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HDM > Final Exam > Flashcards

Final Exam Flashcards

1
Q

isotype switching

A

antigen binding stays same
effector cell changes
ALWAYS starts w/IgM
occurs by class switch recombination in heavy chain (Constant region)
constant regions loop out and switch regions recombine
During maturation (after activation), B cell cuts off IgM constant region and pastes on another

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2
Q

Pro-inflammatory cytokines

A

NFkB- DEpendent transcription
IL-1, TNFa, IL-6
IL-8, IL-11, IL-12, IL-15, IL-18

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3
Q

Anti-inflammatory cytokines

A

NFkB- INdependent transcription

IL-10, TGFb

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4
Q

Th1 cytokines

A

differentiated by macrophages (IFNg) and IL-12

secrete IFNg, IL-2, TNFb

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5
Q

Th2 cytokines

A

differentiated by IL-4

secrete IL-4, IL-5, IL-10

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6
Q

auto

A

self

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7
Q

iso

A

same/identical

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8
Q

allo

A

different

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9
Q

xeno

A

foreigner/alien

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10
Q

PGI

A

vasodilation

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11
Q

PGE

A

permeability

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12
Q

LTB4

A

neutrophils come B4 macrophages

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13
Q

Th1 isotype switch

A

OPSONIZATION: IgG

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14
Q

Th2 isotype switch

A

NEUTRALIZATION: IgE (allergies, parasites)

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15
Q

Th1 transcription factor

IFNg receptor

A

T-bet (IFNg)

You BET IFNg is gonna be on the test

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16
Q

Th2 transcription factor

A

GATA 3 (IL 4, 5, 13)

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17
Q

Th17 transcription factor

A

RORgT (IL 17, 22)

My husband Rory is 17, but he wants to be 22.

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18
Q

Innate imbalance towards inflammatory cytokines

A

local cytokines spill over into systemic-> systemic inflammation-> septic shock
Sepsis caused by cytokines in circulation (not necessarily the pathogen)
Severe sepsis-> cardiovascular collapse (intravasc coag) and multiple organ failure -> death

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19
Q

Systemic Inflammatory response syndrome (SIRS)

A

due to overwhelming inflammation by innate imm sys cytokines (TNFa, IL-1, IL-6, IL-12)
leads to early death

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20
Q

Compensatory Anti-inflammatory response syndrome (CARS)

A 
strong inflammatory response (cytokine storm) can inc susceptibility to future infections
persistent immunosuppression (IL-10, IL-4, TGFb) and recurrent infections lead to late deaths
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21
Q

Pro-inflammatory cytokine TIMELINE

A

0 hr: TNF
2 hr: IL-1
4 hr: IL-6
Lack of TNF allows pathogen to proliferate before other cytokines attack

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22
Q

TNF/IL-1 local effects

A

Vascular endothelium: leukocyte adhesion molecules, IL-1/chemokines, procoag (INFLAM)
Leukocytes: activation, cytokines (INFLAM)
Fibroblasts: proliferation, collagen synth (REPAIR)

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23
Q

TNF/IL-1 systemic effects

A 
Fever
Leukocytosis
Acute phase proteins
Sleep
decreased appetite
(INFLAM, "sickness syndrome")
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24
Q

IL-12/18/IFNg synergy

A

activate macrophages and NK cells
IL-12/18: macrophage binds to NK
IFNg: NK kills phagocytosed microbes in macrophage

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25
Q

Classically activated macrophage (M1)

A

TLR ligands/IFNg: Monocyte-> Macrophage ->
1. ROS, NO, lysosomal enzymes: phagocytosis/killing of microbes
2. IL-1, IL-12, IL-23, chemokines: inflam (inh by IL-10, TGFb)
Inh by IL-4, IL-13

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26
Q

Alternatively activated macrophage (M2)

A 
IL-4, IL-13: Monocyte-> Macrophage -> 
   1. IL-10, TGFb: anti-inflam
   2. Proline, polyamines, TGFb: wound repair
Inh by TLR ligands, IFNg
granulomas
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27
Q

Th1 phenotypes

A 
Cytokines: IFNg
Immune rxn: M1 activ, IgG prod
Against: INTRAcellular microbes
Disease: autoimmune diseases, tissue damage (from chronic infections)
TF: T-bet
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28
Q

Th2 phenotypes

A

Cytokines: IL-4, 5, 13
Immune rxn: mast cell/eosinophil activ, IgE prod, M2 activ
Against: helminthic parasites (EXTRAcellular digestion)
Disease: allergic diseases
TF: GATA-3

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29
Q

Th17 phenotypes

A 
Cytokines: IL-17, 22
Immune rxn: neutrophilic/monocytic inflam
Against: EXTRAcell bacteria, fungi
Disease: autoimmune/inflam diseases
TF: RORgT
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30
Q

IgM

A

default B cell product
pentamer
complement activ
FIRST antibody that appears when an antigen is encountered for the first time (usually the one to activate B cells)
important for encapsulated bacteria
low affinity interaction enhanced by 5 adhesion sites
POTENT COMPLEMENT ACTIVATOR/OPSONIN

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31
Q

IgG

A

B cell + Th (CD40L, cytokines) + IFNg
monomer
Fc-dependent phagocytosis, complement activ, placental transfer of immunity
Neutralizes bacterial toxins and opsonizes bacteria
Neonatal immunity

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32
Q

IgE

A

B cell + Th (CD40L, cytokines) + IL-4
monomer
immunity against helminthic parasites
mast cell degranulation (immediate hypersensitivity)

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33
Q

IgA

A

B cell + Th (CD40L, cytokines) + mucosal cytokines (TGFb, BAFF)
dimer (or monomer)
proteolysis-resistant (GI tract)
mucosal immunity

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34
Q

Th1-mediated immunity

A
  1. APC + microbes -> Naive CD4+ T cell
  2. T cell prolif/diff -> Th1
  3. IFNg: M1 activation, B cell complement binding/opsonizing abs
  4. Abs + Fc receptor -> Opsonization and phagocytosis
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35
Q

Th2-mediated immunity

A
  1. APC + microbes/protein antigens -> naive CD4+ T cell
  2. Prolif/diff -> Th2 cells
  3. IL-4: B cells -> IgE
    IL-5: eosinophils activation
  4. IgE -> mast cell degranulation
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36
Q

