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M1 - Immuno > Exam 1 > Flashcards

Exam 1 Flashcards

1
Q

Which region on an antibody determines its class?

A

heavy chain constant region

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2
Q

Clonal selection

A

when a B or T cell is activated, it proliferates and forms lots of “clones” to help fight off the antigen for which it is specific

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3
Q

proliferation

A

When a B cell’s receptors bind to its cognate antigen, that B cell is triggered to double in size and divide into two daughter cells; both daughter cells then double in size and divide to produce a total of four cells, and so forth

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4
Q

proliferation period

A

lasts about a week

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5
Q

General characteristics of B cells

A

B cells use relatively few genes to create a huge diversity of antibodies
B cells are made on demand
Once selected, B cells proliferate rapidly to produce large #s of clones
Clones become antibody factories that can pump out large amounts of antibodies
When infection conquered, most B cells die

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6
Q

antibody mechanism

A

tag invaders for destruction by other molecules (opsonization); can also form a bridge between invader and phagocyte

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7
Q

neutralizing antibodies

A

can bind to a virus before it enters a cell and prevent it from either entering the cell or proliferating once it enters

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8
Q

can antibodies get to a virus that has already entered a cell?

A

no – this is where killer T cells come in

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9
Q

can you distinguish B and T cells under a microscope?

A

no

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10
Q

where are B cells produced?

A

bone marrow

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11
Q

where are T cells produced?

A

bone marrow

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12
Q

where do B cells mature?

A

bone marrow

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13
Q

where do T cells mature?

A

thymus

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14
Q

B cell receptors

A

antibody-like molecules displayed on surface of B cell w/antigen-binding regions facing out; all BCRs on one B cell recognize the same antigen

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15
Q

T cell receptors

A

antibody-like molecules displayed on surface of T cell

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16
Q

what can B cell antibodies recognize?

A

any organic molecule

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17
Q

what can T cell receptors recognize?

A

protein antigens (mostly inside cells)

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18
Q

what is one major difference between B cell receptors and T cell receptors?

A

a B cell can export (secrete) its receptors in the form of antibodies, but a T cell’s receptors remain tightly glued to its surface

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19
Q

how do B cells recognize antigens?

A

by themselves

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20
Q

how do T cells recognize antigens?

A

must be presented by APCs

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21
Q

4 types of T cells

A

cytotoxic
helper
regulatory
memory

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22
Q

Killer T cells

A

destroy virus-infected cells – trigger apoptosis

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23
Q

Helper T cells (Th)

A

cytokine factories that stimulate other immune cells (including B cells)

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24
Q

Regulatory T cells

A

help keep the immune system from overreacting

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25
Q

MHC proteins

A

used by APCs to present antigens to T cells; also involved in compatibility of transplanted organs

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26
Q

Class I MHC function

A

function as “billboards” that inform killer T cells (CD8+) about what is going on inside the cells they are sitting on

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27
Q

Class II MHC function

A

expressed only by certain cells (APCs like macrophages); function as “billboards” that alert helper T cells (CD4) that something is going on outside the cell that needs attention (i.e. presents fragments of something the macrophage ate)

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28
Q

Class II MHC structure

A

two long chains (α and β); contains peptide binding region and invariant portion (β2) that binds CD4; open ends so can hold longer peptide

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29
Q

Class I MHC structure

A

one long chain (heavy chain) plus a short chain (β2-microglobulin); contains peptide binding region and invariant portion (α3) that binds CD8; closed ends so can only hold shorter peptides

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30
Q

Class I MHC protein holding

A

holds protein fragments that must be just the right size to fit (~9 AAs) b/c ends are closed (i.e. hotdog exactly the same length as bun)

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31
Q

Class II MHC protein holding

A

holds protein fragments that can be longer (~20 AAs) b/c the ends are open (i.e. hotdog longer than bun)

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32
Q

most important physiologic function of the immune system?

A

prevent infections and eradicate established infections

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33
Q

lymphocyte activation

A

requires 2 signals:

  1. antigen recognition (on APC for T cells)
  2. 2nd nonspecific signal (from costimulators, cytokines, or complement system)
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34
Q

why 2 signals required for lymphocyte activation?

A

helps prevent autoimmune responses

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35
Q

secondary/peripheral lymphoid organs

A

responsible for initiating adaptive immune response; organized in a manner that optimizes interactions btwn lymphocytes and antigens; includes lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues

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36
Q

lymph node function in antigen recognition

A

“dating bars” – places where T cells, B cells, APCs, and antigens all gather for communication and activation; increases probability that all these molecules will interact to efficiently activate the adaptive immune system

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37
Q

memory cells

A

B and T cells that were activated in response to a particular antigen and that don’t die off after infection is eradicated – allow faster response to future infection by same microbe

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38
Q

innate immune system characteristics

A

fast
always ready
tuned to recognize common pathogens

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39
Q

adaptive immune system characteristics

A

slow
highly specific
highly diverse

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40
Q

innate immune system components

A 
epithelial barriers
phagocytes
dendritic cells
complement
NK cells
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41
Q

adaptive immune system components

A

lymphocytes (B & T cells)
antibodies
effector T cells

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42
Q

TLRs

A

toll-like receptors; recognize endotoxins, viral RNA; activate inflammatory, antiviral genes, adaptive immunity (NF-kB, IRFs)

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43
Q

TLR1

A

surface; bacterial lipoproteins

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44
Q

TLR2

A

surface; bacterial lipoproteins

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45
Q

TLR3

A

endosome; viral NAs

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46
Q

TLR4

A

surface; bacterial LPS

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47
Q

TLR5

A

surface; bacterial flagellin

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48
Q

TLR6

A

surface; bacterial lipoproteins

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49
Q

TLR7

A

endosome; viral NAs

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50
Q

TLR8

A

endosome; viral NAs

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51
Q

TLR9

A

endosome; bacterial CpG DNA

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52
Q

NF-kB

A

stimulated by TLRs and NOD2; increases cytokines, adhesion, costimulators; mediates acute inflammation and adaptive immunity

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53
Q

IRFs

A

Interferon Regulatory Factors; stimulated by TLRs; increase Type I IFN (α/β) production; antiviral defense

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54
Q

Type I IFNs ( (α/β)

A

produced by macrophages (α), dendritic cells (α), fibroblasts (β); activated by TLRs; activate NK cells; antiviral functions

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55
Q

defensins

A

natural antibiotics; part of epithelial barrier

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56
Q

cathelicidings

A

natural antibiotics; part of epithelial barrier

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57
Q

γδ T cells

A

present in large #s at birth and help out until αβ T cells produced; hybrid B-T cell (TCR looks more like antibody); more flexible and recognize more presentation molecules than MHC; target microbial lipids; part of epithelial barrier

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58
Q

eosinophils

A

granulocytes that produce histamine and proteolytic enzymes

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59
Q

mast cells

A

granulocytes that mediate allergic rxns, parasite defense; activated by TLRs or antibody-dependent mechanisms

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60
Q

TLR downstream signaling mutations

A

can lead to bacterial pneumonia

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61
Q

NLRP3

A

NLR that activates inflammasome → IL-1β → inflammation/fever

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62
Q

NOD2

A

NLR that activates NF-kB (NOT inflammasome)

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63
Q

NLR-related diseases

A

autoinflammatory diseases; gout; atherosclerosis; obesity-associated type II diabetes

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64
Q

neutrophils

A

most abundant leukocyte; dominate during inflammation; short half-life (6-8hrs); also called PMNs; ingest & destroy microbes

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65
Q

monocytes

A

differentiate into macrophages when enter extravascular tissue

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66
Q

macrophages

A

resident in all body tissues; longer half-life; initiate & regulate inflammation & adaptive immunity; ingest & destroy microbes; clear dead tissue; initiate tissue repair

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67
Q

M1 macrophage

A

Classically Activated; stimulated by IFN-γ and TLRs; induces microbicidal activity and inflammation

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68
Q

M2 macrophage

A

Alternatively Activated; stimulated by IL-3 and IL-4; induces anti-inflammatory and wound repair functions

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69
Q

IFN-γ

A

produced by NK cells, T-cells; activates M1 macrophages; promotes inflammation

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70
Q

Produced by M1 macrophage to stimulate inflammation

A

IL-1
IL-12
IL-23
chemokines

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71
Q

Produced by M1 macrophage to stimulate microbicidal actions

A

ROS
NO
lysosomal enzymes

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72
Q

Produced by M2 macrophage to stimulate anti-inflammatory effects

A

IL-10

TGF-β

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73
Q

Produced by M2 macrophage to stimulate wound repair

A

TGF-β

proline pyramidines

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74
Q

NK Cells

A 
recognize & kill infected cells
secrete IFN-γ to stimulate M1 macrophages
contain cytoplasmic granules
do NOT express Ig's
express unique surface proteins
have activating and inhibitory receptors
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75
Q

NK Cell activating receptors

A

NKG2D (ligand: Class I MHC-like proteins)

CD16 (ligand: IgG)

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76
Q

NK Cell inhibitory receptors

A

Killer Cell Immunoglobulin-like Receptors (KIRs)
Receptors w/Protein CD94 + Lectin Subunit NKG2
(ligand for all: Self Class I MHC)

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77
Q

Macrophage-NK Cell interactions

A

Macrophages secrete cytokines that activate NK cells (IL-12, IL-15, Type I IFNs); some NK actions then improve macrophage effectiveness (IFN-γ release)

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78
Q

Factors that promote inflammation

A 
C3a
C5a
Chemokines
Inflammasome
IFN-γ 		
IL-1(β)
IL-12 		
IL-23		 
NF-kB
NLRP3
TLRs
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79
Q

Anti-inflammatory factors

A 
IL-3 	
IL-4
IL-10
TGF-β
Proline polyamines
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80
Q

Signal Phagocytosis

A 
C3b 
CRPs
IgG
Mannose-binding Lectin
Class I MHC-like proteins
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81
Q

C3a

A

complement protein that signals inflammation

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82
Q

C5a

A

complement protein that signals inflammation

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83
Q

C3b

A

complement protein that opsonizes

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84
Q

NK T-cells

A

located in epithelia & lymphoid organs; recognize CD1-bound microbial lipids

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85
Q

B-1 Cells

A

located in peritoneal cavity & mucosa; produce IgM; recognize bacterial cell wall carbs; produce antibodies against non-host blood types

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86
Q

Produce antibodies against non-host blood types

A

B-1 cells

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87
Q

marginal zone B-cells

A

located in edges of lymph follicles in spleen & elsewhere; recognize blood-borne polysaccharide-rich microbes

