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MICR 3230 > Midterm > Flashcards

Midterm Flashcards

1
Q

Anatomic barriers

A

skin, oral mucosa, respiratory epi, intestine

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2
Q

Chemical barrier

A

Complement/antimicrobial proteins
- C3, defensins, RegIIIy

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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

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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”

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5
Q

Granulocytes

A

-Neutrophils
-Basophils
-Eosinopils
-Mast cells

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6
Q

Myeloid antigen-presenting cells

A

-Monocytes
-Macrophages
-Dendritic cells

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7
Q

Innate lymphocytes

A

-NK cells
-ILCs

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8
Q

Phagocytes

A

-Macrophage
-Granulocytes
Dendritic cells

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9
Q

Myeloid lineage

A

MOST innate cells

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10
Q

Lymphoid lineage

A

MOST adaptive cells + ILC and NK

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11
Q

Neutrophil

A

phagocytosis and activation of bactericidal mechanisms

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12
Q

Eosinophil

A

Killing of antibody-coated parasites
ANTIPARASITIC

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13
Q

Basophil

A

Promotion of allergic responses and augmentation of anti-parasitic immunity
ANTIPARASITIC AND ALLERGIC

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14
Q

Most important APC

A

Dendritic cells, present antigens

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15
Q

Mast cell

A

Release of granules containing histamine and active agents
ALLERGIC RXNS

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16
Q

Macrophage

A

Phagocytosis and activation of bactericidal mechanisms, antigen presentation, cytokine production

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17
Q

Dendritic cells

A

-Antigen uptake in peripheral sites, antigen presentation and cytokine production

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18
Q

NK cells

A

Recognize and destroy virus-infected and tumor cells

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19
Q

General principle of innate

A
  1. Inflammatory inducers (lipopolysaccharides, ATP, urate crystals)
  2. Sensor cells
    (macrophage, neutrophils, dendritic cells)
  3. Mediators
    (cytokines, cytotoxicity)
  4. Target tissues
    (production of antimicrobial proteins, induction of intracell antiviral proteins, killing of infected cells)
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20
Q

ILC

A

-secrete cytokines to activate innate immune cells

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21
Q

Interstitial spaces, blood, lymph protective immunity

A

complement, phagocytosis, antibodies

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22
Q

Epithelial surfaces

A

antimicrobial peptides, antibodies (especially IgA)

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23
Q

cytoplasmic protective immunity

A

NK cells
Cytotoxic T cells

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24
Q

vesicular protective immunity

A

T-cell dependant and NK cell dependant macrophage activation

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25
Q

PAMPS

A

PGN, LPS, CpG DNA

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26
Q

PRRs

A

TLRs, NLR

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27
Q

macrophage receptors ex.

A

mannose
TLR1-TLR2 dimer
NOD1
TLR-4
glucan
scavenger

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28
Q

sensor cell inflam response

A
  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
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29
Q

Cytokines

A

increase blood vessel permeability, allow fluid and proteins to pass into tissues

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30
Q

Chemokines

A

direct migration of neutrophils to infection site

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31
Q

Families of PRR

A
  1. TLR
  2. lectin
  3. scavenger receptor
  4. cytosolic
    5.opsonin
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32
Q

Lectin

A

-e.g. mannose receptor
-binds to carbs (sulfated sugars and polysaccharides)
-prompts phagocytosis

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33
Q

scavenger receptor

A

-e.g. SR-A and SR-B
-binds to negatively charged ligands (sulfated polysaccharides and LTA( G+), LPS (G-))
-prompts phagocytosis

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34
Q

cytosolic innate receptor

A

-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

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35
Q

opsonin rec

A

e.g. complement receptors CR3 and CR4
e.g. Fc receptor
-binds pathogens or foreign molecules tagged with opsonins

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36
Q

Anti-viral (intracell) TLRs

A

3,7,8,9

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37
Q

Bacterial or fungal (extracell) TLRs

A

1, 2, 5, 10

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38
Q

TLR 4

A

LPS (Gram negative)

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39
Q

Features shared between TLRs

A

-Leucine-rich repeat.s (LRRs)
-Overall C form
-Toll-IL-1 receptor (ITRs) (initiates signalling)

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40
Q

TLR-4 signaling pathway

A
  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
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41
Q

TLR signaling to produce interferons (antiviral cytokins) –> 2 different pathways

A
  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
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42
Q