CD8+ T cells

A
  1. CD8+ Tc cells recognize Ag + costim on APC -> CTL diff (w/o Th cells)
  2. CD4+ Th cells -> cytokines -> CTL diff
  3. CD4+ Th cells (CD40/CD40L) inc APC stimulation of CTL diff
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37
Q

CD8+ Tc cell killing mechanisms

A

Apoptosis caused by…

  1. Exocytosis: Granzyme and Perforin released on target cell after binding
  2. Fas-L-Fas (Fas-L on activated CTL, CD95 on target cell) binding (w/MHC-CD8/TCR binding)-> activates caspases (induces apoptosis)
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38
Q

gamma/delta T cells

A 
DEFENSE against infection/sterile stress
1. cytokine/chemokine production
2. lyse infected/stressed cells
3. regulate stromal cell fxn w/growth factors
4. DC maturation
5. ab T cell priming w/Ag presentation
6. B cell help, IgE production
FOR MY MEMORY: CK Lykes Strong, able, DC BoyEs
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39
Q

NKT cell antigen recognition

A

semi-invariant Va14-Ja18 TCR binds glycolipid on CD1d (on APC)

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40
Q

Cellular immunity (effector cells, pathogen location, Ag presentation, action)

A

Effector cells: CD8+ CTLs
Pathogen location: cytoplasm
Ag presentation: MHC I
Action: induced apoptosis

Effector cells: Type 1 CD4+ T lymphocytes
Pathogen location: MP phagolysosome
Ag presentation: MP MHC II
Action: activated pathogen killing

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41
Q

Humoral immunity (effector cells, pathogen location, Ag presentation, action)

A

Effector cells: Type 2 CD4+ T lymphocytes
Pathogen location: extracellular
Ag presentation: Pro-APC MHC II
Action: Abs prod by plasma cells

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42
Q

AA

A

Arachidonic Acid

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43
Q

COX

A

CycloOXygenase enzyme

rich in fibroblasts, smooth muscle, epithelial, endothelial, and hematopoietic cells

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44
Q

GSH

A

reduced glutathione

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45
Q

H1 and H2

A

Histamine receptors

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46
Q

IL

A

InterLeukin

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47
Q

IgE

A

Immunoglobulin E

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48
Q

LPS

A

LipoPolySaccharide

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49
Q

LT

A

LeukoTriene (LTA4, LTB4, LTC4, LTD4, LTE4)
made by leukocytes
have conjugated triene in structure

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50
Q

5-LO

A

5-LipOxygenase (enzyme)
Substrate: AA (and related PUFA)
Fxn: convert AA + O2 -> LTA4
rich in myeloid cells (macrophages, mast cells, basophils, neutrophils; inducible in monocytes)
Self-reliant chemotaxis: made by neutrophils to attract more neutrophils

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51
Q

NSAID

A

Non-Steroidal Anti-Inflammatory Drug

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52
Q

PG

A

ProstaGlandin (PGE2, PGF2, PGI2)

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53
Q

PGI2

A

ProstaGlandin I2 (prostacyclin)

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54
Q

PUFA

A

PolyUnsaturated Fatty Acid

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55
Q

TNFa

A

Tumor Necrosis Factor

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56
Q

TxA2

A

ThromboXane A2

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57
Q

PLA2

A

PhosphoLipase A2 (enzyme)
Substrate: cell membrane phospholipids
Fxn: liberates AA

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58
Q

FLAP

A

5-LO activating protein (enzyme)
Substrate: 5-LO accessory protein
Fxn: converts AA + O2 -> LTA4

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59
Q

LTA4 hydrolase

A

Enzyme that converts LTA4 -> LTB4

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60
Q

LTC4 synthase

A

Enzyme that converts LTA4 -> LTC4

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61
Q

Peptidases

A

Enzymes that convert LTC4 -> LTD4 -> LTE4

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62
Q

LTA4

A

Fxn: biosynthetic intermediate

involved w/asthma

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63
Q

LTB4

A

Receptor: BLT1,2
Fxn: augments neutrophil EC adhesion, POTENT neutrophil chemotaxis and degranulation, eosinophil chemotaxis
involved w/asthma
main LT made by neutrophils

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64
Q

LTC4 = LTD4

A

Receptor: CysLT2
Fxn: bronchoconstriction, mucus secretion
involved w/asthma

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65
Q

LTD4 > LTC4

A

Receptor: CysLT1
Fxn: bronchoconstriction, mucus secretion
involved w/asthma

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66
Q

LTE4

A

Receptor: CysLT
Fxn: less active metabolite
involved w/asthma

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67
Q

Histamine

A

Synthesized and stored pre-formed (latent) in granules of mast cells and basophils
Substances in granules (ex- heparin) form complexes w/histamine to keep inactive until released
Increases capillary permeability to leukocytes/plasma proteins to attack pathogens in tissue

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68
Q

Histamine synthesis/inactivation for storage

A

Dietary histidine -(decarboxylase) -> CO2 + Histamine

  1. Diamine oxidase: imidazole aldehyde (inactive)
  2. Histamine N-methyl transferase: N-methyl histamine (inactive)
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69
Q

Histamine v Prostaglandins/Thromboxane/Leukotrienes

A

Synth/Storage: Histamine made all the time, RELEASED on demand; P/T/L precursors stored, MADE on demand
Lifespan: both short, Histamine inactivated enzymatically, P/T/L inactivated enzymatically OR spontaneously
Physiology: both local (not systemic)
Pathology: both due to unwarranted SYSTEMIC exposure

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70
Q

H1 receptor

A

tissue-specific GPCR for histamine
Nasal/bronchial- mucus secretion
Bronchial/intestinal smooth muscle- constriction
Sensory nerves- pain

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71
Q

H2 receptor

A

tissue-specific GPCR for histamine

Stomach- gastric acid secretion

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72
Q

H1 and H2 receptors

A

tissue-specific GPCRs for histamine
Heart- HR
Vessels- peripheral resistance
Skin capillary blood vessels- dilation, permeability, pain sensitization

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73
Q

COX-1

A

helps maintain normal cell fxn
constitutive in platelets, ECs, fibroblasts, smooth muscle, monocytes, macrophages, mast cells, basophils, neutrophils (less)

