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Final Exam Flashcards

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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
Classically activated macrophage (M1)
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
26
Alternatively activated macrophage (M2)
``` IL-4, IL-13: Monocyte-> Macrophage -> 1. IL-10, TGFb: anti-inflam 2. Proline, polyamines, TGFb: wound repair Inh by TLR ligands, IFNg granulomas ```
27
Th1 phenotypes
``` Cytokines: IFNg Immune rxn: M1 activ, IgG prod Against: INTRAcellular microbes Disease: autoimmune diseases, tissue damage (from chronic infections) TF: T-bet ```
28
Th2 phenotypes
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
29
Th17 phenotypes
``` Cytokines: IL-17, 22 Immune rxn: neutrophilic/monocytic inflam Against: EXTRAcell bacteria, fungi Disease: autoimmune/inflam diseases TF: RORgT ```
30
IgM
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
31
IgG
B cell + Th (CD40L, cytokines) + IFNg monomer Fc-dependent phagocytosis, complement activ, placental transfer of immunity Neutralizes bacterial toxins and opsonizes bacteria Neonatal immunity
32
IgE
B cell + Th (CD40L, cytokines) + IL-4 monomer immunity against helminthic parasites mast cell degranulation (immediate hypersensitivity)
33
IgA
B cell + Th (CD40L, cytokines) + mucosal cytokines (TGFb, BAFF) dimer (or monomer) proteolysis-resistant (GI tract) mucosal immunity
34
Th1-mediated immunity
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
35
Th2-mediated immunity
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
36
CD8+ T cells
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
37
CD8+ Tc cell killing mechanisms
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)
38
gamma/delta T cells
``` 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 ```
39
NKT cell antigen recognition
semi-invariant Va14-Ja18 TCR binds glycolipid on CD1d (on APC)
40
Cellular immunity (effector cells, pathogen location, Ag presentation, action)
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
41
Humoral immunity (effector cells, pathogen location, Ag presentation, action)
Effector cells: Type 2 CD4+ T lymphocytes Pathogen location: extracellular Ag presentation: Pro-APC MHC II Action: Abs prod by plasma cells
42
AA
Arachidonic Acid
43
COX
CycloOXygenase enzyme | rich in fibroblasts, smooth muscle, epithelial, endothelial, and hematopoietic cells
44
GSH
reduced glutathione
45
H1 and H2
Histamine receptors
46
IL
InterLeukin
47
IgE
Immunoglobulin E
48
LPS
LipoPolySaccharide
49
LT
LeukoTriene (LTA4, LTB4, LTC4, LTD4, LTE4) made by leukocytes have conjugated triene in structure
50
5-LO
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
51
NSAID
Non-Steroidal Anti-Inflammatory Drug
52
PG
ProstaGlandin (PGE2, PGF2, PGI2)
53
PGI2
ProstaGlandin I2 (prostacyclin)
54
PUFA
PolyUnsaturated Fatty Acid
55
TNFa
Tumor Necrosis Factor
56
TxA2
ThromboXane A2
57
PLA2
PhosphoLipase A2 (enzyme) Substrate: cell membrane phospholipids Fxn: liberates AA
58
FLAP
5-LO activating protein (enzyme) Substrate: 5-LO accessory protein Fxn: converts AA + O2 -> LTA4
59
LTA4 hydrolase
Enzyme that converts LTA4 -> LTB4
60
LTC4 synthase
Enzyme that converts LTA4 -> LTC4
61
Peptidases
Enzymes that convert LTC4 -> LTD4 -> LTE4
62
LTA4
Fxn: biosynthetic intermediate | involved w/asthma
63
LTB4
Receptor: BLT1,2 Fxn: augments neutrophil EC adhesion, POTENT neutrophil chemotaxis and degranulation, eosinophil chemotaxis involved w/asthma main LT made by neutrophils
64
LTC4 = LTD4
Receptor: CysLT2 Fxn: bronchoconstriction, mucus secretion involved w/asthma
65
LTD4 > LTC4
Receptor: CysLT1 Fxn: bronchoconstriction, mucus secretion involved w/asthma
66
LTE4
Receptor: CysLT Fxn: less active metabolite involved w/asthma
67
Histamine
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
68
Histamine synthesis/inactivation for storage
Dietary histidine -(decarboxylase) -> CO2 + Histamine 1. Diamine oxidase: imidazole aldehyde (inactive) 2. Histamine N-methyl transferase: N-methyl histamine (inactive)
69
Histamine v Prostaglandins/Thromboxane/Leukotrienes
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
70
H1 receptor
tissue-specific GPCR for histamine Nasal/bronchial- mucus secretion Bronchial/intestinal smooth muscle- constriction Sensory nerves- pain
71
H2 receptor
tissue-specific GPCR for histamine | Stomach- gastric acid secretion
72
H1 and H2 receptors
tissue-specific GPCRs for histamine Heart- HR Vessels- peripheral resistance Skin capillary blood vessels- dilation, permeability, pain sensitization
73
COX-1
helps maintain normal cell fxn constitutive in platelets, ECs, fibroblasts, smooth muscle, monocytes, macrophages, mast cells, basophils, neutrophils (less)
74
COX-2
inducible in ECs, fibroblasts, smooth muscle, monocytes, macrophages, mast cells, basophils, neutrophils (less)
75
Leukotriene synthesis
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
76
Leukotriene breakdown
spontaneous hydrolysis into inactive products | helps prevent LT excess
77
Self-reliant chemotaxis (neutrophils)
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)
78
pyogenic infection
characterized by neutrophil-rich pus
79
Mediators of inflammation
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