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88
Q

C-Reactive Protein (CRP)

A

binds microbial phosphorylcholine; targets for phagocytosis; marker for chronic inflammation in adults and acute inflammation in peds

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89
Q

TNF

A

secreted by macrophages & T cells; stimulates inflammation (neutrophil/monocyte recruitment); increased concentration can lead to septic shock

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90
Q

IL-1

A

secreted by macrophages, endothelial cells, some epithelial cells; stimulates inflammation (neutrophil/monocyte recruitment)

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91
Q

chemokines

A

secreted by macrophages, dendritic cells, endothelial cells, T-cells, fibroblasts, platelets; stimulate inflammation

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92
Q

IL-12

A

secreted by macrophages, dendritic cells; activates NK cells; stimulates CD4+ differentiation into Th1

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93
Q

Steps of inflammatory response

A
  1. recruitment and leakage of cells & plasma proteins into extravascular tissue
  2. phagocytosis of microbes
  3. destruction of harmful substances
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94
Q

inflammation defends against

A

extracellular bacteria & fungi; intracellular bacteria

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95
Q

innate immunity primary functions

A

inflammation; antiviral activity

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96
Q

Inflammation - extracellular stimulus

A

recruit neutrophils, monocytes, complement; E & P selectins mediate initial weak adhesion; integrin activation allows firm adhesion; chemokines & chemoattractants allow transmigration into tissue

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97
Q

Inflammation - intracellular stimulus

A

recruit macrophages through cytokines, TLRs, other receptors

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98
Q

Leukocyte Adhesion Deficiency (LAD)

A

inherited; problems with selectin and integrin prevent recruitment of leukocytes

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99
Q

5 pillars of inflammation

A

heat, redness, swelling, pain, loss of function

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100
Q

phagocytosis pathway

A

ingest microbe → phagosome fuses w/lysosome → enzyme activation

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101
Q

phagocytic enzymes

A

Phagocyte Oxidase
Inducible Nitric Oxide Synthase (iNOS)
Lysosomal Proteases

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102
Q

Phagocyte Oxidase

A

phagocytic enzyme; converts O2 → ROS (toxic)

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103
Q

iNOS

A

phagocytic enzyme; converts Arg → NO (microbicidal)

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104
Q

Lysosomal Proteases

A

phagocytic enzyme; degrade proteins

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105
Q

Chronic Granulomatous Disease (CGD)

A

deficiency in phagocyte oxidase → can’t destroy intracellular microbes → recruit more macrophages/lymphocytes → granulomas form

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106
Q

Neutrophil Extracellular Traps (NETs)

A

neutrophils commit suicide → extrude nuclear contents → histone networks trap microbes
*granular contents (ROS/NO) also released → can damage tissue

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107
Q

Innate Immunity Regulatory Mechanisms

A

IL-10
Il-1 Antagonists
Feedback Mechanisms

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108
Q

IL-10

A

anti-inflammatory cytokine produced by macrophages & dendritic cells; inhibits M1 activation; induces CD4 T-cells to become Regulatory T-cells (FoxP3+), which then inhibit T-cell responses

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109
Q

IL-1 Antagonists

A

block IL-1 → block inflammation

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110
Q

innate feedback mechanisms

A

inhibit cytokine signaling

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111
Q

innate stimulation of adaptive immunity

A

2 signals: one from microbe; second from molecule produced by innate system (costimulant, cytokine, complement) in response to microbes

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112
Q

IL-1, IL-6, IL-12

A

stimulate immature T-cells → effectors

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113
Q

C3d

A

made from C3b; B-cells bind microbe + C3d → differentiate into antibody-secreting cells

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114
Q

innate immunity

A

fast, always present, less specific, first responder

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115
Q

adaptive immunity

A 
slow 
huge diversity/specificity
can evolve
memory
clonal expansion
nonreactivity to self
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116
Q

humoral immunity

A

mediated by antibodies; extracellular; blocks infections and eliminates extracellular microbes

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117
Q

cell-mediated immunity

A

mediated by T cells; intracellular

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118
Q

APCs

A

present antigens to T-cells

include dendritic cells, macrophages, B-cells

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119
Q

mucosal linings

A

constant interactions btwn innate & adaptive systems; lymphocytes in epithelium, lamina propria, MALT

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120
Q

Peyer’s Patches

A

type of MALT/GALT; located in lamina propria; contain follicles for B-cell maturation and areas for T cells to be exposed to antigens

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121
Q

what happens if an antigen is encountered at one mucosal site?

A

you gain immunity at all other mucosal sites!

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122
Q

where do villi and Peyer’s Patches drain?

A

lymphatic networks → mesenteric nodes

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123
Q

goblet cells

A

secrete mucin glycoproteins that increase thickness of mucosal layer → protective barrier that reduces bacterial adhesion to epithelium

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124
Q

Paneth (Crypt) Cells

A

sense microbes using TLRs 2, 4, 5, and 9 → secrete antimicrobial proteins & immunosuppressants into intestinal lumen that reduce bacterial adhesion to epithelium and prevent inflammatory response; regulated by NK T cells

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125
Q

M cells

A

primary fcn: antigen uptake; located above Peyer’s Patches; have folded luminal surface and NO glycocalyx, which provides route for antigens to access lymph follicle underneath

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126
Q

which cells can pathogens use to access circulation?

A

M cells

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127
Q

commensal organisms

A

bacteria in gut that have symbiotic relationship with body; play a role in regulating intestinal epithelial cell function; provide various protections; 10x more of these than any other cell in body

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128
Q

benefits of commensal bacteria

A

occupy space to prevent pathogenic bacterial colonization
synthesize vit B12 and K
aid in calorie extraction
regulate composition of antimicrobial peptides secreted by Paneth cells

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129
Q

how is elimination of good bacteria from intestines prevented?

A
  1. intestinal epithelial cells (IECs) express low levels of TLR4/MD2 → suppressed response to LPS (bacterial endotoxin)
  2. IECs express low levels of TLR2 → normally responds to mRNA & proteins
  3. IECs express high amt of TOLLIP inhibitory protein → poor response to Gram (+) and mycobacterial ligands.
  4. commensals dampen inflammatory response (inhibit NF-kB)
  5. polarized IECs allow differential responses
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130
Q

IEC recognition of bacteria

A
  1. TLR & NOD1/NOD2 activation → cytokine/chemokine release
    2 . Recruitment of neutrophils, macrophages, DCs
  2. Commensal intervention → PPARγ activated, IkB degradation prevented
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131
Q

M cell - dendritic cell interaction

A

IECs secrete CCL9 & CCL20 to recruit DCs (CCR6/CCR1+) → DCs process antigens from M cells → DCs present antigens to T cells in Peyer’s Patches and mesenteric lymph nodes

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132
Q

CCL9

A

secreted by IECs to recruit DCs to intestine

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133
Q

CCL20

A

secreted by IECs to recruit DCs to intestine

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134
Q

IEC activity in presence of commensal bacteria

A

produce TGF-β and prostaglandins (PGE2)→ maintain anti-inflammatory state w/i DCs → DCs travel to lymph nodes, secrete IL-10 and Retinoic Acid, which inhibit inflammatory response (activate reg T-cells)

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135
Q

what happens if pathogenic bacteria make it through the mucosal epithelium?

A

activated DC travels to mesenteric lymph node and stimulates CD4 T-cells → differentiate into Th1, Th2 and Th17

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136
Q

how could DCs “sample” intestinal contents w/o destroying barrier?

A
  1. nonspecific transport across epithelium
  2. FcRn-dependent transport
  3. apoptosis-dependent transport
  4. antigen capture (reach across lumen)
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137
Q

Salmonella infection

A

enters & kills M cell → infects neighboring epithelial cells & macrophages → macrophages secrete chemokines/cytokines to attract neutrophils & DCs → if this fails to destroy it, salmonella enters bloodstream and infection becomes systemic

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138
Q

lymphocyte locations in villi

A
  1. epithelium - CD8
  2. lamina propria - CD4
    * important b/c allows body to respond immediately to any penetration of mucosa
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139
Q

integrin

A

cell-cell adhesion

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140
Q

CCR9

A

chemokine receptor used to attract lymphocytes from the bloodstream to the intestine

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141
Q

T-cell affinity for area

A

T-cell can express different receptors and adhesion molecules to increase the likelihood that it is in an area at any given time

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142
Q

L-selectin

A

expressed by naive T-cells; directs them to undergo extravasation from HEVs to Peyer’s Patches, where DCs present antigens to them

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143
Q

CCR7 in mucosa

A

expressed by naive T-cells; directs them to undergo extravasation from HEVs to Peyer’s Patches, where DCs present antigens to them

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144
Q

Priming

A

DCs present antigens to naive T-cells in T-cell regions of Peyer’s Patches → T-cells activate, stop expressing L-selectin and begin expressing

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145
Q

unprimed (naive) T-cell expression

A

L-selectin, CCR7

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146
Q

regional dendritic cells

A

imprint homing on lymphocytes

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147
Q

IgA

A

associated w/mucosa; produced locally by plasma cells in lamina propria; about 5g secreted per day (more than all other Ig classes combined); Poor at C’ activation; Poor at opsonization

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148
Q

IgA1

A

monomer found mainly in blood; binds peptides

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149
Q

IgA2

A

dimer linked by J-chain; binds LPS and carbs

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150
Q

IgA binding

A
  1. binds plgR on basal epithelial membrane → endocytosis/secretion into gut lumen
  2. binds pathogenic & commensal bacteria in gut lumen to prevent adherence to epithelium
    * does NOT activate classical complement pathway
    * does NOT act as opsonin (no induction of inflammation)
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151
Q

Selective IgA Deficiency (SlgAD)

A

occurs in 1:50 celiac disease patients; IgM compensates

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152
Q

Intraepithelial Lymphocytes (IELs)

A

found in mucosa

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153
Q

IEL activation

A

stress activates via MIC-A/B and IL-15

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154
Q

TGF-β

A

anti-inflammatory cytokine; secreted by M2 macrophages and IECs

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155
Q

PGE2

A

anti-inflammatory cytokine (prostaglandin); secreted by IECs

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156
Q

regulation of tolerance and immunity in mucosa

A

GALT DCs

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157
Q

mesenteric lymph nodes

A

commensal-loaded DCs do not penetrate beyond here → prevents unwanted inflammatory response- oral tolerance induced exclusively here

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158
Q

oral tolerance

A

induced exclusively in mesenteric lymph nodes; mice fed ovalbumin had a lower systemic immune response when exposed to it again later

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159
Q

CDR diversity in B cells dramatically increased by?