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74
Q

COX-2

A

inducible in ECs, fibroblasts, smooth muscle, monocytes, macrophages, mast cells, basophils, neutrophils (less)

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75
Q

Leukotriene synthesis

A

5-LO arm of AA cascade, lipid/peptide hybrid
1. PLA2: AA released from membrane
2. 5-LO, Ca2+ + FLAP: O2 inserted into AA -> LTA4
3. 2 pathways
LTA4 hydrolase: adds H2O -> LTB4
LTC4 synthase: adds GSH -> LTC4
peptidases: LTC4 -> LTD4 and LTE4

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76
Q

Leukotriene breakdown

A

spontaneous hydrolysis into inactive products

helps prevent LT excess

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77
Q

Self-reliant chemotaxis (neutrophils)

A

neutrophils encounter threat -> inflammation favors eicosanoid synth in neutrophils -> 5-LO makes lipid mediators (LTs) -> LTB4 (augments EC neutrophil adhesion, potent chemotactic agent for neutrophils)

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78
Q

pyogenic infection

A

characterized by neutrophil-rich pus

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79
Q

Mediators of inflammation

A

Made by phagocytes and granulocytes after they engulf the threat and release ROS and proteases
Send autocrine and paracrine signals telling leukocytes to engage/neutralize threat
Tells epithelial and mesenchymal cells to adapt/migrate/perish
Limit damage to host due to infammation

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80
Q

Asthma elements

A
  1. airway inflmamation (Th2 lymphocytic response-> secrete IL-4/5/13, eotaxin (chemokine), TNFa, LTB4, tryptase (mast cell))
  2. airway hyper-responsiveness (coughing triggered more easily than normal person
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81
Q

Asthmatic airway

A

bronchiolar smooth muscle constriction
inflammation
mucus discharge
pulmonary edema

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82
Q

Hypersensitivity

A
  1. Sensitization: allergen exposure-> IgE abs
  2. IgE abs bind mast cell receptors
  3. Re-exposure: allergen binds IgE-> CROSS LINKS RECEPTORS
  4. Cross-linking triggers DEGRANULATION-> histamine release-> activate eicosanoid synth (LTC4/D4, PGD2)
  5. Mediators + histamine -> redness, local edema, pain, itching (symptoms of allergic immediate hypersensitivity)
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83
Q

Histamine hypersensitivity

A

Originates from H1 receptors on vessel wall (esp. venous side)
Causes vasodilation and inc permeability
Causes pain (mechanical pressure on peripheral nerves due to tissue swelling)

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84
Q

Mast cell/histamine location

A 
Concentrated in areas of the body most vulnerable to antigen/pathogen exposure
Nasal passage
Trachea, bronchi, lungs
Stomach, intestines
Skin
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85
Q

allergy treatment

A

inhibit RECEPTORS specific to area w/symptoms

inhibiting synthesizing enzyme risks having a shortage of histamine in other important areas of the body

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86
Q

Circulating inflammatory cells

A 
Neutrophils: 40-60%
lymphocytes: 20-40%
Monocytes: 2-8%
Eosinophils: 1-4%
Basophils: .5-1%
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87
Q

Gout

A

Failure to excrete uric acid at an appropriate rate

Treat inflammation AND metabolism (synth) of uric acid

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88
Q

Gout mechanism

A
  1. urate crystals in joint -> sterile inflammation
  2. MP/monocyte engulfs crystals -> releases IL-1b (inflam) and IL-8 (chemotactic)
  3. IL-1b -> EC adhesion molecules and MP/monocyte/conn tissue/EC COX-2
  4. IL-1b + IL-8 -> neutrophil recruitment
  5. MP/monocytes/neutrophils/conn tissue -(COX-2)-> local inc lipid inflam mediators (dil/perm) -> redness/swelling/heat/pain
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89
Q

IL-1 beta (gout)

A

Binds membrane receptor
Releases substrate (AA) and activates enzyme (COX-2)
Induces adhesion molecules in EC (inc neutrophil margination)

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90
Q

PGE2 and PGI2 (gout)

A

PGI2: vasodilation
PGE2: permeability
Leaky vessels-> plasma extravasion-> local edema
(redness, heat, swelling, pain)

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91
Q

IL-8 (gout)

A

Chemotactic factor initiating movement of neutrophils from blood -> leaky vessels -> tissue w/activated MP/monocyte

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92
Q

Neutrophil adaptability

A

Normal: reside in blood
Pathology: EXIT blood, enter tissue site, 2 fxns
1. granulocyte: discharge degradation mediators
2. phagocyte: engulf and digest

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93
Q

Inflammation (gout)

A

fails to eliminate uric acid crystals
ineffective proteases and lysosomal enzymes (phagocyte)
ineffective oxidative bursts (granulocyte)
May aggravate: uric acid ppts at acidic pH

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94
Q

Bacteria vs gout

A

Stimulus: LPS/bact/fungus v Uric acid crystals
Cytokines: TNFa/IL-1/IFNg v IL-1b/IL-8
Involvement: Systemic v Local

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95
Q

Inflammation (bacteria)

A
  1. Bact/LPS -> inflam
  2. MPs/monocytes -> inflam (TNFa/IL-1/IFNg) and chemotactic cytokines
  3. LPS/TNFa/IL-1 induce EC adhesion molecules and MP/mono/conn tiss/EC COX-2
  4. Neutrophil recruitment by cytokines/inflam med.s
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96
Q

Chlorox

A

mimics hypochlorous acid in our phagocytic cells (bacteriocidal oxidative burst)

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97
Q

Septis

A

Systemic inflammation due to circulating cytokines
Damage caused by COX-2, adhesion molecules, and myeloid activation
Systemic vasodilation and plasma extravasion -> BP drop
Can occur if microbe enters bloodstream (body mounts immune response towards entire bloodstream)
Can lead to septic shock (low BP), multi-organ failure, and death

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98
Q

Anaphylaxis

A
  1. Exposure (resp tract to allergen)
  2. Activation: mast cells (bound IgE receptor)
  3. Degranulation: mast cells-> histamine
  4. Respiratory excess: airway constr, impaired breathing
  5. Vasculature excess: hypotension (10 min: histamine inc, 30-60 min: normal)
  6. Urine: histamine and N-methylhistamine