80
Asthma elements
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
81
Asthmatic airway
bronchiolar smooth muscle constriction inflammation mucus discharge pulmonary edema
82
Hypersensitivity
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)
83
Histamine hypersensitivity
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)
84
Mast cell/histamine location
``` Concentrated in areas of the body most vulnerable to antigen/pathogen exposure Nasal passage Trachea, bronchi, lungs Stomach, intestines Skin ```
85
allergy treatment
inhibit RECEPTORS specific to area w/symptoms | inhibiting synthesizing enzyme risks having a shortage of histamine in other important areas of the body
86
Circulating inflammatory cells
``` Neutrophils: 40-60% lymphocytes: 20-40% Monocytes: 2-8% Eosinophils: 1-4% Basophils: .5-1% ```
87
Gout
Failure to excrete uric acid at an appropriate rate | Treat inflammation AND metabolism (synth) of uric acid
88
Gout mechanism
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
89
IL-1 beta (gout)
Binds membrane receptor Releases substrate (AA) and activates enzyme (COX-2) Induces adhesion molecules in EC (inc neutrophil margination)
90
PGE2 and PGI2 (gout)
PGI2: vasodilation PGE2: permeability Leaky vessels-> plasma extravasion-> local edema (redness, heat, swelling, pain)
91
IL-8 (gout)
Chemotactic factor initiating movement of neutrophils from blood -> leaky vessels -> tissue w/activated MP/monocyte
92
Neutrophil adaptability
Normal: reside in blood Pathology: EXIT blood, enter tissue site, 2 fxns 1. granulocyte: discharge degradation mediators 2. phagocyte: engulf and digest
93
Inflammation (gout)
fails to eliminate uric acid crystals ineffective proteases and lysosomal enzymes (phagocyte) ineffective oxidative bursts (granulocyte) May aggravate: uric acid ppts at acidic pH
94
Bacteria vs gout
Stimulus: LPS/bact/fungus v Uric acid crystals Cytokines: TNFa/IL-1/IFNg v IL-1b/IL-8 Involvement: Systemic v Local
95
Inflammation (bacteria)
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
96
Chlorox
mimics hypochlorous acid in our phagocytic cells (bacteriocidal oxidative burst)
97
Septis
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
98
Anaphylaxis
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
99
Self-Nonself Model
Each lymphocyte expresses a single surface receptor specific for a foreign Ag Receptor signaling initiates imm resp Self-reactive lymphocytes deleted EARLY in life
100
Danger Signals
Stimulate DC maturation in lymph node 1. microbe infection 2. necrosis/stress products 3. immunostimulators (heparan sulfate) 4. inflam cytokines 5. vessel rupture/chemotaxis
101
Dendritic cells vs macrophages
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
102
M. tuberculosis T cells
Th1 prevents fusion of phagosome and lysosome, grows slowly, more common in crowded/hot/humid conditions b/c transmitted by droplets
103
Asthma T cells
Th2
104
Chemokine receptor and example
GPCR, IL-8
105
most potent inducer of TNFa/IL-1
LPS/endotoxin
106
keloid scar
TGFb -> myofibroblasts -> fibrosis -> keloid scar
107
fibroblasts vs myofibroblasts
myofibroblasts have more actin, make more conn tissue
108
Innate cytokines
TNF/IL-1, IL-6 IL-8, IL-10, IL-12 IFN (a/b/g) IL-15, IL-18
109
Adaptive cytokines
``` 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
T-bet
transcription factor for Th1 (intracellular bacteria)
111
GATA-3
transcription factor for Th2 (helminths)
112
RORgT
transcription factor for Th17 (extracellular bacteria/fungi)
113
FOXP3
transcription factor for Treg cells
114
IL-2R
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
IL-12 knockout mice
can't control m. tuberculosis infection because no Th1 (adaptive/cell-mediated immunity) die late
116
IFNg knockout mice
die early because macrophages (M1) aren't activated-> no phagocytosis/inflammation (innate immunity)
117
granulomas
created by M2 macrophages
118
Type I cytokine receptor
``` hemopoietin Jak STAT IL-2/3/4/5/6/7/9/11/12/13/15/21 IL-2Rbgc/IL-2Rabgc G/GM-CSF ```
119
cytokine synergy
synergistic EFFECTS from receptors, but each cytokine has different receptor (receptors don't actually work together)
120
Type II cytokine receptor
Jak STAT IFNa/b/g IL-10
121
TNF receptor
``` TRAF I: TNFrp75 II: TNFrp55 TNFa TNFb/lymphotoxin LTs ```
122
IL-1 receptor
IRAK | IL-1/18
123
chemokine receptor
(IL-8) | GPCR
124
Positive T cell selection
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
Negative T cell selection
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
T cell co-receptors
CD4 and CD8
127
T cell activation
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
afferent lymphatic vessel
where activated DCs enter LN to deliver Ag to T cells
129
parafollicular cortex
T cell zone of LN | where activated DC (w/B7) activate T cells
130
CD3 proteins
gamma, delta, epsilon, zeta needed for T cell activation with TCR and CD4/8 cytoplasmic tail is long enough to signal
131
T cell activation proteins
``` Costimulation**** TCR + Ag CD28 + B7 (CD80/86) CD3 CD4 or 8 + MHC II or I CD40L + CD40 ```
132
T cell stimulation process
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
T cell homing
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
Th1/2 polarization