A

somatic hypermutation

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160
Q

Ig function depends on…

A

C segments, TCR/MHC contact (cell-to-cell)

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161
Q

what dictates isotype switch?

A

cytokine environment

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162
Q

immunity

A

resistance to disease

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163
Q

immune response

A

the coordinated reaction of immune system cells and molecules to microbes

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164
Q

functions of immune system

A

defense against wide variety of pathogens
waste management
wound healing
tumor defense
inflammatory diseases (allergies, autoimmune disorders)

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165
Q

what can impair immune function (particularly for med students?)

A

stress & lack of sleep

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166
Q

3 components of immune system

A

epithelial barrier
innate system
adaptive system

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167
Q

immunological triad

A

interactions btwn epithelial barriers, innate system, and adaptive system

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168
Q

epithelial barriers

A

first line of defense; block microbe entry; produce natural antibiotics; contain intraepithelial lymphocytes

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169
Q

innate immunity

A

defense mechanism that is always present in all organisms, ready & primed to eliminate microbes and dead cells immediately upon infection; usually responds the same way to each repeat encounter with a microbe; enhances adaptive immune response

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170
Q

adaptive immunity

A

the defense mechanism that requires expansion and differentiation of lymphocytes in response to microbes before it can provide effective defense

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171
Q

lymphocytes

A

B & T cells; originate from a common precursor in bone marrow; naïve lymphocytes will differentiate into effector cells and memory cells

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172
Q

B lymphocytes

A

can differentiate into plasma cells, which secrete antibodies

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173
Q

T lymphocytes

A

an differentiate into helper T cells, cytotoxic T cells, memory T cells, and regulatory T cells

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174
Q

phases of adaptive immune response

A

challenge, recognition, response, and outcome

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175
Q

what most effectively eliminates free extracellular antigens?

A

B lymphocytes

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176
Q

what most effectively eliminates phagocytosed extracellular antigens?

A

helper T lymphocytes

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177
Q

what most effectively eliminates intracellular microbes?

A

cytotoxic T lymphocytes

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178
Q

generative/central lymphoid organs

A

where T and B lymphocytes are produced and mature; bone marrow & thymus

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179
Q

B cell zone in lymph node

A

follicles within the cortex

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180
Q

T cell zone in lymph node

A

paracortex

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181
Q

CXCR5

A

directs B cell attraction to follicles in lymph node cortex by binding chemokines there

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182
Q

CCR7 in lymph node

A

directs T cell attraction to paracortex in lymph nodes by binding chemoattractants there

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183
Q

Dendritic cells

A

activated by phagocytosis of microbes; respond by producing cytokines that initiate inflammation and stimulate adaptive immunity; also can travel to lymph node, where interact w/other cells of adaptive immune system, causing them to differentiate into effectors

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184
Q

how are lymphocytes distinguishable?

A

by surface proteins (CD #) that can be ID’d using a panel of monoclonal antibodies

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185
Q

CD nomenclature

A

Cluster Differentiation numerical designation; assigned to surface proteins that can be used to differentiate lymphocytes

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186
Q

CD3

A

surface protein expressed by ALL T lymphocytes

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187
Q

CD4

A

surface protein expressed by helper T lymphocytes

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188
Q

CD8

A

surface protein expressed by cytotoxic T lymphocytes

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189
Q

Cytokines

A

a class of small molecules that promote cell signaling and cell communication; include chemokines, interleukins, tumor necrosis factor, interferons, and other molecules

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190
Q

Interleukins

A

molecules that induce growth and differentiation; named using the designation IL followed by a number (IL-#)

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191
Q

Chemokines

A

small molecules that function as chemoattractants – guide migration of other cells; nomenclature is CC or CXC followed by L or R and then # ex: CCL25 or CXCR5.
(L=ligand; R=receptor)

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192
Q

2 ways the innate system recognizes common structures on foreigners and damaged cells via receptors

A

PAMPs and DAMPs

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193
Q

PAMP

A

Pathogen-Associated Molecular Pattern; innate system uses these to recognize structures shared by different microbes (lipopolysaccharides, mannose residues); encoded in germline

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194
Q

DAMP

A

Damage-Associated Molecular Patterns; innate system uses these to recognize molecules released from damaged or necrotic cells; encoded in germline

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195
Q

where/how are innate system receptors encoded?

A

germline

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196
Q

where/how are antibodies encoded?

A

somatic gene recombination

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197
Q

4 families of innate receptors

A

TLRs
NLRs
CLRs
RLRs

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198
Q

NLRs

A

NOD-like receptors; cytosolic receptors that respond to various stimuli (Bacterial products, Crystals, K+ efflux & ROS); form inflammasome → IL-1β → inflammation/fever

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199
Q

CLRs

A

C-Type Lectin Receptors; extracellular

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200
Q

RLRs

A

RIG-like receptors; cytosolic

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201
Q

5 types of cells that express innate system receptors

A 
Phagocytes
Dendritic Cells
Lymphocytes
Epithelial cells
Endothelial cells
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202
Q

TLR recognition

A

Surface: extracellular microbes - bacteria - lipopeptides, LPS, flagellin
Endosomal: ingested microbes - viruses - DNA sequences

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203
Q

TLRs that recognize bacterial lipopeptides

A

TLR1
TLR2
TLR6

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204
Q

TLRs that recognize bacterial LPS

A

TLR4

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205
Q

TLRs that recognize bacterial flagellin

A

TLR5

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206
Q

TLRs that recognize viral RNA

A

TLR3
TLR7
TLR8

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207
Q

TLRs that recognize bacterial CpG DNA

A

TLR9

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208
Q

Transcription factors that can be activated by TLRs

A

NF-kB –> cytokine, adhesion, costimulator molecule expression
IRFs –> Type I IFN production

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209
Q

2 mechanisms for epithelial barrier protection

A

natural antibiotics

intraepithelial lymphocytes

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210
Q

natural antibiotics produced by epithelial barriers

A

defensins and cathelicidings

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211
Q

intraepithelial lymphocytes

A

γδ T cells

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212
Q

most abundant leukocyte in blood?

A

neutrophils

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213
Q

GM-CSF

A

granulocyte/macrophage colony stimulating factor; stimulates neutrophil production in bone marrow

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214
Q

KIRs

A

receptors that recognize inhibitory signals (Self Class I MHC) for NK cells

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215
Q

Self Class I MHC

A

inhibitory ligand for NK cells

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216
Q

NKG2D

A

receptor that recognizes activating signals (Class I MHC-like proteins) for NK cells

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217
Q

CD16

A

receptor that recognizes activating signals (IgG) for NK cells

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218
Q

if a cell expresses Self MHC I complex, will NK cells be activated?

A

No. This is an inhibitory signal for NK cells.

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219
Q

what two things are required for NK cell activation?

A

lack of inhibitory signal (Self Class I MHC)

presence of activating ligand

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220
Q

what does an NK cell do when activated?

A

empties contents of cytoplasmic granules extracellulary; granules enter cell and activate apoptotic proteins

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221
Q

IL-15

A

stimulates NK cell development & maturation

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222
Q

complement system

A

group of serum proteins that acts as an enzymatic cascade

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223
Q

3 main complement system functions

A
  1. opsonize microbes w/C3b and CR1
  2. recruit neutrophils for inflammation w/C3a and C5a
  3. lyse microbes via MACs
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224
Q

MACs

A

membrane attack complexes; made up of complement proteins that lyse microbes

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225
Q

Lymphocytes w/somatically rearranged antigen receptors

A

γδ T cells
NK T cells
B-1 cells
Marginal zone B cells

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226
Q

antiviral defense

A

mediated by Type I IFNs and NK cells

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227
Q

what can serve as signal 2 for adaptive system activation?

A
  1. costimulator (from dendritic cells): binds & activates T cells
  2. cytokines IL-1, IL-6, IL 12 (from dendritic cells, macrophages): T cell differentiates into effector
  3. complement protein C3d: B cell differentiates into antibody-secreting cells
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228
Q

alpha4:beta7

A

integrin on CD4 T cells that binds to MadCam in the lamina propria; secretes CCR9, which binds to CCL25

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229
Q

alphaE:beta7

A

integrin on CD8 T cells that binds to E-Cadherin on enterocytes; secretes CCR9, which binds to CCL25

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230
Q

unprimed T cells

A

express L-selectin and CCR7

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231
Q

primed T cells

A

express

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232
Q

what causes heat and redness in inflammation?

A

leaky vessels

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233
Q

intestinal epithelial cells express low levels of what to suppress immune response and keep commensal bacteria?

A

TLR2 and TLR4

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234
Q

what regulates paneth cells?

A

NK T cells

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235
Q

3 types of APCs

A

dendritic cells
macrophages
B cells

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236
Q

cell-mediated immunity - CD4

A

phagocytosed microbes activate and bind CD4 T cell, which works to eliminate the microbes

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237
Q

cell-mediated immunity - CD8

A

intracellular microbes (viruses) activate CD8 T cell, which binds and destroys infected cell

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238
Q

What are the origins of the antigens that are presented by MHC Class I molecules?

A

cytosol

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239
Q

most effective APC?

A

dendritic cells

240
Q

what happens after recognition of antigen-peptide by APC?

A

antigen must be processed to a peptide and presented to receptors on lymphocytes that detect that specific antigen-peptide

241
Q

2 things a dendritic cell can do

A
  1. present antigens to naive T cells

2. express costimulators to fully activate T cells

242
Q

2 types of dendritic cells

A

Conventional DCs

Plasmacytoid DCs

243
Q

Conventional DCs

A

induce T cell responses against most pathogens

244
Q

Plasmacytoid DCs

A

antiviral innate immunity and induce T cell responses against viruses

245
Q

site of antigen presentation to T cells?

A

lymph node and spleen

246
Q

APC migration to lymph nodes once activated stimulated by

A

CCR7 expression in lymph tissues

247
Q

APC maturation

A

occurs once the APCs reach the T-cell rich regions of the lymph node (or spleen).

248
Q

TCRs

A

T cell receptors; recognize specific antigen-peptide presented by APC with MHC; this interaction directs the immune response

249
Q

what interaction directs the immune response to a pathogen presented by APC?

