the end of V gene segment and beginning of J gene segment, and nucleotides aded or lost when gene segments joined during development
134
Steps of gene segment construction
1. somatic recombination:
DNA: D-J rearranged, DNA joined
1. somatic recombination
V-J or V-DJ joined, rearranged DNA (irreversible)
2.Transcription:
Primary trascript RNA
3.Splicing:
mRNA
4.Translation:
polypeptide chain (protein)
135
Light chain gene
VJ
136
Heavy chain gene
VDJ
137
rule for rearrangement of V,D,J segments
12/23
-brought together by V(D)J recombinase, that brings the exons together
-recombination of V and J exons occurs by deletion of intervening DNA and ligation of V and J segments
138
23 bp spacer
heptamer on left, nonamer on right
139
12 bp spacer
nonamer on left, heptamer on right
140
Enzymatic steps in V(D)J recombination
1. Synapsis
- 2 distinct selected coding segments and adjacent RSS brought together by chromosomal looping event, held in position for cleavage, processing and joining
2.Cleavage
-V(D)J recombinase creates double-stranded breaks at RSS-coding sequence junctions
-recombinase composed of RAG1 and RAG2
-RAG genes only in developing T and B cells, inactivated in proliferating cells
3.Hairpin opening and end processing
-after form of double-strand breaks, hairpins opened at coding junctions and nucleotides added or removed from coding ends
-ARTEMIS is endonuclease that opens hairpins
-Terminal deoxynucleptidyl transferase (TdT) adds nucleotides to broken DNA ends
4.Joining
- broken cording end and signal ends brought together, ligated by a double-stranded break repair process called nonhomologous end joining (NHEJ)
-NHEJ ubiquitous proteins: KU70, KU80 bind to breaks and recruit catalytic subunit of DNA-dependant protein kinase (DNA-PK)
-DNA-PK also phosphorylates and activated Artemis, ligation of processed ends mediated by DNA ligase IV and XRCC4
141
what opens up hairpins
Artemis
142
2 proteins in V(D)J recombinase
RAG 1 and RAG 2
143
2 types of diversity (antigen receptor genes)
Combinatorial diversity:
-use of different V,D and J segments
Junctional diversity
- different N and P nucleotides in each clone
144
Junctional diversity: how are joints diversified between segments
Introduction of P and N-nucleotides
145
Introduction of P and N-nucleotides
1. form of DNA hairpins leads to ligation of heptamer sequencing forming single joint
2. artemis: DNA-PK cleaves DNA hairpin at random sites, producing single-stranded DNA ends
3. single-stranded ends may have complementary nucleotides, forming short palindromic sequences (eg. TCGA, ATAT)
4. Presence of terminal deoxynucleotidyl transferase (TdT) adds random nucleotides (N) to single-strand ends
5. 2 single- strand ends pair together
6. unpaired nucleotides trimmed by exonucleases
7. final coding joint repaired via DNA synthesis and ligation, retaining P and N nucleotides
8. random insertion of P and N nucleotides creates unique markers, useful for tracking individual B cell clones in studies like somatic hypermutation
146
which 2 Igs are derived from same pre-mRNA transcript a and are both expressed on surface of mature B cells
IgM and IgD
147
to initiate immune responses, antigens are
are captured from their side of entry and concentrated in secondary (peripheral) lymphoid organs through which naive T cells circulate constantly
148
Antigen processing
generation of peptides from native proteins
149
2 categories of major intracellular compartments (separated by membranes)
1. cytosol
2. vesicular compartments (endocytosis and secretion)
150
Peptides loaded onto MHC I (locations)
-derivaed from cytosol, transportd into ER, loaded onto MHC I
151
cytosolic pathogens (degraded in/bind to/presented to/effect on presenting cell)
Degraded in: cytosol
Peptide bind to: MHC I
Presented to: CD8
Effect on presenting cell: death
DIRECT PRESENTATION, SOMATIC AND IMMUNE CELLS
152
intravesicular pathogens (degraded in/bind to/presented to/effect on presenting cell)
Degraded: endocytic vesicles (low pH)
Peptides bind to: MHC II
Presented to: CD4
Effect: activation of macrophage to kill intravesicular bacteria and parasites
IMMUNE CELLS
153
extracell pathogens and toxins (degraded in/bind to/presented to/effect on presenting cell)