Cytosolic innate immune receptors and recognition strategies

A

RIG-1: triphosphate dsRNA
MDA-5: dsRNA
cGAS: DNA
NOD1: y-glutamyl diaminopimelic acid (iE DAP)
Nod2: muramyl dipeptide (MDP)

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43
Q

Inflammatory cytokines

A

TNFa: secreted by macrophages, inflammation
IL-1: secreted by macrophages, DCs, inflammation

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44
Q

Signaling cytokines (secreted by/ function)

A

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

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45
Q

Chemokines

A

CXCL8 (IL8): by monocytes, macrophages, mobilizes and activates neutrophils

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46
Q

Many receptor signals use rapid pathway called

A

JAK-STAT pathway

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47
Q

IL-1B local and systemic effects

A

Local:
- activates vascular endothelium
-activates lymphocytes
-increases access of effector cells
INCREASED VASCULAR PERM

Systemic
- fever
-production of IL-6

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48
Q

TNF-a local and systemic

A

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

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49
Q

IL-6

A

Local:
-lymphocyte activation
-increased antibody production (!!!!!)

Systemic
-fever
-induced acute-phase protein production

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50
Q

CXCL8 (IL8) (local and systemic)

A

Local:
- chemotactic factor recruits neutrophils (!!!) , basophils and T. cells to infection site

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51
Q

IL-12 local and systemic

A

Local:
- activates NK cells (!!!!)
-induces differentiation of CD4 T cells into TH1 cells

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52
Q

Leukocyte recruitment

A

1.Tethering

2.Rolling

3.Activation
- neutrophils stop rolling

4.Firm adhesion

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53
Q

4 types of cell adhesion molecules

A

*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
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54
Q

What molecule causes rolling of leukcyte and stopping

A

Selectin: weak interaction, can continue to roll

Integrin: causes complete stop

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55
Q

Selectins

A
  • 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)
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56
Q

Integrins

A

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

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57
Q

Integrin-mediated adhesion is

A

non-reversible, tight binding
leads to diapedesis

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58
Q

SUMMARY: leukocyte-vessel wall interactions

A
  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
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59
Q

What is the complement system

A

system of soluble plasma protiens (complement) that opsonizwe and lyse pathogens

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60
Q

Complement proteins produced mainly by _____, activated how

A

liver, circulate in inactive form and are activated in presence of pathogens or antibodies bound to pathogen

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61
Q

Many of complement proteins are _______

A

proteases. synthesized as inactive proteases or zymogens

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62
Q

Complement activates

A

inflammation, phagocytosis, membrane attack

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63
Q

Effector pathways of complement system

A
  1. Pathogen recognition
    - self vs non-self
  2. Inflammation
  3. Pathogen destruction
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64
Q

C3 cleaves to produce

A

C3a (smaller) and C3b (larger)

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65
Q

Proteins of alternative pathway

A

factor B and factor D
-factor B cleaves into Ba (smaller) and Bb (larger)

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66
Q

Exceptions with complement protein naming

A
  1. C2 produces C2a (LARGER)
  2. C1q, C1r and C1s not cleavage proteins of C1 but distinct proteins that compose C1
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67
Q

Order of discovery complement proteins

A

C1, C4, C2, C3 ……. (classical)

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68
Q

Lectin pathway initiation

A
  • 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
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69
Q

Classical pathway initiation

A

-initiated when C1 either recognizes microbial surface directly or bind to antibodies already bound to a pathogen

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70
Q

Alternative pathway

A

-initiated by spontaneous hydrolysis and activation of C3, which can bind directly to a microbial surface

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71
Q

All complement pathways generate

A

a C3 convertase that cleaves C3, leaves C3b bound to microbial surface and releases C3a

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71
Q

3 results from cleavage of C3

A
  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

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72
Q

C3a

A

anaphylatoxin
–> capable of activating an inflammatory response by triggering degranulation of cells capable of inducing inflam

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73
Q

C3b

A

opsonin
–> covalently attaches (complement fixation) to pathogen surface, marks for destruction - renders pathogen more susceptble to phagocytosis

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74
Q

C3 cleavage process

A
  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

  1. Cleavage of C3 releases C3a, changes conformation of C3b allows thioester bond to react with chemical group on pathogen surface
  2. C3b bound to pathogen surface, C3b thioester bond inactivated by hydrolysis
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75
Q