A

MHC-TCR interaction

250
Q

MHC-TCR interface

A

regions on the antigen-peptide bind to each molecule here: peptide anchor residue binds to MHC; T cell contact residue of peptide causes specificity of antigen and binds TCR

251
Q

Cross Presentation

A

the presentation of extracellular antigens using the intracellular pathway

252
Q

human leukocyte antigen (HLA) genes

A

code for MHCs; locus and subunits determine differences btwn Class I and Class II

253
Q

Co-dominant expression of MHC molecules

A

both parental alleles of each MHC genes are expressed; allows for diversity among MHC molecules in an individual

254
Q

Polymorphic genes of MHC molecules

A

provide diversity of MHC genes among the population

255
Q

importance of many cell types expressing MHCs?

A

helping ensure a body-wide immune response.

256
Q

MHC restriction

A

T lymphocyte clones can ONLY recognize peptides when they are displayed on the MHC molecules

257
Q

Class I MHC Pathway

A
  1. internal antigen (i.e. virus) ubiquitinated & degraded to peptide
  2. peptide transported into ER by TAP and cleaved further
  3. newly synthesized MHC I attached to TAP by tapasin
  4. MHC I binds peptide and β2m
  5. MHC I–peptide complex transported to cell surface for presentation to CD8+ T cells
258
Q

TAP

A

transporter associated with antigen processing protein; transports intracellular antigens into ER and cleaves them in MHC I pathway

259
Q

tapasin

A

attaches newly synthesized MHC I to TAP

260
Q

Class II MHC Pathway

A
  1. extracellular antigen ingested into endocytic vesicular compartments of cell
  2. peptide processed in endosomal/lysosomal vesicles
  3. MHC II synthesized and transported to endosome containing peptide
    3a. MHC II binding site occupied by CLIP during synthesis for stabilization
    3b. CLIP removed in endosome, facilitated by HLA-DM
  4. HLA-DM helps load peptide into MHC II binding site
  5. MHC II–peptide complex transported to cell surface for presentation to CD4+ T cells
261
Q

CLIP

A

class II invariant chain peptide; occupies MHC II binding site during MHC II synthesis to stabilize the molecule

262
Q

HLA-DM

A

removes CLIP from MHC II binding site in endosome and helps load peptide in

263
Q

Differences btwn MHC I and MHC II pathways

A

MHC I: intracellular; ER; TAP and tapasin

MHC II: extracellular; endosome; CLIP and HLA-DM

264
Q

Cross-Presentation Pathway

A
  1. dendritic cell recognizes virus-infected cell
  2. APC ingests and processes infected CELL (not just antigen)
  3. APC presents peptides to CD8+ T cell using MHC I molecules
265
Q

genes that code for Class I MHC

A

HLA-A, HLA-B, HLA-C

266
Q

genes that code for Class II MHC

A

HLA-DR, HLA-DP, HLA-DQ

267
Q

how many peptides can MHC present at once?

A

MHC can bind many different peptides, but it is limited to presenting only ONE peptide at a given time

268
Q

what property of MHCs ensures body-wide immune response?

A

many different cells can express MHCs

269
Q

what property of MHCs ensures diversity within a population?

A

polymorphic genes - many alleles exist in the population

270
Q

what property of MHCs ensures diversity within an individual?

A

co-dominant expression - both parental alleles expressed

271
Q

how does peptide binding to MHC increase the chances for an immune response?

A
  1. many different peptides can bind to an MHC
  2. each T cell responds to a single MHC-peptide complex
  3. MHC-restricted T cells respond only to protein antigens
  4. Class I & II MHC display antigens from different cell compartments
  5. stable surface expression of MHC requires bound peptide
  6. MHC displays bound peptide long enough for T cell to recognize
272
Q

which cells express Class I MHC?

A

all nucleated cells

273
Q

which cells express Class II MHC?

A 
APCs!
dendritic cells
mononuclear phagocytes
B cells
endothelial cells
thymic epithelium
274
Q

β2m

A

β2 microglobulin; helps stabilize MHC I–peptide complex

275
Q

segregation of antigen-processing pathways

A

ensures that different classes of T lymphocytes recognize antigens from different compartments

276
Q

what accounts for the immunodominance of some peptides derived from complex protein antigens?

A

structural constraints on peptide binding to different MHC molecules

277
Q

immunodominant peptides of antigen

A

When any protein is proteolytically degraded in APCs, many peptides may be generated, but only those able to bind to the MHC molecules can be presented for recognition by T cells – these are the immunodominant peptides

278
Q

what accounts for the inability of some individuals to respond to certain protein antigens?

A

some individuals may not express MHC molecules capable of binding any peptide derived from a particular antigen; these individuals would be nonresponders to that antigen

279
Q

Bare Lymphocyte Syndrome

A

MHC molecules may not form stably due to mutations in Ii or TAP

280
Q

how do B cells recognize native antigens?

A

using antibodies

281
Q

what types of antigens do antibodies recognize?

A

specific peptides, polysaccharides, lipids and other small chemicals.

282
Q

how are antigens presented to B cells?

A

Follicular Dendritic Cells or complement system

283
Q

which TCR chains participate in specific recognition of MHC molecules and bound peptides?

A

Both the α chain and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides

284
Q

What types of epitopes does TCR hold?

A

linear

285
Q

which part of the TCR mediates antigen recognition?

A

variable (V) regions of the α and β chains

286
Q

what mediates the signaling function of the TCR?

A

proteins in a complex associated with the TCR found in the cell membrane: CD3 and ζ

287
Q

general pathway of TCR response to antigen

A

The TCR simply recognizes that an antigen is present and, through a signaling cascade, T cell response to the infection is mediated through other proteins.

288
Q

TCR structure

A

has α chain and β chain w/2 domains on each chain: constant (C) region and variable (V; antigen-binding) region
also has CD3 complex and ζ chain needed for signal transduction

289
Q

variable/antigen-binding region of TCR

A

α chain and β chain each contain 3 CDRs (complementarity determining regions); V regions constructed from unique splicing of several genetic elements to make large diversity of TCRs

290
Q

constant region of TCR

A

does not change between TCRs; involved in anchoring the receptor to the membrane.

291
Q

dual specificity

A

TCR must bind both the MHC and peptide in order to get a stable interaction between the T cell and the APC

292
Q

does the affinity of antigen binding for the TCR change during times of immune response as opposed to times of rest?

A

no

293
Q

what are the on and off rates for TCRs?

A

slow – meaning the TCR slowly binds to antigens displayed on MHCs and slowly dissociates

294
Q

General phases of B/T cell maturation and selection

A 
commitment
proliferation
Pre-B/T antigen receptor expression
more proliferation
antigen receptor expression
positive and negative selection
295
Q

C3bBb

A

C3 convertase enzyme generated in the alternative complement pathway and is responsible for splitting off the small peptide C3a, leaving C3b as a residue

296
Q

interferons

A

Induce enzyme synthesis in the target cell (protein kinase and endonuclease)

297
Q

Anaphylatoxins

A

fragments (C3a, C4a and C5a) produced as part of the activation of the complement system

298
Q

Acute inflammation can be initiated by?

A

Activation of mast cells, which release chemotactic factors for neutrophils and also vasoactive mediators such as histamine

299
Q

Tolerance

A

Immunological unresponsiveness to self antigens

300
Q

the basic Ig unit is composed of…

A

2 identical heavy and 2 identical light chains

301
Q

Fab fragment

A

fragment antigen binding – binds antigen

302
Q

The first immunoglobulin heavy chain class to be expressed on the surface of a newly produced B-cell

A

IgM, shortly followed by IgD

303
Q

where are T cell progenitors produced?

A

bone marrow

304
Q

where do T cell progenitors go from bone marrow?

A

enter thymus through HEVs, migrate to subcapsular region

305
Q

what happens when T cell progenitors reach the subcapsular region of the thymus?

A

begin maturation by rearranging their receptor genes to generate a unique TCR through VDJ joining

306
Q

what happens as T cell progenitors begin to express specific receptors?

A

they migrate further into the cortex

307
Q

what happens if the pro-B/T cell fails to express pre-antigen receptor?

A

death

308
Q

what happens if the pre-T cell fails to express 1 chain of antigen receptor?

A

death

309
Q

General progression of B/T cell development and maturation

A

common lymphoid progenitor –>
Pro-B/T cells that express pre-antigen receptor (failure to express = death) –>
Pre-B/T cells that express 1 chain of antigen receptor (failure to express = death) –>
Immature B/T cells that express complete antigen receptor –>
–strong antigen recognition –> negative selection
–weak antigen recognition –> positive selection –> mature B/T cells

310
Q

what happens if an immature B/T cell displays strong antigen recognition?

A

negative selection and death

311
Q

what happens if an immature B/T cell displays weak antigen recognition?

A

positive selection and transformation into mature B/T cell

312
Q

what receptor(s) does/do an immature T cell express?

A

CD4, CD8, unique αβ TCR

313
Q

what happens after pre-T cells express 1 chain of antigen receptor?

A

pass through thymic epithelial cells that have lots of MHC I & II molecules on surface; T cells that can weakly bind MHC I gets survival signal + maturation signal that causes loss of CD4; T cells that can weakly bind MHC II get survival signal + maturation signal that causes loss of CD8 (positive selection!)

314
Q

positive selection

A

thymocytes receive a “survival signal” to keep on living if they can appropriately bind MHC I or II

315
Q

what happens to thymocytes that don’t recognize MHC I or II?

A

no survival signal –> death

*a large percentage are lost at this stage!

316
Q

what happens to thymocytes that recognize MHC I or II too strongly?

A

death

317
Q

at what stages of development/maturation can T cells undergo apoptosis?

A

Pro-T cells in thymus don’t express complete β chain / pre-TCR complex
Pre-T cells in thymus don’t express complete α chain / complete TCR
Immature T cells in thymic cortex express strong antigen recognition
Thymocytes in thymic epithelial cells don’t recognize MHC I or II
Thymocytes in thymic epithelial cells recognize MHC I or II too strongly
Thymocytes near medulla bind too strongly to body antigens

318
Q

negative selection

A

thymocytes that don’t recognize MHC I or II or recognize MHC I or II too strongly die

319
Q

central tolerance

A

through negative selection, T cells learn not to attack self

320
Q

what happens after thymocytes recognize MHC I or II and begins to express exclusively CD4 or CD8?

A

continue moving toward thymic medulla, and medullary interdigitating cells present thymocytes with other antigens that belong to body

321
Q

what is the progression of T cell types through maturation?

A
  1. double-negative (CD4-, CD8-) pro-T cell that expresses complete β chain / pre-TCR complex
  2. pre-T cell that expresses complete α chain / pre-TCR
  3. double-positive (CD4+, CD8+) immature-T cell that expresses complete αβ TCR
  4. mature single-positive (CD4+ or CD8+) cell OR death
322
Q

what happens to a T cell near the medulla that reacts too strongly to body antigen?