BONUS: mast cells make LTC4, LTD4, PGD2 -> inc perm, dec vasc periph resist, hypotension, mucus, bronchoconstr
TREAT: epinephrine (vasoconstr/bronchodil) and agents to counter histamine/LTs/eicosanoids

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99
Q

Self-Nonself Model

A

Each lymphocyte expresses a single surface receptor specific for a foreign Ag
Receptor signaling initiates imm resp
Self-reactive lymphocytes deleted EARLY in life

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100
Q

Danger Signals

A

Stimulate DC maturation in lymph node

  1. microbe infection
  2. necrosis/stress products
  3. immunostimulators (heparan sulfate)
  4. inflam cytokines
  5. vessel rupture/chemotaxis
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101
Q

Dendritic cells vs macrophages

A

DCs have much higher expression of costimulatory molecules
Macrophages don’t have enough costim expression to activate naive T cells
ONLY DCs can activate naive T cells

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102
Q

M. tuberculosis T cells

A

Th1
prevents fusion of phagosome and lysosome, grows slowly, more common in crowded/hot/humid conditions b/c transmitted by droplets

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103
Q

Asthma T cells

A

Th2

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104
Q

Chemokine receptor and example

A

GPCR, IL-8

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105
Q

most potent inducer of TNFa/IL-1

A

LPS/endotoxin

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106
Q

keloid scar

A

TGFb -> myofibroblasts -> fibrosis -> keloid scar

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107
Q

fibroblasts vs myofibroblasts

A

myofibroblasts have more actin, make more conn tissue

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108
Q

Innate cytokines

A

TNF/IL-1, IL-6
IL-8, IL-10, IL-12
IFN (a/b/g)
IL-15, IL-18

109
Q

Adaptive cytokines

A 
IL-2- T cell prolif/diff (Tc/Th/Treg)
IL-4- IgE switch
IL-5- eosinophils, IgA
IFNg- M1
IL-17- inflam
TGFb- Treg, inh T cells
110
Q

T-bet

A

transcription factor for Th1 (intracellular bacteria)

111
Q

GATA-3

A

transcription factor for Th2 (helminths)

112
Q

RORgT

A

transcription factor for Th17 (extracellular bacteria/fungi)

113
Q

FOXP3

A

transcription factor for Treg cells

114
Q

IL-2R

A

naive T cell: low affinity, beta-gamma-c
activated T cell: high affinity, alpha-beta-gamma-c
stimulates IL-2R expression on activated T cells (after a few hrs)
decreases w/dec in antigen

115
Q

IL-12 knockout mice

A

can’t control m. tuberculosis infection because no Th1 (adaptive/cell-mediated immunity)
die late

116
Q

IFNg knockout mice

A

die early because macrophages (M1) aren’t activated-> no phagocytosis/inflammation (innate immunity)

117
Q

granulomas

A

created by M2 macrophages

118
Q

Type I cytokine receptor

A 
hemopoietin
Jak STAT
IL-2/3/4/5/6/7/9/11/12/13/15/21
IL-2Rbgc/IL-2Rabgc
G/GM-CSF
119
Q

cytokine synergy

A

synergistic EFFECTS from receptors, but each cytokine has different receptor (receptors don’t actually work together)

120
Q

Type II cytokine receptor

A

Jak STAT
IFNa/b/g
IL-10

121
Q

TNF receptor

A 
TRAF
I: TNFrp75   II: TNFrp55
TNFa
TNFb/lymphotoxin
LTs
122
Q

IL-1 receptor

A

IRAK

IL-1/18

123
Q

chemokine receptor

A

(IL-8)

GPCR

124
Q

Positive T cell selection

A

Thymus: method of maturation of MHC-restricted T cells
positively select only T cells w/WEAK recognition of MHC I/II (one or the other)
Failure (no MHC recognition) -> apoptosis
Too much strength could lead to hypersensitive T cells that respond to self

125
Q

Negative T cell selection

A

Thymus: method of maturation of MHC-restricted T cells
negatively select against T cells w/STRONG recognition of MHC I/II
Too much strength could lead to hypersensitive T cells that respond to self

126
Q

T cell co-receptors

A

CD4 and CD8

127
Q

T cell activation

A
  1. skin: langerhans cells uptake antigen
  2. LH cells w/Ag enter lymphatic system
  3. LH cells enter lymph node (afferent vessel) -> become DCs that have B7
  4. LN: B7 DCs activate naive T cells (parafollicular cortex)
128
Q

afferent lymphatic vessel

A

where activated DCs enter LN to deliver Ag to T cells

129
Q

parafollicular cortex

A

T cell zone of LN

where activated DC (w/B7) activate T cells

130
Q

CD3 proteins

A

gamma, delta, epsilon, zeta
needed for T cell activation with TCR and CD4/8
cytoplasmic tail is long enough to signal

131
Q

T cell activation proteins

A 
Costimulation****
TCR + Ag
CD28 + B7 (CD80/86)
CD3
CD4 or 8 + MHC II or I
CD40L + CD40
132
Q

T cell stimulation process

A

1st interaction w/APC: produce ONLY IL-2, NOT committed to Th1/2
2nd interaction w/APC: produce OTHER CK’s, commit to Th1/2, effector cell HOMING, memory cells stay in LN
Th1-> IFNg, TNFb, IL-2
Th2-> IL-4, IL-5, IL-10

133
Q

T cell homing

A

Occurs with RE-stimulation (2nd interaction w/APC)
T cells return to part of body from which APC’s (tissue macrophages) came
effector T cells move from LN -> tissue
memory T cells remain in LN

134
Q

Th1/2 polarization

A

takes about 2 days

memory cells remaining in LNs help skip this delay in subsequent infections

135
Q

Th1 differentiation results from…

A

presence of activated macrophages/DCs and IL-12

default unless no IL-12

136
Q

Th2 differentiation results from…

A

presence of IL-4

ABSENCE of IL-12

137
Q

CD40-CD40L

A

T cell activation (by APC)-> express CD40L
CD40L -> binds CD40 (on APC) and increases MHC/B7 (on APC), helps w/B cell activation
CD40 -> inc APC potency

138
Q

Ab activation

A

need Ag binding

Exception: mast cells w/IgE (bind IgE’s Fc)