Order of when each pathway acts

A
  1. alternative
  2. lectin
  3. classical
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76
Q

Lectin (complement)

A

-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

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77
Q

Classical C3 convertase

A

C4bc2a

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78
Q

Alternative C3 convertase

A

C4bBb

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79
Q

Lectin C3 convertase

A

C4bc2a

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80
Q

how does c3b tag fr phagocytosis

A

macrophages have CR1, binds to C3b

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81
Q

c3b recognition by different receptors

A
  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
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82
Q

Factor I

A

serine protease, inactivates C3b through cleavage into smaller fragments known as iCb, which cannot function as a component of C3 convertase

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83
Q

2 plasma proteins that regulate complement

A

-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

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84
Q

2 membrane proteins that regulate complement

A

-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
Q

Membrane attack complex

A

C5, C6, C7, C8, C9
-work to form holes in bacterial and eukaryotic membranes
-C5b an initiating factor in formation of MAC

86
Q

What plasma proteins regulate MAC

A

s protein, clusterin, factor J

87
Q

What human cell-surface proteins regulate MAC

A

CD59, HRF

88
Q

Extracell regonition

A

By TLR and Lectin
-bacteria to TLR, fungal to Lectin

89
Q

Intracell recognition: cytosolic

A

By NLR (nod-like) and RLR (RIG-like)
-bacterial PGNs to NLR, viral RNA to RLR

90
Q

Intracell recognition: endosomal

A

TLR (3,7,8,9,= viral)

91
Q

Integrin binds _______ to initiate neutrophil recruitment

A

iCAM
- neutrophil stops, squeezes out, goes to chemokine signal

92
Q

4 basic principles of clonal secretion

A
  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

  1. 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
Q

process of clonal selection

A
  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
Q

T cells and B cells develop where

A

T: start developing in bone marrow, complete in thymus

B: start developing in bone marrow, complete in bone marrow

95
Q

Activation of T cells location (and where do dendritic cells go)

A
  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
Q

Where do circulating lymphocytes encounter antigens

A

Peripheral lymphoid organs

97
Q

Inner and outer cortex of lymphnodes, what is found

A

inner; T cells

outer: B cells

98
Q

Helper T cell and Cytotoxic T cell

A

Helper: CD4
Cytotoxic: CD8

99
Q

Epitope

A

region or sites of antigen recognized by immune system

100
Q

Immunoglobins also known as

A

antibodies

101
Q

Membrane bound vs secreted form of Igs

A

Membrane bound: BCR
Secreted form: Igs

102
Q

Heavy/light and heavy/heavy chains are joined by

A

disulphide bonds

103
Q

Avidity

A

the total strength of interaction between antibody and antigen

104
Q

Affinity

A

the strength of the interaction between a single antigen-binding site and antigen

105
Q

L chain has _____ Ig domains

A

2

106
Q

H chain has ______ Ig domains

A

4 or 5

107
Q

Variable region

A

-made up of VH and VL chains
-on amino (N) terminus
-determines antigen binding specificity

108
Q

Constant domains

A

distinguishes different classes

109
Q

Antibody molecule cleaves into distinct fragments:

A

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
Q

5 main heavy chain isotypes

A

IgM, IgD, IgG, IgE, IgA

111
Q

Subclasses of Ig isotypes

A

IgG: 4 subclasses
IgA: 2 subclasses

112
Q

Which antibody (Ig) isotype is most abundant in serum

A

IgG

113
Q

what antibody (Ig) isotype is the first produced after B cell activation

A

IgM
-secreted as a pentamer, present in bloodstrem, not tissues
-pentamer increases avidity

114
Q

Which isotypes interact with C1/activate complement

A

IgM IgG

115
Q

Which Ig acts at mucosal surfaces

A

IgA

116
Q

Which Ig works in parasite immunity and allergic rxns

A

IgE

117
Q

Which Ig has the highest molecular mass

A

IgM

118
Q

Which Ig has high affinity binding to mast cells and basophils

A

IgE

119
Q

Which Ig molecules can form polymers and how

A

IgM and IgA form polymers by interacting with J chain

120
Q

Which Ig found as pentamers in plasma (10 antigen bind sites)