A

death

323
Q

what percentage of the original thymocytes survive the maturation process?

A

1-4%

324
Q

what happens to mature CD4+ and CD8+ T cells?

A

leave the thymus through bloodstream or lymphatics; travel to secondary lymphatic organs; wait there until stimulated by antigen (APCs)

325
Q

what type of peptides are used for T cell positive and negative selection and why?

A

self-peptides
T cells need to be able to bind antigens well enough, but not so well that they will bind body cells and cause an autoimmune reaction

326
Q

how many times does negative selection take place?

A

twice:
MHC I or II recognition in thymic epithelial cells
T cell exposure to body antigens in thymic medulla

327
Q

interdigitating cells

A

bone marrow-derived cells, including medullary epithelial cells, dendritic cells, and
macrophages, that bring body antigens to developing T cells in the thymic medulla

328
Q

what happens to the peptides from the T cells that die during maturation?

A

used by cortical epithelial cells or interdigitating cells in the medulla to further educate surviving T cells

329
Q

why do T cells proliferate at various stages of maturation?

A

increases the chances that one of the copies will survive

330
Q

which type of selection (pos/neg) is stronger?

A

positive - must be stronger otherwise would end up with no T cells

331
Q

can T cells move backward in the development process?

A

No. After a T cell has progressed through a given stage, the enzyme that was required for that step is shut off, and it can only move in the direction the next enzyme wants it to go. (signaling dependent on APCs)

332
Q

Allelic exclusion

A

only one version of a T cell is kept after each stage of maturation (b/c enzymes are shut off after each step)

333
Q

one reason for sibling transplant incompatibility?

A

allelic exclusion

334
Q

what happens if you have no thymus?

A

can’t produce T cells

335
Q

what happens if you have a defect in an enzyme necessary for producing lymphocytes in circulation?

A

can’t produce T cells

336
Q

what happens if you transplant a thymus into an animal without a thymus, but with a normal ability to produce lymphocytes into circulation?

A

can produce T cells!

337
Q

what happens if you transplant bone marrow stem cells into an animal without lymphocytes but with a normal thymus?

A

can produce T cells!

338
Q

what happens when the thymus degenerates in adulthood?

A

we retain T cell function b/c those suckers live for a long time once they’ve made it through the gauntlet!

339
Q

alloreactivity

A

your T cells will respond to someone else’s T cells if they have a different set of MHC and TCRs than you – important for transplants

340
Q

VDJ Joining

A

method of alternative splicing that creates diversity in TCRs/BCRs; cell randomly selects one piece from V, D, and J regions and combines them to form unique TCR; imperfections in this process add to diversity

341
Q

combinatorial diversity

A

VDJ joining

342
Q

junctional diversity

A

2 ways:

  1. imprecise cutting of segments at D and J regions
  2. TdT enzyme randomly adds in additional nucleotides
343
Q

4 ways diversity is generated in TCR

A
  1. baseline variability in V segments
  2. combinatorial diversity (VDJ joining)
  3. junctional diversity (imprecise cutting, TdT additions)
  4. secondary combinatorial diversity (random assortment of heavy/light chains)
344
Q

secondary combinatorial diversity

A

random assortment of heavy/light chains in TCR assembly

345
Q

which method of generating TCR diversity leads to permanent changes?

A

VDJ joining - this is DNA splicing so diversity generated here becomes a permanent part of that clone

346
Q

Erk

A

protein involved in γδ T cell development

  • -strong Erk –> γδ TCR
  • -weak Erk –> αβ TCR
347
Q

what directs the development of secondary lymphoid tissues?

A

the TNF family – trimeric cytokine molecules that are very stable and can be manipulated by small alterations in specific regions

348
Q

in what gene region is the TNF family located?

A

in the middle of the MHC gene region (so if you alter the MHC, you also alter the TNF)

349
Q

what is the result of the large variation within the TNF family?

A

TNF family members can cross-react with each other

350
Q

how does immunodeficiency relate to vaccination?

A

people with these conditions cannot be given normal vaccines – they will die

351
Q

what stimulates pro-T cell (double negative) proliferation?

A

IL-7 from thymus

352
Q

what must happen for a pro-T cell to become a pre-T cell?

A

a complete TCR β chain must be produced and expressed on the surface in association with invariant protein pre-Tα to form the pre-TCR complex

353
Q

pre-TCR complex

A

a complete TCR β chain + invariant protein pre-Tα expressed on surface of developing T cell; allows pro-T cell to become pre-T cell

354
Q

Different clones of double-positive T cells express what?

A

different αβ TCRs

355
Q

cytotoxic T cells

A 
express CD8
respond to MHC I
respond to cytosolic antigens
cell-mediated immunity
secrete cytotoxins that induce apoptosis in infected cells
356
Q

helper T cells

A 
express CD4
respond to MHC II
respond to endosomal antigens
cell-mediated immunity
secrete cytokines that induce activation of specific immune responses
357
Q

αβ T cells

A

pretty much all T cells!

358
Q

CDRs (T cells)

A

complementarity-determining regions; hypervariable; produced by VDJ recombination; located on α and β chains; bind antigen and MHC to provide signal 1 for T cell activation

359
Q

B7 proteins

A

expressed on APCs; upregulated by microbes; binds to CD28 on T cell to provide signal 2 for T cell activation (costimulators)

360
Q

General steps of initial T cell activation

A
  1. T cell αβ TCR binds APC MHC/antigen peptide (signal 1)
    1a. T cell CD4/CD8 binds APC MHC I/II (right class)
  2. T cell CD28 binds APC B7 (signal 2)
  3. T cell LFA-1 binds APC ICAM-1 for adhesion
  4. T cell CD3 proteins (γ, δ, ε) and zeta chain (ζ) mediate intracellular signaling and allow ZAP70 docking
    4a. T cell CD45 mediates intracellular signaling and phosphatase
  5. T cell CTLA-4 can bind B7 to INHIBIT immune response
361
Q

CD28

A

expressed on T cells; binds to B7 on APCs to provide signal 2 for T cell activation

362
Q

CD3

A

T cell proteins (γ, δ, ε) that contain cytosolic domains that can be phosphorylated and mediate intracellular signaling by serving as docking stations (ZAP70)

363
Q

ζ chains

A

T cell proteins that contain cytosolic domains that can be phosphorylated and mediate intracellular signaling by serving as docking stations (ZAP70)

364
Q

T cell proteins that mediate intracellular signaling by serving as docking stations

A

CD3

ζ chains

365
Q

CD45

A

T cell protein that mediates intracellular signaling and phosphatase

366
Q

CTLA-4

A

T cell protein that can bind B7 to INHIBIT immune response; role in autoimmunity

367
Q

LFA-1

A

T cell integrin that binds ICAM-1 on APC to ensure the two stick together; affinity increased when T cell activated

368
Q

ICAM-1

A

APC ligand that binds LFA-1 on T cell to ensure the two stick together

369
Q

how are all of the molecules involved in T cell activation co-localized within the membranes of the T cell and APC?

A

lipid rafts allow them to stay close together – optimizes T cell ability to respond quickly and effectively

370
Q

general sequence of T cell response to antigen

A
  1. T cells activated by APC/antigen in lymph node
  2. T cells expand and differentiate
  3. differentiated T cells enter circulation
  4. effector T cells & other leukocytes migrate to site of infection
  5. effector T cells are activated by antigens and carry out their function
  6. some T cell clones become memory cells
371
Q

what specifically provides signal 1 for T cell activation?

A

αβ TCR binds MHC/antigen peptide on APC
AND
T cell CD4/CD8 coreceptor binds MHC I/II on APC

372
Q

what specifically provides signal 2 for T cell activation?

A

CD28 on T cell binds B7 on APC

373
Q

what happens when a T cell is activated?

A

a signaling cascade is initiated that results in alteration of gene transcription

374
Q

major T cell integrin involved in binding to APCs?

A

LFA-1

375
Q

costimulators for T cell activation?

A

B7 proteins, which bind to CD28 on T cell

376
Q

CD40

A

expressed on APCs; binds T cell CD40L, which activates APCs to express more B7 costimulators and secrete cytokines (IL-12) that enhance T cell differentiation; also expressed on B cells and is important mediator of B cell isotype switching

377
Q

CD40L

A

expressed on T cells (particularly CD4+); binds CD40 on APC, which activates APCs to express more B7 costimulators and secrete cytokines (IL-12) that enhance T cell differentiation; also important mediator of B cell isotype switching with Th cell assistance

378
Q

CD40-CD40L interaction

A

promotes T cell activation by making APCs better at stimulating T cells

379
Q

adjuvants

A

substances that enhance T/B cell activation mainly by promoting accumulation & activation of APCs at site of antigen exposure; stimulate expression of T cell-activating costimulators and cytokines by APCs, and may also prolong expression of peptide-MHC complexes on APC surface; used in vaccines to provide signal 2

380
Q

Agents that block B7:CD28 are used in the treatment of?

A

rheumatoid arthritis, other inflammatory diseases, and graft rejection

381
Q

antibodies to block CD40:CD40L interactions could be used for?

A

treating inflammatory diseases; preventing graft rejection

382
Q

what would happen if you blocked CTLA-4?

A

immune response would be enhanced; potential for treating tumors/cancer

383
Q

HIV kills what kind of cells?

A

CD4+ T cells

384
Q

immunologic synapse

A

region of contact between the APC and T cell

385
Q

NFAT (Nuclear factor of activated T cells)

A

Transcription factor required for the expression of IL-2, IL-4, TNF, and other cytokine genes; the 4 different NFATs are each encoded by separate genes

386
Q

NFAT activation and nuclear translocation depends on?