139
Q

Cross-presentation

A

LN: DCs present intracell microbes on MHC I and extracell microbes on MHC I and II
CD8 T cells recognize MHC I, CD4 T cells recognize MHC II
CD4 T cells and DCs stimulate CD8 T cells
CD8 T cells proliferate -> leave LN

140
Q

Granzyme

A

enters target cells through

  1. receptor-med endocytosis
  2. membrane holes created by perforin
141
Q

gd T cells

A 
gd TCR (not alpha/beta) + CD3 (no CD4/8)
Location: intestine, uterus, tongue (epithelium)
Function: 1st line of defense, regulation (make CK's), link inn/adap
Adaptive: TCR gene rearrangement, memory
Innate: PRRs
do NOT need APCs (or MHC)
142
Q

NKT cells

A

T and NK CDs
recognize lipids and glycolipids (w/CD1d)
helps against Tb
secrete IFNg and IL-4

143
Q

deficient NKT cells

A

autoimmunity
cancer
asthma progression

144
Q

somatic recombination

A

gene rearrangement in non-dividing/somatic cell (ex- immune cell) to create T/B cell diversity
lots of mutations due to lack of DNA repair mechanisms
combinatorial diversity
TCR a/b chains and BCR (Ig) H/L chains
beta/Heavy: VDJ recombination
alpha/Light: VJ recombination
Followed by transcription, mRNA splicing, translation

145
Q

junctional diversity

A

increases BCR and TCR diversity
due to random NT removal/addition
exonuclease and terminal deoxyribonucleotidyl transferase (TdT)
almost unlimited

146
Q

somatic hypermutation

A

Only in B cells, after Ag exposure/memory re-stim
Point mutations in heavy chain and variable region due to C->U (deamination) repair (U replaced with incorrect NT)
May lead to affinity maturation (inc ab affinity for its epitope)
Followed by selection of high-aff B cells by Ag-presenting follicular DCs (in lymphoid follicle germinal centers)

147
Q

active immunity

A

acquired by T cells after disease

148
Q

Double-negative T cell

A

precursor cells from bone marrow w/o TCRs or CD4/8

reside in subcapsular cortex region (thymus)

149
Q

Double-positive T cell

A

begin TCR gene rearrangement
both coreceptors expressed
reside in deep cortex (thymus)

150
Q

Single-positive T cell

A

inc TCR expression
lose either CD4 or 8 (whichever receptor binds self too strongly)
reside in medulla (thymus)

151
Q

T helper mechanism

A
  1. Macrophage engulfs microbe, breaks down, presents to Th on MHC II
  2. CD4 Th w/proper specificity undergoes clonal expansion -> effector cells and memory cells
  3. T effector cells interact w/B cells (B cells w/proper specificity neutralize Ag and undergo clonal expansion-> plasma cells and memory cells)
  4. Plasma cells secrete Igs to block Ag
152
Q

complementarity determining regions

A

regions where light chains are complementary to heavy chains

in variable region of light chains and heavy chains

153
Q

Kappa light chain genes

A

L/V: 35 (but maybe 300) (2 exons: L and V)
no D region
J: 5 (b/w V and C)
Constant: 1

Rearrangement: V+J

154
Q

Lambda light chain genes

A

L/V: 30 (2 exons: L and V)
no D region
J: 4 (b/w V and C)
Constant: 4

Rearrangement: V+J

155
Q

complementarity determining regions

A

regions where light chains are complementary to heavy chains
in variable region of light chains and heavy chains
CDR3 is most variable and most IMPORTANT for Ag recognition

156
Q

Combinatorial diversity

A

increases BCR and TCR diversity
due to somatic recombination
V(D)J recombinase
limited by available V/D/J gene segments

157
Q

V(D)J recombinase

A

COLLECTION of enzymes in immature B/T cells
sloppy somatic recombination of VDJ gene segments in B/TCR
Recombinase-activating gene (RAG)-1 and RAG-2
Exonuclease
Ligase

158
Q

RAG-1 and 2

A

bind recombination switch sequence spacer (12-23 bp b/w heptamer and nonamer)

159
Q

TdT

A

randomly adds NTs to V/D/J gene segments at site of V(D)J gene recombination
contributes to hypervariability of CDR3

160
Q

CDR3

A

most variable CDR in V region

most IMPORTANT for Ag recognition by B/T cells

161
Q

human leukocyte antigens

A

MHC proteins
each molecule has 1 peptide-binding cleft
determine graft acceptance between individuals
highly polymorphic (only same if monozygotic twins)
express paternal/maternal equally (codominant)
3 million bps on Chr 6

162
Q

MHC I

A 
binds peptides (8-10 AAs) in the CYTOSOL
recognized by CD8 CTLs
presents peptide fragment epitope at antigen binding cleft
Domains: a1, a2, a3, b2m
a1/a2 (cleft) vary b/w people 
a3 invariant, binds CD8
beta2microglobin maintains conformation
163
Q

MHC II

A

binds peptides (13-25 AAs) from w/in VESICLES
recognized by CD4 Thelpers
presents peptide fragment epitope at antigen binding cleft
Domains: a1, a2, b1, b2
a1/b1 (cleft) vary b/w people
b2 binds CD4

164
Q

MHC I genes

A

HLA-A, B, C (D/E/F not important)

inherit one set from each parent -> any cell can have 6 diff MHC I molecules

165
Q

MHC II genes

A

HLA-DP, DQ, DR (DM/DO not important)

alpha/beta chain = polymorphic -> any cell can have 10-20 diff MHC II molecules

166
Q

autografts (autologous)

A

tissue grafted from one place to another in same person

ex- skin

167
Q

isografts (syngeneic)

A

tissue transplants b/w genetically identical people

168
Q

allogenic grafts

A

tissue grafts b/w genetically different members of SAME species
ex- kidney transplants

169
Q

xenogenic grafts

A

tissue grafts between members of DIFF SPECIES

ex- pig heart valves for humans

170
Q

Transplant Test

A

ABO blood typing compability
HLA typing
preformed Abs
Crossmatching

171
Q

hyperacute graft rejection

A

caused by ABO blood type incompabilities

172
Q

HLA typing

A

focuses on HLA-A, B, DR

more HLA matches = better graft survival

173
Q

haplotype

A

set of alleles of linked genes one 1 parental chromosome
determine different antigens, but inherited as unit
minimized chance of crossing over
never identical unless monozygotic twins
new haplotype can occur within same individual if recombination takes place