A

IgM

121
Q

IgA molecules found as

A

dimers in mucous secretions and monomers in plasma

122
Q

Hypervariable regions

A

CDRs, in H and L chains (variable reg) make up antigen-binding site

123
Q

Antibodies composed of

A

repeating 110 aa unites referred to as domains or folds

124
Q

TCR

A

-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
Q

TCR Structure

A

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
Q

MHC restriction

A

each T-cell receptor specific for particular peptide bound to particular MHC molecule

127
Q

MHC I

A

2 subunits:
1. a chain (a1, a2, a3)
-a1 and a2 form peptide-binding groove)

  1. B2 macroglobulin
    -soluble
    -provides structural support

-Binds small peptides of 8-10aa in length, generated from intracell proteins

128
Q

MHC II

A

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
Q

CD4

A

-binds to MHC II
-targets extracell pathogens

130
Q

CD8

A

-binds to MHC I
-targets intracell pathogens

131
Q

TCR is not expressed without

A

CD3

132
Q

CD3

A

brings TCR to surface, recruits signal molecules activated upon TCR engagement

-6 subunits

133
Q

what gene segments form the hypervariable regions

A

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
Q

Steps of gene segment construction

A
  1. somatic recombination:
    DNA: D-J rearranged, DNA joined
  2. 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
Q

Light chain gene

A

VJ

136
Q

Heavy chain gene

A

VDJ

137
Q

rule for rearrangement of V,D,J segments

A

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
Q

23 bp spacer

A

heptamer on left, nonamer on right

139
Q

12 bp spacer

A

nonamer on left, heptamer on right

140
Q

Enzymatic steps in V(D)J recombination

A
  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
Q

what opens up hairpins

A

Artemis

142
Q

2 proteins in V(D)J recombinase

A

RAG 1 and RAG 2

143
Q

2 types of diversity (antigen receptor genes)

A

Combinatorial diversity:
-use of different V,D and J segments

Junctional diversity
- different N and P nucleotides in each clone

144
Q

Junctional diversity: how are joints diversified between segments

A

Introduction of P and N-nucleotides

145
Q

Introduction of P and N-nucleotides

A
  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
Q

which 2 Igs are derived from same pre-mRNA transcript a and are both expressed on surface of mature B cells

A

IgM and IgD

147
Q

to initiate immune responses, antigens are

A

are captured from their side of entry and concentrated in secondary (peripheral) lymphoid organs through which naive T cells circulate constantly

148
Q

Antigen processing

A

generation of peptides from native proteins

149
Q

2 categories of major intracellular compartments (separated by membranes)

A
  1. cytosol
  2. vesicular compartments (endocytosis and secretion)
150
Q

Peptides loaded onto MHC I (locations)

A

-derivaed from cytosol, transportd into ER, loaded onto MHC I

151
Q

cytosolic pathogens (degraded in/bind to/presented to/effect on presenting cell)

A

Degraded in: cytosol
Peptide bind to: MHC I
Presented to: CD8
Effect on presenting cell: death

DIRECT PRESENTATION, SOMATIC AND IMMUNE CELLS

152
Q

intravesicular pathogens (degraded in/bind to/presented to/effect on presenting cell)

A

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
Q

extracell pathogens and toxins (degraded in/bind to/presented to/effect on presenting cell)

A

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
Q

Cross-presentation of antigen

A

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
Q

Autophagy pathway is for the

A

delivery of cytosolic antigens for presentation by MHC II

155
Q

Cross-presentation is important in

A

-exogenous (eg. tumor cells)
-MHC I

156
Q

Autophagy is important in

A

-self-antigens
-MHC II

157
Q

where are cytoplasmic proteins delivered and why

A

delivered into endocytic system (autophagosomes) for degradation in lysosomes

158
Q

Protein degradation in cytosol

A

-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
Q

Ubiquitin-proteasome system

A

-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
Q

How is chain recognized by 19S cap

A

K48

161
Q

_____ and ______ form peptide transporter in ER membrane

A

TAP1 and TAP2

162
Q

TAP1 and TAP2 do what

A

transport proteins from cytosol into ER before binding to MHC1

163
Q

Mechanism of peptide processing and loading on MHC Class I molecules

A
  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
  3. peptide binds MHC class I molecule, completes folding
    MHC class I released from TAP complex, exported to cell mem
164
Q

IFN-Y Important in

A

anti-viral defense

165
Q

______ trims proteins that are too long to bind MHC I

A

ERAP

166
Q

ERAP I increased by

A

IFN-y stim

167
Q

Peptide loading complex (PLC)