A

concentration of Ca2+ ions in the cell

387
Q

intracellular signaling pathway following T cell activation

A
  1. CD4/CD8 binding to MHC causes co-localization of these molecules
    (1a. CD28-B7 costimulation)
  2. CD45 phosphatase activated, removes P from/activates Lck
  3. Lck adds P to/activates ITAMs located in CD3 and zeta chain cytosol
  4. CD3 and zeta chains can now serve as docking stations for ZAP70
  5. ZAP70 docks on ITAMs
  6. Lck adds P to/activates ZAP70
388
Q

3 cascades initiated by active ZAP70

A
  1. phospholipase C (PLC) cascade
  2. MAP kinase cascade
  3. PI-3 kinase/Akt & mTOR cascades
389
Q

PLC cascade

A

Active PLC → DAG and IP3

a. IP3 → Ca2+ release from ER → Ca2+–calmodulin complex → calcineurin activation → removes P from/activates NFAT → NFAT enters nucleus & regulates transcription
b. DAG → PKC activation → adds P to IKB → IKB releases NF-kB → NF-kB enters nucleus & regulates transcription

390
Q

MAP Kinase cascade

A

ZAP70 recruits Rac and Ras (G proteins) → MAP Kinase cascades → AP-1 activated → AP-1 enters nucleus & regulates transcription

391
Q

PI-3 kinase/Akt & mTOR cascades

A

ZAP70 + costimulation recruit PI-3 kinase → adds P to/activates PIP3 → PIP3 activates PKB & mTOR pathways → increased transcription of AP-1 or NF-kB

392
Q

IL-2

A

causes T cells to differentiate into effector T cells and undergo clonal expansion;
IL-2 receptors are upregulated on activated T cells and can be involved in autocrine signaling

393
Q

what kinds of effects do cytokines have in general?

A

wide variety of effects on a wide variety of cell types; effects of different cytokines also overlap

394
Q

2 types of T cell migration

A
  1. naive T cell: blood → lymph tissue → blood (until encounter APC)
  2. activated T cell: blood/lymph → site of infection
395
Q

Which protein chains of the IL-2 receptor is/are expressed on the surface of activated T cells to form the high-affinity IL-2 receptor?

A

α, β, and γ

396
Q

Which protein chains of the IL-2 receptor is/are expressed on the surface of T cells to form the low-affinity IL-2 receptor?

A

β and γ

397
Q

cells that express CD40

A

dendritic cells
B lymphocytes
macrophages

398
Q

dendritic cell CD40 activation by CD40L causes?

A

increase in co-stimulation and cytokine production

399
Q

B lymphocyte CD40 activation by CD40L causes?

A

secretion of antibodies with high affinity for the antigen

400
Q

Macrophage CD40 activation by CD40L causes?

A

upregulation of lysosomal proteases and enzymes that stimulate synthesis of ROS

401
Q

3 major subsets of CD4+ effector cells

A
  1. Th1
  2. Th2
  3. Th17
402
Q

What drives CD4+ differentiation to Th1?

A

IFN-γ and IL-12
through
STAT1, STAT4, and T-bet transcription factors

403
Q

What drives CD4+ differentiation to Th2?

A

IL-4
through
STAT6 and GATA3 transcription factors

404
Q

What drives CD4+ differentiation to Th17?

A

TGF-β, IL-6, and IL-22
through
STAT3 and RORgT transcription factors

405
Q

Can Th1 cells re-differentiate into Th2 or Th17?

A

No

406
Q

Can Th2 cells re-differentiate into Th1?

A

Yes

407
Q

Can Th17 cells re-differentiate into Th1?

A

Yes

408
Q

What is notable about the cytokines that induce differentiation of each CD4+ cell?

A

they are also the cytokines produced by those Th subsets

ex: IFN-γ stimulates Th1 differentiation, and then Th1 cells produce IFN-γ

409
Q

How do Th1 cells activate macrophages?

A

CD40-CD40L interaction + IFN-γ → classical macrophage (M1) activation

  • macrophage response enhanced by Th1
  • macrophages also secrete IL-12, which stimulates further CD4+ diff into Th1 cells
410
Q

Th1 cell effects

A
  1. enhance macrophage killing function through IFN-γ

2. enhance macrophage recognition of antigens through stimulation of B cell secretion of IgG, an opsonizer

411
Q

Th2 cell effects

A
  1. mast cell & eosinophil activation through IL-4 stimulation of IgE for parasite defense, allergic rxns
  2. alt macrophage (M2) activation through IL-4 for tissue repair
  3. sometimes suppress Th1-mediated immunity by inhibiting macrophage microbicidal activity
412
Q

Match the CD4+ subset with its general function(s) and cytokine(s)

A

Th1: macrophage enhancement; IFN-γ
Th2: parasite defense, tissue repair; IL-4
Th17: inflammation, bacterial/fungal defense; IL-17 / IL-22

413
Q

Th17 cell effects

A
  1. attract neutrophils through stimulation of chemokine production by IL-17
  2. increase barrier functions of epithelial cells and stimulate defensin production through IL-22
414
Q

IL-4

A

stimulates and produced by Th2 cells; activates mast cell, eosinophils, and M2 macrophages and sometimes suppresses Th1 responses

415
Q

IL-17

A

stimulates and produced by Th17 cells; induces inflammation by stimulating production of chemokines that attract neutrophils

416
Q

IL-22

A

stimulates and produced by Th17 cells; increases barrier functions of epithelial cells and stimulates defensin production

417
Q

what cytokine acts on naive T cells to stimulate differentiation into effectors and clonal expansion?

A

IL-2

418
Q

3 mechanisms for CD8+ cell effector functions

A
  1. Perforin & Granzymes (main mechanism)
  2. FasL-Fas
  3. TNF-α & IFN-γ Cytokines
419
Q

Perforin & Granzymes

A

main effector mechanism for CD8+; perforin perforates cell membrane, allowing granzymes to enter cell and induce apoptosis

420
Q

FasL-Fas

A

CD8+ effector mechanism; induces apoptosis via a similar pathway to perforin-granzyme

421
Q

TNF-α & IFN-γ

A

CD8+ effector mechanism; induces apoptosis via NF-κB/Stat-1 pathway

422
Q

3 ways CD4+ cells interact with CD8+ cells

A
  1. cytokine production (IL-2)
  2. CD40-CD40L
  3. CD4-CD8 cooperation
423
Q

What signaling molecule is inhibited by Cyclosporin?

A

Calcineurin

424
Q

What is highly expressed on High Endothelial Venules (HEVs) that allows for T-cell adhesion that is NOT expressed on regular venules?

A

Sialomucins

425
Q

factors expressed for T cell migration from Blood → Lymph Node (via HEVs)

A
  1. Naive T-cells express L-Selectin (CD62L), CCR7, & LFA-1 Integrins
  2. L-Selectin Ligands on HEVs bind L-Selectin
  3. CCL19/21 from HEVs bind CCR7
  4. ICAM-1 on HEVs bind LFA-1
426
Q

factors expressed for T cell migration from Lymph Node → site of infection

A
  1. activated T cells downregulate L-selectin & CCR7, begin expressing CXCR3, S1PR1, ligands for E-selectin or P-selectin, LFA-1, and VLA-4
  2. S1Ps bind S1PRs
  3. CXCL10 from endothelium of site of infection binds CCR3
  4. ICAM-1 or VCAM-1 on endothelium of SoI bind LFA-1 or VLA-4, respectively
427
Q

HEVs

A

located in Peyer’s Patches & peripheral Lymph Nodes; special characteristics facilitate T-cell adhesion, including:

a. high levels of ICAM-1
b. high levels of Sialomucin
c. chemokines (CCL19/21, CXCL12/13)
d. Prominent Perivascular Sheaths

428
Q

S1P gradient

A

guides T-cell migration; levels higher in blood/lymph than inside lymph nodes

429
Q

FTY720

A

interferes w/T cell S1PR → T cell can’t bind & follow the S1P gradient → T cell sequestration
*basis of MS drug Gilenya

430
Q

Gilenya

A

Drug based on FTY720 that decreases relapses in relapsing-remitting MS

431
Q

3 stages of adaptive immune response

A
  1. Initial Response
  2. Protective Immunity
  3. Memory
    * each stage begins with expansion and ends with contraction
432
Q

L-selectin

A

expressed by naive T cells; mediates selective migration into lymph nodes through HEVs, specifically through rolling interactions that allow chemokines to bind to T cell CCR7

433
Q

CCR7

A

expressed by naive T cells; mediates selective migration into lymph nodes (parafollicular regions) through HEVs

434
Q

why are effector T cells not drawn toward lymph nodes?

A

they don’t express CCR7 or L-selectin

435
Q

why are naive T cells not drawn toward sites of infection?

A

they don’t express ligands for E-selectin or P-selectin, and they don’t express receptors for chemokines produced at inflammatory sites

436
Q

what determines effector T cell homing to site of infection?

A

adhesion molecules and chemokines; any T cell can go there but the ones that recognize the antigens are preferentially retained

437
Q

expansion

A

antigen exposure + costimulation induce T & B cell expansion to fight off the antigen

438
Q

contraction

A

after defeating antigen, T & B cells die (leaving memory cells behind)

439
Q

memory

A

how the immune system reactivates an expansion of effector cells after a contraction has occurred; also how vaccines work!

440
Q

Central Memory

A

in lymphoid organs → undergo rapid clonal expansion following antigen re-exposure

441
Q

Effector Memory

A

in peripheral tissues → rapid effector functions upon antigen re-exposure

442
Q

CD8+ lymphocytes are used primarily to combat what kind of infections?

A

viral infections, plus some intracellular bacterial infections

443
Q

Mycobacteria

A

inhibits phagolysosomes

444
Q

Herpes Simplex Virus

A

inhibits TAP transporter (MHC Class I assembly!)

445
Q

Cytomegalovirus

A

Inhibits Proteasome & MHC I removal from ER

446
Q

Epstein-Barr Virus

A

Inhibits Proteasome & M2 activation via IL-10

447
Q

Pox Virus

A

Induces production of soluble cytokine receptors (IL-1 or IFN-γ) which act as decoys so cytokines can’t act on effector cells

448
Q

how are NK cells’ responses tempered?

A

by the balance of activating & inhibitory receptors expressed on their surface

449
Q

Which T-cell subset contributes the most to an allergic response?

A

Th2 (mast cells!)

450
Q

Cytotoxic T-Lymphocytes use which mechanisms to lyse target cells?

A

Perforin/Granzymes, Fas/Fas Ligand, & TNF-α

451
Q

Which adhesion molecules facilitate naïve T-cell entry into the lymph node?

A

L-selectin & CCR7

452
Q

immunoglobulin

A

BCR / antibody

453
Q

what is the difference between BCR and antibody?

A

BCR is membrane-bound; antibody is soluble

454
Q

BCR

A

membrane-bound receptor that recognizes antigens and uses Igα and Igβ for signaling functions

455
Q

what determines B or T cell lineage?

A

changes in common progenitors in bone marrow

456
Q

what kinds of molecules can Ig recognize?