174
Q

haplotype matching

A

need same genes AND same sequence

175
Q

B7-1/2

A

co-stimulatory molecule (CD80/86) expressed by activated APCs with MHC II
Ag binding activates APCs and increases B7 expression
binds CD28 on T cell to activate (w/MHC II)

176
Q

Necrosis

A

passive, catabolic cell death in response to external toxic factors
induces caspase cascade
characterized by swelling and rupture of cell membrane (lysis), which may cause inflammation or harm other cells

177
Q

Inflammation

A 
physiological: 
   eliminates initial cause
   removes necrotic cells
   initiates repair
pathophysiological:
   injury bystander normal tissue
normally self-limited, can become chronic
178
Q

Humoral response to danger signals

A

activation of complement

activated immune cells: chemokines, leukotrienes/prostaglandins, ROI, NO

179
Q

necrotic danger signals

A

HMGBI
Uric acid
Heat Shock Proteins

180
Q

acute inflammation process

A
  1. Detect damage: vascular coagulation, PRRs recognize pathogens/cell injury
  2. Leukocyte Recruitment and Stimuli: C5a, PRR-> EC adhesion molecules and plasma exudation (neutrophils first)
  3. Resolution: Microorganisms/necrotic tissues eliminated-> apoptotic neutrophils phagocytized by MPs (scavenger receptors)
  4. Wound healing: angiogenesis, re-epitheliziation, collagen deposition, MP-(TGFb)-> fibroblasts
181
Q

Uric acid

A

necrotic danger signal

activates NFkB

182
Q

HSPs

A

necrotic danger signal

activates NFkB and release of pro-inflam CK’s (TNFa/IL-1b)

183
Q

HMGB1

A 
necrotic danger signal received by DCs
High Motility Group Box 1
passively-released protein during necrosis
activates NFkB
Receptor: RAGE
184
Q

Uric acid

A

necrotic danger signal received by DCs

activates NFkB

185
Q

HSPs

A

necrotic danger signal received by DCs

activates NFkB and release of pro-inflam CK’s (TNFa/IL-1b)

186
Q

RAGE

A

DC Receptor of Advanced Glycation End Products

receptor for high motility group box 1 (HMGB-1, necrotic danger signal)

187
Q

chronic inflammation

A 
cancer
diabetes
cardiovascular
neurological disease
autoimmunity
arthritis
pulmonary disease
alzheimer's disease
188
Q

artherosclerosis

A
  1. monocytes recruited by activated ECs -> MPs
  2. TLRs recognize microbes -> activate MPs (foam cells filled w/lipids)
  3. Pro-inflam CK’s, ROI, NO, etc.
  4. Inflammation and tissue damage
  5. MP’s accumulate lipids-> become foam cells
189
Q

scavenger receptors

A

no feedback mechanism(/refractory period) (unlike normal receptors that have refractory periods)

190
Q

statins

A

break down lipid foam cells (possible correlation w/Alezheimers)

191
Q

Apoptosis molecular triggers

A 
DNA damage
CK starvation
hypoxia
temperature
death receptors
192
Q

Apoptosis molecular regulators

A 
Maintain equilibrium b/w pro- and anti-apoptotic signals
Death domain factors
cytochrome c
p53
Bcl-2 family
Myc/oncogenes
193
Q

Apoptosis molecular executioners

A

caspases

194
Q

apoptosis-inducing DNA damage ex

A

DNA damage: keratinocyte exposed to UV

Cytokine: cells w/o CKs

195
Q

Caspases

A

cysteine proteases
orchestrate morphologic changes
destroy key components of cellular infrastructure-> initiate apoptosis

196
Q

Apoptosis molecular mechanisms

A
  1. Intrinsic (mitochon), Extrinsic (Fas, TNFr), CTLs (granzyme), Injury (toxins, free radicals)
  2. pro-apoptotic molecules (ex- cytochrome c)
  3. executioner caspases -> endonucleases and cytoskeleton breakdown
  4. phagocytic cell receptor ligands (cytoplasmic bud-> apoptotic body-> phagocytosis)
197
Q

Fas

A

CD95
expressed by every cell
only activated lymphocytes express Fas ligand

198
Q

Intrinsic Mitochondrial pathway

A 
TRIGGERS: 
   1. Bcl-2 (BAK/BAX)
   2. Ca
   3. Free radicals
REGULATORS: 
    1. Cytochrome c
    2. Smac/Diablo
    3.  Apoptosis-inducing factor
    4. Endonuclease G
EXECUTIONERS: (not immediatly activated)
   - Caspase 9
   - Caspase 3
   - Apaf-1
199
Q

Caspase activation

A

executioner phase of apoptosis

“point of no return”

200
Q

Extrinsic Apoptotic pathway

A
  1. Fas ligand (TNF ligand family) binds Fas (TNFr family)
  2. FADD activation
  3. death effector domain activation
  4. procaspase-8, 10 -> Caspase 8, 10 -> cascade
  5. mitochondrial damage, membrane changes, proteolysis, nuc condensation/DNA fragmentation
  6. APOPTOSIS
201
Q

Autoimmune Lymphoproliferative Syndrome

A

ALPS patients: heterozygous mutations in Fas gene
early life: chronic adenopathy/splenomegaly
chronic persistence/activation of both T cells -> B cell maturation -> Ab secretion
defective Fas-med apoptosis-> extended survival of lymphocytes -> possible malignant transformation
T cells normal in beginning, but don’t die-> LN swelling

202
Q

B cell selection

A
  1. Negative selection against B cells w/HIGH affinity for self antigen
  2. Receptor editing: self Ag recognition reactivates Ig gene recomb-> new light chain expressed (not specific for self antigen)
203
Q

Negative selection

A

first part of B cell selection

gets rid of B cells w/HIGH affinity for self antigen (apoptosis)

204
Q

receptor editing

A

second part of B cell selection
when BCR recognizes self antigen, it reactivates Ig gene recomb and creates a new light chain NOT specific for self antigen

205
Q

B cell activation (by Ag)