takes about 2 days | memory cells remaining in LNs help skip this delay in subsequent infections
135
Th1 differentiation results from...
presence of activated macrophages/DCs and IL-12 | default unless no IL-12
136
Th2 differentiation results from...
presence of IL-4 | ABSENCE of IL-12
137
CD40-CD40L
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
Ab activation
need Ag binding | Exception: mast cells w/IgE (bind IgE's Fc)
139
Cross-presentation
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
Granzyme
enters target cells through 1. receptor-med endocytosis 2. membrane holes created by perforin
141
gd T cells
``` 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
NKT cells
T and NK CDs recognize lipids and glycolipids (w/CD1d) helps against Tb secrete IFNg and IL-4
143
deficient NKT cells
autoimmunity cancer asthma progression
144
somatic recombination
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
junctional diversity
increases BCR and TCR diversity due to random NT removal/addition exonuclease and terminal deoxyribonucleotidyl transferase (TdT) almost unlimited
146
somatic hypermutation
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
active immunity
acquired by T cells after disease
148
Double-negative T cell
precursor cells from bone marrow w/o TCRs or CD4/8 | reside in subcapsular cortex region (thymus)
149
Double-positive T cell
begin TCR gene rearrangement both coreceptors expressed reside in deep cortex (thymus)
150
Single-positive T cell
inc TCR expression lose either CD4 or 8 (whichever receptor binds self too strongly) reside in medulla (thymus)
151
T helper mechanism
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
complementarity determining regions
regions where light chains are complementary to heavy chains | in variable region of light chains and heavy chains
153
Kappa light chain genes
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
Lambda light chain genes
L/V: 30 (2 exons: L and V) no D region J: 4 (b/w V and C) Constant: 4 Rearrangement: V+J
155
complementarity determining regions
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
Combinatorial diversity
increases BCR and TCR diversity due to somatic recombination V(D)J recombinase limited by available V/D/J gene segments
157
V(D)J recombinase
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
RAG-1 and 2
bind recombination switch sequence spacer (12-23 bp b/w heptamer and nonamer)
159
TdT
randomly adds NTs to V/D/J gene segments at site of V(D)J gene recombination contributes to hypervariability of CDR3
160
CDR3
most variable CDR in V region | most IMPORTANT for Ag recognition by B/T cells
161
human leukocyte antigens
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
MHC I
``` 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
MHC II
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
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MHC I genes
HLA-A, B, C (D/E/F not important) | inherit one set from each parent -> any cell can have 6 diff MHC I molecules
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MHC II genes
HLA-DP, DQ, DR (DM/DO not important) | alpha/beta chain = polymorphic -> any cell can have 10-20 diff MHC II molecules
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autografts (autologous)
tissue grafted from one place to another in same person | ex- skin
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isografts (syngeneic)
tissue transplants b/w genetically identical people
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allogenic grafts
tissue grafts b/w genetically different members of SAME species ex- kidney transplants
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xenogenic grafts
tissue grafts between members of DIFF SPECIES | ex- pig heart valves for humans
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Transplant Test
ABO blood typing compability HLA typing preformed Abs Crossmatching
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hyperacute graft rejection
caused by ABO blood type incompabilities
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HLA typing
focuses on HLA-A, B, DR | more HLA matches = better graft survival
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haplotype
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
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haplotype matching
need same genes AND same sequence
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B7-1/2
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)
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Necrosis
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
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Inflammation
``` physiological: eliminates initial cause removes necrotic cells initiates repair pathophysiological: injury bystander normal tissue normally self-limited, can become chronic ```
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Humoral response to danger signals
activation of complement | activated immune cells: chemokines, leukotrienes/prostaglandins, ROI, NO
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necrotic danger signals
HMGBI Uric acid Heat Shock Proteins
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acute inflammation process
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