A

peptides, lipids, polysaccharides, and nucleic acids; can recognize entire molecules (as opposed to only fragments)

457
Q

antibody structure

A

heavy chain w/several constant regions and 1 variable region; light chain w/1 constant and 1 variable region; Fab region; Fc region

  • heavy chain determines class
  • each V region made up of 3 CDRs
458
Q

Fab region

A

antigen binding occurs here

459
Q

Fc region

A

where BCR attaches to B cell membrane
OR
where antibody can bind to phagocyte Fc receptors

460
Q

how many antigen binding sites per antibody?

A

2 (except IgA and IgM)

461
Q

isotype switching

A

Ig molecules can change their class of antibody through heavy-chain switching; antibody specificity (V region) does not change; mediated by interaction btwn B cell CD40 receptor and Th cell CD40L

462
Q

specifically which part of an antibody does antigen bind to?

A

CDRs in V regions of heavy & light chains

463
Q

BCR vs TCR affinity

A

affinity of a BCR is 1,000 to 10,000x higher than that of a TCR, and it changes
and increases with repeated exposure to an antigen

464
Q

BCR on/off rate

A

rapid on rate, variable off rate – grab on quickly, then decide what to do

465
Q

antibody isotypes

A

IgM, IgG, IgA, IgE, IgD

466
Q

how many antigen binding sites does IgA have?

A

4 - it is a dimer, so has 2x that normal amount

467
Q

how many antigen binding sites does IgM have?

A

10 - it is a pentamer, so has 5x the normal amount

468
Q

which antibody isotypes are expressed on the surface of naive B cells?

A

IgM & IgD

469
Q

which antibody isotype has no secreted form?

A

IgD

470
Q

which antibody isotype is most prevalent in circulation?

A

IgG - longest half-life

471
Q

which antibody isotype is most prevalent in mucosa?

A

IgA

472
Q

B cell maturation steps

A
  1. pro-B cell rearranges V regions through VDJ recombination
  2. success in making heavy chain → pre-B cell w/Igμ protein
  3. μ chain associates w/Igα and Igβ signaling molecules to form pre-BCR complex
  4. pre-BCR complex sends cell survival signals, among others
  5. light chain associates w/μ chain to form complete IgM receptor → immature B cell
  6. IgM receptor sends out survival signals, among others
  7. coexpression of IgM & IgD → mature B cell
473
Q

first checkpoint in B cell development?

A

correctly assembled pre-BCR complex sends signals to cell to continue development

474
Q

what happens to pro-B cells that don’t succeed in rearranging heavy chain?

A

death

475
Q

what happens to developing B cells that don’t express pre-BCR complex?

A

death

476
Q

signals sent out by pre-BCR complex?

A
  1. signals to cell to continue development
  2. allelic exclusion: signals to shut off recombination of Ig heavy chain genes on 2nd chromosome
  3. triggers recombination at κ light-chain locus
477
Q

second checkpoint in B cell development?

A

fully-expressed IgM receptor sends out survival signals

478
Q

what molecules do B cells express during each phase of development?

A

pro-B cell: CD10, CD19
pre-B cell: Igμ; recombined H chain
immature B cell: IgM; recombined H chain; κ or λ light chain
mature B cell: IgM & IgD

479
Q

B cell negative selection

A

if an immature B cell binds an antigen in bone marrow with high affinity, the VDJ recombinase may be reactivated to change the antigen receptor specificity (receptor editing); may also involve deletion of self-reactive B cells

480
Q

receptor editing

A

if an immature B cell binds an antigen in bone marrow with high affinity, the VDJ recombinase may be reactivated to change the antigen receptor specificity

481
Q

what role do bone marrow stromal cells play in B cell development?

A

presents antigens to developing B cells (similar to thymic epithelial cells in T cell development)

482
Q

IL-7

A

necessary for lymphocyte growth

483
Q

SCF

A

helps early B cells develop by stimulating proliferation

484
Q

Kit

A

helps early B cells develop by stimulating proliferation

485
Q

what happens if SCF and/or Kit don’t function?

A

you won’t get B cells! (not enough clones will be made to ensure some make it through selection)

486
Q

SLC / CCL21

A

attracts dendritic cells to lymph nodes; secreted by stromal cells and dendritic cells in node

487
Q

affinity maturation

A

affinity of antibodies produced in response to an antigen increases with prolonged/repeated exposure to antigen

488
Q

what do dendrites in lymph nodes secrete to attract B & T cells?

A

SLC / CCL21 and MIP3β

489
Q

follicular dendritic cells

A

establish B cell areas in lymph node by secreting BLC / CXCL13

490
Q

BLC / CXCL13

A

secreted by follicular dendritic cells to attract B cells to particular areas in lymph nodes

491
Q

C regions

A

constant region genes that can form the different heavy chains

492
Q

heavy chain segments in VDJ recombination

A

mix and match with V, D, and J segments

493
Q

light chain segments in VDJ recombination

A

only V and J segments

494
Q

RSS motifs

A

specific signal sequences expressed by genes that can be recombined; randomly bind to complexes containing RAG1 & RAG2; eventually, cleaved at these motifs and ends are joined to form a closed loop of DNA that is no longer used

495
Q

RAG1 / RAG2

A

recombination activator genes; randomly bind to RSS motifs

496
Q

RAG protein complex

A

brings together the gene segments to be recombined and cleave the DNA exactly at the junction of the gene segment at the RSS motif

497
Q

proteins involved in recombining cleaved DNA / gene segments

A

DNA-PK, Ku, Artemis, and DNA ligase/XRCC4

498
Q

5 ways diversity is generated in BCR

A
  1. baseline variability in V segments
  2. combinatorial diversity (VDJ joining)
  3. junctional diversity (imprecise cutting, TdT additions)
  4. secondary combinatorial diversity (random assortment of heavy/light chains)
  5. somatic hypermutation (cell mutations during germinal center rxn)
499
Q

2 ways to activate B cell

A
  1. clustering of IgG receptors bound to antigens → receptor cross-linking → activation signal through Igαβ receptors to ITAMS → phosphorylation → recruitment of Syk kinase → signal propagation
  2. complement-coated microbes attach to BCR & C3d binds CD21 (CR2) receptor → activate CD19 and Igαβ phosphorylation → recruitment of Syk kinase → signal propagation
500
Q

what happens after B cell activation?

A

B cells interact w/CD4+ T cells outside of B cell follicles in lymph node → present antigen to T cells → T cell CD40 binds B cell CD40LR → T cells secrete cytokines → some B cells proliferate/differentiate into antibodies immediately; other B cells migrate back into follicles to undergo germinal center rxn

501
Q

germinal center reaction

A

when somatic hypermutation and potentially isotype switching occur

502
Q

why do B cells undergo somatic hypermutation and isotype switching?

A

help make the antibody affinity for the antigen much greater and help the body mount a more effective defense

503
Q

T-FH cells

A

T follicular helper cells: some T cells migrate into B cell follicles and develop into these

504
Q

somatic hypermutation

A

occurs in germinal center; introduces many mutations in V region of BCR genome to generate BCRs that have a higher affinity for the antigen being presented

505
Q

molecules involved in somatic hypermutation

A
  • AID promotes mutations by changing cytosine → uridine

- UNG corrects these mutations using BER → other mutations

506
Q

what happens to B cells after somatic hypermutation?

A

mutated BCRs compete to bind to antigens displayed by follicular dendritic cells in B cell follicle; those that bind strongly are given a survival signal, and the many that are non-functional or weakly-binding die

507
Q

enzymes involved in isotype switching

A

AID, UNG, and APE1

508
Q

APE1

A

induces double stranded breaks that allows the initial C region to be swapped out for a different C region denoting a different heavy chain

509
Q

AID

A

promotes mutations by changing cytosine → uridine

510
Q

UNG

A

corrects mutations induced by AID using BER → other mutations

511
Q

what determines isotype switching?

A

cytokine environment secreted by surrounding helper T cells

512
Q

IgM principal effector function

A

complement activation

513
Q

IgG3 principal effector function

A

complement activation

514
Q

IgG1 principal effector function

A

complement activation; can cross placental barrier

515
Q

IgE principal effector function

A

high-affinity binding to mast cells and basophils to defend against helminths

516
Q

IgA principal effector function

A

mucosal immunity

517
Q

what will a lab report show on first exposure to antigen?

A

lots of IgM (naive B cells)

518
Q

what will a lab report show on subsequent exposure to antigen?

A

lots of IgG (longest lasting; form memory cells)

519
Q

thymus-dependent reaction

A

any reaction that involves T cells / antigens with protein component

520
Q

thymus-independent reaction

A

any reaction to a lipid, polysaccharide, or nucleic acid antigen (i.e. lacking peptide component)

521
Q

Termination of BCR signaling

A

as the antibodies bind antigens, they also tend to conglomerate with other antibodies binding antigens, and these large complexes bind the surface of B cells, activating ITIMS, which are inhibitory and terminate the signals.

522
Q

antibody feedback

A

complexes of antibodies responding to antigens bind the surface of B cells and activate inhibitory ITIMS

523
Q

Omenn syndrome

A

no RAG → no B cells

524
Q

IR/RS SCID

A

lack of Artemis → defects in DNA repair & low Ig and TCR diversity b/c lack ability to do VDJ recombination properly

525
Q

Ataxia Telangiectasia

A

ATMmut → low B/T cells, low Ab switch

526
Q

AID deficiency

A

low Ab diversity, high IgM due to lack in class switching and hypermutation

527
Q

X-linked hyper IgM

A

defect in CD40L → No class switching, most antibodies will be IgM

528
Q

IgG functions

A
  • microbe/toxin neutralization
  • antigen opsonization
  • classical pathway complement activation
  • antibody-dependent cellular cytotoxicity (NK cells)
  • neonatal immunity
  • feedback inhibition of B cell activation
529
Q

IgM functions

A

classical pathway complement activation

530
Q

IgA functions

A
  • mucosal immunity

- IgA secretion into GI & respiratory tracts

531
Q

IgE functions

A

parasite defense and hypersensitivity (allergic) reactions

532
Q

FcRn

A

Neonatal Fc Receptor; found on placental tissue, endothelium, phagocytes and a few other cell types; contributes to long half-life of IgG (increases by 3 weeks)

533
Q

how does FcRn contribute to long half-life of IgG?

A
  • circulating IgG ingested by endothelial cells & bind Fc-region of FcRn
  • FcRn sequesters IgG in endosomal vesicles (pH 4)
  • FcRn-IgG complexes recycled back to surface
  • IgG released back into blood
534
Q

neutralization

A

antibodies inhibit the infectivity of a pathogen or the toxicity of a toxin; foundation for vaccines (stimulate neutralizing antibodies)

535
Q

neutralizing antibodies are like goalies

A

they’re always blocking stuff

536
Q

types of antibody neutralization

A
  1. block microbe penetration through epithelial barrier
  2. block microbe from binding to and infecting cells by binding to the microbe
  3. block infection of adjacent cells
  4. block toxin binding to cellular receptor by binding to toxin
537
Q

major defense mechanism against encapsulated bacteria?