A
  1. Ag recognition by naive IgM+/D+ B cell
  2. B cell activation by helper T cells and other stimuli
  3. B lymphocyte activation/Clonal Expansion
  4. Differentiation to effector cells (ab-secreting plasma cells, ab-expressing B cells, high-affinity Ig-expressing B cell)
    Effector fxns: Ab secretion, isotype switching, affinity maturation, memory B cell
206
Q

IgD

A

membrane bound, high in new born babies

207
Q

B cell can make ____ plasma cells which make ____ abs per day

A

4000

10^12

208
Q

B cell Ag recognition (occurs where, initiates what)

A

occurs in LN
Ag does not require processing
activates B cells
Initiates…
1. B cell proliferation (enter cell cycle-> mitosis)
2. Inc expression of costim (MHC II, B7) and CK receptors (Thelper cells)
3. Low levels of IgM secretion

209
Q

B cell gene mutations

A

V/D/J gene segments have a mutation every 1000 bases (normal DNA has 1 every 10^8)
called somatic hypermutation
results in affinity maturation

210
Q

B cell proliferation

A

must constantly be RE-stimulated by binding to their cognate antigens
higher affinity BCR (diff ones due to somatic hypermutation) means they get Ag first-> stimulated first/more easily/more
Result: more B cells w/high affinity BCR for Ag

211
Q

C3d

A

protease-modified version of C3b (from innate complement system)
C3b stays bound to microbe-> persists and modified to C3d bound to microbe
recognized and bound by CR2 (adaptive immunity) on B cell

212
Q

CR2

A

adaptive immunity receptor
helps B cells recognize microbes early in infection when Ag is low
binds C3d (bound to microbe) and increases Ag sensitivity of BCR 100x (helps activate B cell)

213
Q

B cell migration

A

B cells activated in the lymphoid follicle (B cell zone)

Migrate to central zone to interact w/T follicular helper cells in parafollicular cortex (T cell zone)

214
Q

parafollicular cortex

A

T cell zone of LN

215
Q

lymphoid follicle

A

B cell zone of LN

216
Q

T follicular helper (Tfh) cells

A

interact with B cells in central zone of LN

217
Q

B cells vs DCs (as APCs)

A

B cells: activated by Ag/BCR or rec-med endocytosis-> Ag processing-> presented on MHC II to T helper cell
DCs: rec-med endocytosis-> Ag processing-> presented on MHC I to CTLs

218
Q

Hyper IgM Syndrome

A

caused by defect in ability to switch from production of IgM to IgG/A/E
defect is either in CD40L (X-linked) or CD40

219
Q

CD40L defect

A

results in Hyper IgM syndrome

X-linked-> ONLY MALES AFFECTED

220
Q

CD40 defect

A

results in Hyper IgM syndrome

affects males and females equally

221
Q

B cell Activation (by T cells)

A
  1. cytokines + direct contact b/w B cell and Th cell
  2. activated Th cells have CD40L that binds CD40 on B cells -> costimulation
  3. BCR cross-linking-> B cell activation
  4. B cell prolif, initial ab production (IgM w/some IgD), germ center rxn
222
Q

tiger licks baby

A
  1. mom licks Ags off cub
  2. Ags picked up by IgA in intestine
  3. Ag-specific IgA and Ags secreted in breast milk
  4. cub drinks milk
  5. cub develops OWN IgA abs against Ags
  6. establishment of Humoral Imm Sys

BREAST FEEDING ESTABLISHES IMM SYS

223
Q

final step in B cell maturation

A

PLASMA CELL
or
MEMORY CELL

224
Q

plasma cell lifespan

A

~5 days (make 2000 abs/sec)

225
Q

plasma cell location

A

spleen

bone marrow

226
Q

memory cell

A

depends on CD40-CD40L interaction

NO MEMORY WITHOUT B CELL ACTIVATION BY T HELPER CELLS

227
Q

Thymus-dependent antigens

A 
the only ones T cells help with 
proteins
isotype switching
affinity maturation
MEMORY B CELLS
228
Q

Thymus-independent antigens

A

POLYMERIC proteins, carbs, lipids, nucleic acids that persist for long periods of time (resistant to degradation)
IgM, some IgG (no switching)
no affinity maturation
only some Ags produce memory
can’t bind MHC II (no T helper cells)
cross-link many BCRs (polyclonal)-> activate B cells-> prolif/diff
TI-1 and TI-2 Ags

229
Q

TI-1 Ags

A

Thymus-independent
polyclonal activators of B cells
NON-SPECIFIC activation of multiple B cells at a time

230
Q

TI-2 Ags

A

Thymus-independent
not polyclonal
repeating epitopes for cross-linking BCRs
SPECIFIC activation of clones of ONE B cell
Abs have relatively low affinity for TI-2 Ags

231
Q

B cell activation (by TI-1 Ags)

A

Signal 1: BCR binds Ag (ex- LPS)
Signal 2: TLR binds Ag
Multiple B cells initiated (polyclonal)

232
Q

B cell activation (by TI-2 Ags)

A

Signal 1: BCR binds Ag
Signal 2: BCR CLUSTERING/cross-linking
Ags are strongest inducer of COMPLEMENT (b/c multi-epitopal)
Abs produced: mostly IgM (important for encapsulated bacteria)
Relatively low Ab affinity for TI-2 Ags

233
Q

encapsulated bacteria

A

major mechanism of host defense is Ab-mediated Immunity (IgM**)
bacterial cell wall polysaccharides = TI Ags
Activate B cells right away without having to wait for T cell activation

234
Q

Ab-med immunity deficiency (susceptibility to…)

A

congenital or acquired deficient Ab-mediated imm response
very susceptible to infections w/encapsulated bacteria
capsule=TI Ag that would usually induce complement but have to wait for T cell activation, giving bacteria a chance to flourish

235
Q

latent infection

A

immune response controls but does not eliminate the infection
microbe is good at “hiding”
usually slow growing, causes cell lysis
ex- HIV, Tb

236
Q

cause of tissue injury/disease

A

usually due to host immune response to microbe (rather than due to microbe itself)

237
Q

SCID

A

no adaptive imm (B/T cells)

innate immunity suppresses initial infection, but eventually microbes cannot be contained

238
Q

extracellular bacteria pathological mechanisms

A
  1. inflammation (tissue destruction)

2. toxin production (endo/exo)