A

calreticulin, tapasin, ERp57, TAP

168
Q

_____ forms chanel beyween MHC I and TAP

A

tapasin

169
Q

in healthy cell what happens: (regarding protein processing/loading on MHC Class I molecules)

A

Beta chain dissociates
-calnexin bound, keeps MHC I in open form

170
Q

Peptides that bind MHC class II generated in

A

acidified endocytic vesicle

171
Q

Peptides bind to MHC class II molecules

A
  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
  3. vesicles containing peptides fuse with vesicles containing MHC class II molecules
172
Q

What does the invariant chain do

A

directs newly synthesized MHC class II molecules to acidified intracellular vesicles

173
Q

Invariant chain process

A
  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
Q

HLA-DM

A

facilitates loading of antigen peptides onto MHC class II molecules

175
Q

Loading of antigen peptide onto MHC class II molecule

A
  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
Q

mechanism of peptide processing and loading on MHC class II molecules (simple)

A
  1. MHC class II binds invariant chain
    2.Production of CLIP
    3.Phagolysosome fusion with MHC II vesicle
  2. peptide loading
177
Q

what performs cross-presentation

A

dendritic cells

178
Q

what forms production of CLIP

A

protease

179
Q

CLIP derived from

A

invariant chain

180
Q

MHC genes inherited

A

from each parent, known as haplotype

180
Q

Diversity of antigen presentation

A
  1. genetic encoding is polygenic
  2. genes are highly polymorphic, have many variants
    3.several MHC genes expressed from both inherited alleles - codominance
181
Q

3 properties affected by MHC molymorphism

A
  1. range of peptide bound
  2. conformation of bound peptide
  3. direct interaction of MHC molecule with TCR
182
Q

5 differences between MHC I and MHC II

A
  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
Q

Specialized MHC I molecules act as ligands for activation and inhibition of

A

NK cells and unconventional T-cell subsets

184
Q

2 molecules that present non-protein antigens

A

CD1, MR1

185
Q

membrane receptors all have

A

-extracell domains (specifically binds ligands)
-Transmem domains (span PM)
-cytoplasmic domains (participates in signal transduction)

186
Q

Naive T cells express

A

CD28 - receptor for B7 molecules

187
Q

B7

A

a cell-surface protein on an APC –> B7.1 (CD80) and B7.2 (CD86)

188
Q

iTAM

A

-cytoplasmic aa sequences
-docking. sites for other proteins
-mediate interaction with cytoplasmic protein-tyrosine kinases

189
Q

most important kinase in TCR activation

A

ZAP-70

190
Q

what is the docking site for ZAP-70

A

iTAM

191
Q

signal transduction at TCR complex

A
  1. core rec recruit Lck
  2. Lck phosphorylates iTAMS on CD3 subunit
    3.iTAM is docking site for ZAP-70
  3. ZAP-70 phosphorylated by Lck
192
Q

signaling events that induce T-cell activation

A
  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

193
Q

3 signal transduction pathways (T cell activation)

A
  1. NFAT
  2. NFkB
  3. AP-1
194
Q

the most important gene for T-cell proliferation and differentiation into effector T cells

A

IL-2

195
Q

Which IL for B cell activation

A

IL-4

196
Q

What makes up BCR

A

antibody + Ig beta and Ig alpha

197
Q

_______ of BCR complexes drives activation

A

clustering

198
Q

CR2

A

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
Q

CD19

A

has the cytoplasmic domain for signaling events

200
Q

CD81

A

stabilizes coreceptor complex

201
Q

Most important kinase in B-cell (signaling at Ig receptor complex) and what does it induce

A

Syk
-induces NFAT, NFkB and Ap1

202
Q

What other kinase involved in B-cell-signalling Ig rec complex

A

Fyn

203
Q

GEFs

A

catalyze the exchange of guanine nucleotides on guanine nucleotide binding proteins Ras and Raf

204
Q

CTLA4

A

inhibitory receptor on activated T cells
-20x stronger adgesion for B7 than CD28
-check mechanism!

205
Q

What is found on activated T cell vs naive

A

Active: CTLA4
Naive: CD28

206
Q

binding of CD28

A

engages just 1 dimer of B7.1

207
Q

binding of CTLA-4

A

distinct binding orientation allows 1 CTLA-4 dimer to bind 2 diff B7.1 dimers, providing for high-avidity clustering

208
Q
A

MICR 3230 (4 decks)

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