A

opsonization by antibody → phagocytosis by macrophages/neutrophils

538
Q

phagocyte Fc receptors

A

recognize opsonization signals

539
Q

FcγRI

A

recognizes IgG

540
Q

FcγRIIA

A

recognizes IgG (lower affinity)

541
Q

FcγRIIB

A

feedback inhibition of B cells (reduces inflammation)

542
Q

FcγRIIIA/CD16

A

mediates NK-IgG binding in antibody-dependent cellular cytotoxicity (ADCC)

543
Q

FcεRI

A

recognizes/activates mast cells and basophils for allergic reactions by binding IgE

544
Q

ADCC

A

Antibody-dependent cellular cytotoxicity; process by which NK cells target and kill IgG-coated cells; NK-IgG binding mediated by FcγRIIIA/CD16; important anti-viral and anti-tumor process

545
Q

antibody-mediated eosinophil/mast cell activation

A

IgE opsonizes parasite/allergen; pathogen recognized by FcεRI receptors on eosinophil, aided by IL-5 (made by Th2 cells); activated eosinophil kills parasite/neutralizes allergen

546
Q

neonatal immunity

A

maternal antibodies, such as IgG, are actively transported across the placenta via the FcRN receptor to the fetus, across the gut epithelium, entering neonatal circulation and protecting newborn from infections

547
Q

IgA and neonatal immunity

A

After birth, neonates ingest maternal IgA antibodies through colostrum and milk (mucosal immunity). Neonate’s intestinal epithelial cells also express FcRn receptors, which bind ingested IgG antibodies and carry them across the epithelium

548
Q

only example of naturally occurring passive immunity?

A

mother passing antibodies to newborn

549
Q

poly-Ig receptor

A

can bind IgA and IgM; transports IgA across the epithelium/mucosal barrier

550
Q

IgA/poly-Ig receptor complex

A

When it crosses the mucosal barrier, this complex is endocytosed and released into lumen of GI or respiratory tract, after proteolytic cleavage, where the Ab can bind microbes. IgA remains attached to poly-Ig receptor, which helps protect antibody from degradation when it reaches lumen, where it may experience harsh environment (i.e. GI tract)

551
Q

3 pathways to activate complement system

A

1) Classical pathway
2) Lectin pathway
3) Alternate pathway

552
Q

C3 convertase

A

protease generated by all 3 complement pathways; recruits inflammatory mediators and phagocytes, opsonizes pathogens for phagocytosis, and kills pathogens

553
Q

can the Lectin and Alternative complement pathways be activated in the absence of antibodies?

A

Yes!

554
Q

which antibody isotypes can activate classical complement pathway?

A

IgM, IgG1, IgG2, and IgG3

  • role in innate and adaptive immunity
  • GM makes classic cars
555
Q

relative strength of potency of complement inflammatory chemoattractants?

A

C5a > C3a > C4a

556
Q

Classical Complement Pathway

A
  1. activation of protein C1 complex
  2. cleavage of C4 to C4a & C4b
  3. C4b binds pathogen, where it can now bind C2
  4. C4b recruits C1 to cleave C2 to C2a & C2b
  5. C4bC2a complex created (aka classical C3 convertase)
  6. C3 convertase continuously cleaves C3 to C3a & C3b
  7. C3b opsonizes pathogen
  8. C3b covalently binds C3 convertase, forming C4bC2aC3b protease (aka C3/C5 convertase)
  9. C3/C5 convertase cleaves C5 to C5a & C5b
    (1, 4, 2, 3, 5)
557
Q

anaphylatoxin

A

small fragment that can be recognized by receptors to recruit fluids and inflammatory cells

558
Q

Alternate Complement Pathway

A
  1. plasma C3 spontaneously undergoes cleavage to C3a & C3b
  2. C3b opsonizes pathogen, then binds Factor B
  3. C3b/FactorB complex allows factor D to cleave factor B to Ba & Bb
  4. Bb binds C3b, becoming C3bBb (aka alternate C3 convertase)
  5. C3 convertase continuously cleaves C3 to C3a & C3b
  6. C3b covalently binds C3 convertase, forming C3bBbC3b convertase (aka alternate C3/C5 convertase)
  7. alternate C3/C5 convertase promotes terminal steps of pathway cascade
559
Q

Lectin Complement Pathway

A
  1. initiated by Mannose- Binding Lectin (MBL) protein, which binds mannose sugar residues present on many pathogen surfaces
  2. follows same steps as classical pathway
560
Q

Terminal Steps of complement pathway

A
  1. C5b binds C6 and C7, forming C5b67 complex
  2. C5b67 complex binds to microbe membrane using C7
  3. C8 recruited to membrane
  4. C8 induces polymerization of C9, forming pore known as MAC
  5. MAC disrupts lipid bilayer, letting all kinds of characters in and out
561
Q

Complement regulators

A

slow down the system!

562
Q

down-regulation of alternate C3 convertase

A

use membrane proteins CR1, MCP, and DAF:

  1. DAF or CR1 displaces Bb in C3bBb convertase
  2. MCP or CR1 serves as cofactor for Factor I, which cleaves C3b to inactive form
563
Q

classical and MBL pathway regulation

A

primarily by C1-INH, which prevents appropriate assembly of the C1 complex so that it cannot become proteolytically active

564
Q

C4 binding protein

A

can also cause the dissociation of the classical complement pathway; acts as a cofactor for factor-I mediated cleavage of C4b

565
Q

CD59

A

inhibits C9 binding, preventing MAC formation

566
Q

Paroxysmal nocturnal hemoglobinuria (PNH)

A

very rare disorder; RBCs lack DAF / CD59; causes complement pathways to attack RBCs; Currently treated with Eculizumab (anti-C5 antibody)

567
Q

Hereditary angioedema (HAE)

A

lack C1-INH regulator; probably NOT a complement-mediated disease; Treated with C1-INH concentrates

568
Q

Atypical hemolytic uremic syndrome (aHUS)

A

genetic disease that can damage vital organs; occurs in heterozygous individuals with mutations in MCP, Factor H, or Factor I; pts have blood clots form in small vessels (systemic thrombotic microangiopathy)

569
Q

Which immunoglobulin has the highest level in a normal 1-day-old infant?

A

IgG (from mother placental transfer)

570
Q

Which complement component is most closely related to anaphylatoxin?

A

C5b

571
Q

C1 complex

A

classical pathway initiator protein; can bind antibodies such as IgM and IgG subtypes

572
Q

2 sites of tolerance development

A

central (bone marrow/thymus) or peripheral

573
Q

Central tolerance

A

main site for elimination of autoreactive lymphocytes

574
Q

partial defect in central tolerance is associated with…?

A

onset of autoimmunity

575
Q

loss of peripheral tolerance mechanisms leads to…?

A

increased risk of autoimmune disorders

576
Q

2 principal mechanisms of central tolerance in T cells

A
  1. cell death

2. generation of CD4+ regulatory T cells

577
Q

mutations in AIRE gene

A

associated w/autoimmune polyendocrine disorder (APECED)

578
Q

regulatory T cell development

A

express slightly stronger reaction to antigens presented during development, but not strong enough to warrant death

579
Q

regulatory T cell surface markers

A

CD3
CD4+
CD25+ (chain of IL-2 receptor)
FoxP3 TF

580
Q

can regulatory T cells survive w/o CD25?

A

No.

581
Q

peripheral tolerance induction

A

T cell recognizes self-antigen in periphery, leading to:

  1. apoptosis
  2. anergy (functional inactivation)
  3. suppression by reg T cells
582
Q

what happens when a T cell recognizes a self-Antigen?

A

may preferentially bind CTLA-4 (inhibitory) to B7 to prevent autoimmune response

583
Q

Genetic polymorphisms in CTLA4 gene

A

associated with autoimmunity

584
Q

regulatory T cell function

A

block activation of harmful lymphocytes specific for the self-antigens; suppress CD4 and CD8 effector functions

585
Q

regulatory T cell mechanisms

A
  1. expression of CTLA-4, which downregulates B7 costimulator
  2. secretions of inhibitory/anti-inflammatory cytokines like TGF-B and IL-10
  3. “soak up” excess IL-2 to prevent expansion of other T cells
586
Q

Immune Dysregulation Polyendocrinopathy Enteropathy (IPEX)

A

X-linked disease caused by mutation in FoxP3

587
Q

FoxP3 mutation

A

causes IPEX

588
Q

what usually causes inappropriate activation of T cells?

A

lack of signal 2 (costimulation) leads T cells down 1 of 2 pathways:

  1. intrinsic: expression of pro-apoptotic pathways
  2. Coexpression of death receptors and ligands – Both cells express Fas (CD95) and the Fas Ligand (FasL). Binding of these on both cells together induces apoptosis.
589
Q

how does CD4 help regulate B cell development in regard to autoimmunity?

A

Naive B cells can only mature in the presence of proper CD4 T cell signaling. CD4 T cells will not provide these signals to a B cell that is binding self-antigen

590
Q

main cause of autoimmune disorders?

A

chance

some genetic defects may lead to increased risk (mainly defects in peripheral tolerance)

591
Q

how could one self-reactive molecule slipping through the cracks cause a big problem?

A

if self-reactive lymphocyte happens to recognize a self-Ag being presented by an infected APC, which will be expressing high levels of the costimulator B7; now you’ve activated a lymphocyte the recognizes self-antigens and created an autoimmune disorder

592
Q

mutation in AIRE

A

causes autoimmune polyendocrine disorder (APS-1)

593
Q

mutation in Fas

A

causes autoimmune lymphoproliferative syndrome (ALPS)

594
Q

what kinds of defects lead to an increased risk of acquiring an autoimmune disorder?

A

costimulation
antigen presentation or removal
signaling molecules
effector cell clearance

595
Q

HLA phenotype (MHC)

A

has one of the clearest associations with relative risk of autoimmunity

596
Q

TH1 cells express abundant functional ligands for?

A

E-selectin and P-selectin and the chemokine receptors CXCR3 and CCR5, which bind to various chemokines found at sites of active innate immune responses

597
Q

invariant chain

A

ensures peptide gets matched up with correct MHC class

M1 - Immuno (3 decks)

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