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Uric acid
necrotic danger signal | activates NFkB
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HSPs
necrotic danger signal | activates NFkB and release of pro-inflam CK's (TNFa/IL-1b)
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HMGB1
``` necrotic danger signal received by DCs High Motility Group Box 1 passively-released protein during necrosis activates NFkB Receptor: RAGE ```
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Uric acid
necrotic danger signal received by DCs | activates NFkB
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HSPs
necrotic danger signal received by DCs | activates NFkB and release of pro-inflam CK's (TNFa/IL-1b)
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RAGE
DC Receptor of Advanced Glycation End Products | receptor for high motility group box 1 (HMGB-1, necrotic danger signal)
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chronic inflammation
``` cancer diabetes cardiovascular neurological disease autoimmunity arthritis pulmonary disease alzheimer's disease ```
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artherosclerosis
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
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scavenger receptors
no feedback mechanism(/refractory period) (unlike normal receptors that have refractory periods)
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statins
break down lipid foam cells (possible correlation w/Alezheimers)
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Apoptosis molecular triggers
``` DNA damage CK starvation hypoxia temperature death receptors ```
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Apoptosis molecular regulators
``` Maintain equilibrium b/w pro- and anti-apoptotic signals Death domain factors cytochrome c p53 Bcl-2 family Myc/oncogenes ```
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Apoptosis molecular executioners
caspases
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apoptosis-inducing DNA damage ex
DNA damage: keratinocyte exposed to UV | Cytokine: cells w/o CKs
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Caspases
cysteine proteases orchestrate morphologic changes destroy key components of cellular infrastructure-> initiate apoptosis
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Apoptosis molecular mechanisms
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)
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Fas
CD95 expressed by every cell only activated lymphocytes express Fas ligand
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Intrinsic Mitochondrial pathway
``` 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 ```
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Caspase activation
executioner phase of apoptosis | "point of no return"
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Extrinsic Apoptotic pathway
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
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Autoimmune Lymphoproliferative Syndrome
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
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B cell selection
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)
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Negative selection
first part of B cell selection | gets rid of B cells w/HIGH affinity for self antigen (apoptosis)
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receptor editing
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
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B cell activation (by Ag)
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
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IgD
membrane bound, high in new born babies
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B cell can make ____ plasma cells which make ____ abs per day
4000 | 10^12
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B cell Ag recognition (occurs where, initiates what)
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
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B cell gene mutations
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
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B cell proliferation
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
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C3d
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
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CR2
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)
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B cell migration
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)
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parafollicular cortex
T cell zone of LN
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lymphoid follicle
B cell zone of LN
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T follicular helper (Tfh) cells
interact with B cells in central zone of LN
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B cells vs DCs (as APCs)
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
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Hyper IgM Syndrome
caused by defect in ability to switch from production of IgM to IgG/A/E defect is either in CD40L (X-linked) or CD40