Degraded: endocytic vesicles (low pH)
Bind to: MHC II
presented to: CD4
Effect: activation of B cells to secrete Ig to eliminate extracell bacteria/toxins/viruses
154
Cross-presentation of antigen
the ability of certain PACs (mostly DC) to take up, process and present antigens from exogenous sources with MHC I to CD8 cells
--> eg. a virus that affects only epithelial cells
--> activation of naive CD8 into activated is cross-priming
--> immunity against tumors
155
Autophagy pathway is for the
delivery of cytosolic antigens for presentation by MHC II
155
Cross-presentation is important in
-exogenous (eg. tumor cells)
-MHC I
156
Autophagy is important in
-self-antigens
-MHC II
157
where are cytoplasmic proteins delivered and why
delivered into endocytic system (autophagosomes) for degradation in lysosomes
158
Protein degradation in cytosol
-MHC I protein presented
-20S catalytic core and 2 19S regulatory caps (one at each end)
-one cap binds and delivers proteins into proteosome, other keeps from exiting early
-degraded within catalytic core, released into cytosol
159
Ubiquitin-proteasome system
-attachment of ubiquitin molecule chain to target protein
-lysine residue on target protein chemically linked to glycine at carboxyl end of one ubiquitin molecule
-ubiquitin chains formed by linking lysine at residue 48 (K48) of first ubiquitin to carboxyl end of second ubiquitin until at least 4 are bound
-K48 chain recognized by 19s cap, unfolded, introduced into proteasome catalytic core -> chopped into short peptides --> released into cytosol
160
How is chain recognized by 19S cap
K48
161
_____ and ______ form peptide transporter in ER membrane
TAP1 and TAP2
162
TAP1 and TAP2 do what
transport proteins from cytosol into ER before binding to MHC1
163
Mechanism of peptide processing and loading on MHC Class I molecules
1. partly folded MHC class Ia chain binds calnexin until B2-microglobulin binds
2. MHC class I a:B2m complex released from calnexin, binds complex (calreticulin and ERp57, binds to TAP via tapasin
3.cytosolic proteins degraded to peptide fragments by proteosome, TAP delivers peptides to ER
4. peptide binds MHC class I molecule, completes folding
MHC class I released from TAP complex, exported to cell mem
164
IFN-Y Important in
anti-viral defense
165
______ trims proteins that are too long to bind MHC I
ERAP
166
ERAP I increased by
IFN-y stim
167
Peptide loading complex (PLC)
calreticulin, tapasin, ERp57, TAP
168
_____ forms chanel beyween MHC I and TAP
tapasin
169
in healthy cell what happens: (regarding protein processing/loading on MHC Class I molecules)
Beta chain dissociates
-calnexin bound, keeps MHC I in open form
170
Peptides that bind MHC class II generated in
acidified endocytic vesicle
171
Peptides bind to MHC class II molecules
1. antigen is taken up from extracell space into endocytic vesicles
2. in early endosomes of neutral pH, endosomal proteins inactive
3, acidification of vesicles activate proteases to degrade antigen into peptide fragments
4. vesicles containing peptides fuse with vesicles containing MHC class II molecules
172
What does the invariant chain do
directs newly synthesized MHC class II molecules to acidified intracellular vesicles
173
Invariant chain process
1. Invariant chain (Ii) binds in groove of MHC class II molecule
2. Ii is cleaved initially to leave a fragment bound to class II molecule and membrane
3, Further cleavage leaves short peptide fragment CLIP bound to class I molecule
174
HLA-DM
facilitates loading of antigen peptides onto MHC class II molecules
175
Loading of antigen peptide onto MHC class II molecule
1. invariant chain forms complex with MHC class II molecule, blocks binding of peptides and misfolded proteins
2. Ii cleaves in acidified endosome, leaves short eptide (CLIP) still bound to MHC class II mol
3. endocytosed antigens degraded to peptides in endosomes, CLIP peptide blocks binding of peptides to MHC class II molecules
4. HLA-DM binds to MHC class II mol, releases CLIP and allows other peptides to bind, MHC II travels to cell surface
176
mechanism of peptide processing and loading on MHC class II molecules (simple)
1. MHC class II binds invariant chain
2.Production of CLIP