239
Q

Endotoxins

A

components of bacterial cell walls
only released upon CELL DEATH
ex- LPS (potent activator of MPs, DCs, and ECs)

240
Q

Exotoxins

A

secreted by bacteria when they’re ALIVE
many are cytotoxic (ex- diphtheria/cholera/tetanus toxin)
some interfere w/normal cellular fxn (but don’t kill cell)
some stimulate CK production-> cause disease

241
Q

diphtheria toxin

A

exotoxin from extracellular bacteria

Fxn: shuts down protein synthesis in infected cells

242
Q

cholera toxin

A

exotoxin from extracellular bacteria

Fxn: interferes w/ ion and water transport

243
Q

tetanus toxin

A

exotoxin from extracellular bacteria

Fxn: inhibits neuromuscular transmission

244
Q

complement

A 
PGN (G+) and LPS (G-) -> alternative
Mannose -> lectin
MAC -> bact lysis (ex- Neisseria)
C3a + C5a -> leukocyte chemotaxis/activ
C3b -> MAC or opsonization (for phagocytosis)
Result: enhanced phagocytosis
245
Q

acute phase proteins

A

mannose-binding lectin

C-reactive protein

246
Q

Phagocytes

A

neutrophils and macrophages
Recognize extracell bact: MANNOSE and SCAVENGER receptors (which then promote phagocytosis)
Recognize opsonized bact: Fc (Abs) and COMPLEMENT receptors (which then promote phagocytosis AND activation)
microbial products activate them via TLRs
Activation-> phagocytes secrete CK’s-> leukocyte infiltration to infection site (inflammation)-> leukocytes ingest/destroy bacteria

247
Q

ROI effects

A
  1. DNA damage
  2. Lipid peroxidation
  3. AA oxidation
  4. Enzyme inactivation by co-factor oxidation
248
Q

Innate immune evasion by extracellular bacteria

A 
inhibit complement activation (many bacteria)
resist phagocytosis (pneumococcus, Neisseria meningitidis)
scavenge ROI (catalase+ staphylococci)
249
Q

extracellular bacteria that resist phagocytosis (ex)

A

pneumococcus, Neisseria meningitidis

250
Q

extracellular bacteria that scavenge ROS (ex)

A

catalase+ staphylococci

251
Q

peroxynitrite (ONOO-)

A

causes apoptosis (mitochondria: AIF, or cit C-> caspase activation) or necrosis (lipid peroxidation, protein oxidation, protein nitration, inactivation of enzymes)

252
Q

innate immune response against extracellular bact

A
  1. complement (opsonization-> phagocytosis and MAC-> lysis)
  2. inflammation
  3. phagocytosis (neutrophils and macrophages)
253
Q

adaptive immune response against extracellular bact

A

Antibodies…

  1. neutralize microbes/toxins
  2. opsonize microbes for phagocytosis
  3. help NK cells w/Ab-dep cytotoxicity
  4. complement (lysis, opsonization/phagocytosis, inflammation)
254
Q

Ab neutralization

A

prevents bacteria/toxin from binding cells/infecting new cells
utilized by vaccines-> induce Th2 response-> IgE production
inc vaccines may correlate w/inc allergies in modern humans (body prefers to use IgG, not IgE

255
Q

Ab-mediated phagocytosis

A
  1. IgG opsonizes microbe
  2. IgG binds phagocyte Fc receptor (FcgR)
  3. phagocyte activation
  4. phagocytosis
  5. killing
256
Q

Fc receptors

A

FcgRI: IgG
FceRI: IgE
FcaRI: IgA
none for IgM (pentamer-> can’t bind)

257
Q

phagocyte Fc receptors

A

FcgRI: IgG
FcaRI: IgA
bind Ab-Ag COMPLEXES ONLY

258
Q

FceRI

A

binds FREE IGE (not in complex)
On mast cells, eosinophils, basophils
binding-> granule secretion
extremely high binding strength means blood levels of IgE are never very high b/c immediately taken up by mast cells

259
Q

adaptive immune evasion by extracell bacteria

A 
antigenic variation (Neisseria gonorrhoeae, E coli, salmonella typhimurium)
inhibit complement activation (many bacteria)
resist phagocytosis (pneumococcus, Neisseria meningitidis)
scavenge ROI (catalase+ staphylococci)
260
Q

antigenic variation

A

helps extracellular bacteria evade adaptive immunity
bacterium/virus alters surface proteins to evade host immune response
ex- Neisseria gonorrhoeae, E coli, salmonella typhimurium

261
Q

complement inhibition

A

helps many extracellular bacteria evade innate and adaptive immunity
bacterial capsules, C3 convertase decay, blocked MAC formation (vitronectin)

262
Q

vitronectin

A

host protein used by bacteria to block MAC formation and inhibit complement

263
Q

phagocytosis resistance

A

helps extracellular bacteria evade innate and adaptive immunity
interfere w/complement activation and/or deposition at bacterial surface
inject anti-phagocytic effectors into cell
ex- pneumococcus, Neisseria meningitidis

264
Q

scavenge ROI

A

helps extracellular bacteria evade innate and adaptive immunity
catalase-pos pathogens deactivate peroxide radicals-> survive unharmed WITHIN host
ex- catalase-pos staphylococcus

265
Q

pyrogens

A 
cause fever (INNATE RESPONSE)
Endotoxin/LPS (G-)
LTA (G+)
viruses
yeast
molds
environment (packing materials)
266
Q

fever

A

innate response caused mostly by IL-1, but also IL-6, and least by TNFa
manifestation of CK signals to hypothalamus

267
Q

bacterial pneumonia

A

fever => infection
localized crackles => bacteria (crackles everywhere=> virus)
otherwise healthy => ACUTE
Labs: lung x-ray, sputum sample, complement testing (C3 levels)
Do NOT wait for lab results, START W/BROAD ABX b/c infection could lead to septic shock

268
Q

Immunological Tolerance

A

Specific unresponsiveness to an Ag (ex- self-tolerance)
Breakdown-> autoimmunity
Imperfect negative selection of self-reactive T lymphocytes-> low level of auto-reactivity (crucial for normal imm fxn)

269
Q

Remission

A

Occurs because Ags are removed from imm sys but NOT from the BODY

HDM (6 decks)

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