3.Phagolysosome fusion with MHC II vesicle
4. peptide loading
177
what performs cross-presentation
dendritic cells
178
what forms production of CLIP
protease
179
CLIP derived from
invariant chain
180
MHC genes inherited
from each parent, known as haplotype
180
Diversity of antigen presentation
1. genetic encoding is polygenic
2. genes are highly polymorphic, have many variants
3.several MHC genes expressed from both inherited alleles - codominance
181
3 properties affected by MHC molymorphism
1. range of peptide bound
2. conformation of bound peptide
3. direct interaction of MHC molecule with TCR
182
5 differences between MHC I and MHC II
1. MHC.I: short peptides
MHC II: longer peptides
2. MHC I: A1, A2
MHC II: A1, B1
3. MHC 1: intracell
MHC II: extracell
4. MHC 1: CD8
MHC II: CD4
5. MHC I: no CLIP
MHC II: CLIP
183
Specialized MHC I molecules act as ligands for activation and inhibition of
NK cells and unconventional T-cell subsets
184
2 molecules that present non-protein antigens
CD1, MR1
185
membrane receptors all have
-extracell domains (specifically binds ligands)
-Transmem domains (span PM)
-cytoplasmic domains (participates in signal transduction)
186
Naive T cells express
CD28 - receptor for B7 molecules
187
B7
a cell-surface protein on an APC --> B7.1 (CD80) and B7.2 (CD86)
188
iTAM
-cytoplasmic aa sequences
-docking. sites for other proteins
-mediate interaction with cytoplasmic protein-tyrosine kinases
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most important kinase in TCR activation
ZAP-70
190
what is the docking site for ZAP-70
iTAM
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signal transduction at TCR complex
1. core rec recruit Lck
2. Lck phosphorylates iTAMS on CD3 subunit
3.iTAM is docking site for ZAP-70
4. ZAP-70 phosphorylated by Lck
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signaling events that induce T-cell activation
1. phosphorylation of PLCy
2. cleavage of PIP3 into IP3 and DAG
signal path 1:
IP3:
3a. signas opening of calcium stores
4a..Ca2+ secondary messenger - disffuses through cell to activate variety target protein
5a: calcineurindephosphorylates NFAT
6a: NFAT activates genes involved in T-cell expansion and diff
Signal path 2:
DAG:
3b: DAG activates protein kinase C (PKC)
4b: PKC activates NFkB through destruction of IkB
signal path 3: (still DAG)
3c: DAG associates with small GTPase, RAS
4c: RAS triggers MAP kinase cascade to activate Fos
5c: Fos interacts with Jun to form AP-1
6c: Jun activated through co-stim signal provided by CD28
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3 signal transduction pathways (T cell activation)
1. NFAT
2. NFkB
3. AP-1
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the most important gene for T-cell proliferation and differentiation into effector T cells
IL-2
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Which IL for B cell activation
IL-4
196
What makes up BCR
antibody + Ig beta and Ig alpha
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_______ of BCR complexes drives activation
clustering
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CR2
responsible for binding required for costimulatory signal (B-cell corec binding)
--> binds to iC3b and C3d, breakdown products of C3b fixed on pathogen surface by factor I
199
CD19
has the cytoplasmic domain for signaling events
200
CD81
stabilizes coreceptor complex
201
Most important kinase in B-cell (signaling at Ig receptor complex) and what does it induce
Syk
-induces NFAT, NFkB and Ap1
202
What other kinase involved in B-cell-signalling Ig rec complex
Fyn
203
GEFs
catalyze the exchange of guanine nucleotides on guanine nucleotide binding proteins Ras and Raf
204
CTLA4
inhibitory receptor on activated T cells
-20x stronger adgesion for B7 than CD28
-check mechanism!
205
What is found on activated T cell vs naive
Active: CTLA4
Naive: CD28
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binding of CD28
engages just 1 dimer of B7.1
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binding of CTLA-4
distinct binding orientation allows 1 CTLA-4 dimer to bind 2 diff B7.1 dimers, providing for high-avidity clustering
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