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CD40L defect
results in Hyper IgM syndrome | X-linked-> ONLY MALES AFFECTED
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CD40 defect
results in Hyper IgM syndrome | affects males and females equally
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B cell Activation (by T cells)
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
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tiger licks baby
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
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final step in B cell maturation
PLASMA CELL or MEMORY CELL
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plasma cell lifespan
~5 days (make 2000 abs/sec)
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plasma cell location
spleen | bone marrow
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memory cell
depends on CD40-CD40L interaction | NO MEMORY WITHOUT B CELL ACTIVATION BY T HELPER CELLS
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Thymus-dependent antigens
``` the only ones T cells help with proteins isotype switching affinity maturation MEMORY B CELLS ```
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Thymus-independent antigens
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
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TI-1 Ags
Thymus-independent polyclonal activators of B cells NON-SPECIFIC activation of multiple B cells at a time
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TI-2 Ags
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
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B cell activation (by TI-1 Ags)
Signal 1: BCR binds Ag (ex- LPS) Signal 2: TLR binds Ag Multiple B cells initiated (polyclonal)
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B cell activation (by TI-2 Ags)
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
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encapsulated bacteria
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
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Ab-med immunity deficiency (susceptibility to...)
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
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latent infection
immune response controls but does not eliminate the infection microbe is good at "hiding" usually slow growing, causes cell lysis ex- HIV, Tb
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cause of tissue injury/disease
usually due to host immune response to microbe (rather than due to microbe itself)
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SCID
no adaptive imm (B/T cells) | innate immunity suppresses initial infection, but eventually microbes cannot be contained
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extracellular bacteria pathological mechanisms
1. inflammation (tissue destruction) | 2. toxin production (endo/exo)
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Endotoxins
components of bacterial cell walls only released upon CELL DEATH ex- LPS (potent activator of MPs, DCs, and ECs)
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Exotoxins
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
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diphtheria toxin
exotoxin from extracellular bacteria | Fxn: shuts down protein synthesis in infected cells
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cholera toxin
exotoxin from extracellular bacteria | Fxn: interferes w/ ion and water transport
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tetanus toxin
exotoxin from extracellular bacteria | Fxn: inhibits neuromuscular transmission
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complement
``` 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 ```
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acute phase proteins
mannose-binding lectin | C-reactive protein
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Phagocytes
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
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ROI effects
1. DNA damage 2. Lipid peroxidation 3. AA oxidation 4. Enzyme inactivation by co-factor oxidation
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Innate immune evasion by extracellular bacteria
``` inhibit complement activation (many bacteria) resist phagocytosis (pneumococcus, Neisseria meningitidis) scavenge ROI (catalase+ staphylococci) ```
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extracellular bacteria that resist phagocytosis (ex)
pneumococcus, Neisseria meningitidis
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extracellular bacteria that scavenge ROS (ex)
catalase+ staphylococci
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peroxynitrite (ONOO-)
causes apoptosis (mitochondria: AIF, or cit C-> caspase activation) or necrosis (lipid peroxidation, protein oxidation, protein nitration, inactivation of enzymes)
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innate immune response against extracellular bact
1. complement (opsonization-> phagocytosis and MAC-> lysis) 2. inflammation 3. phagocytosis (neutrophils and macrophages)
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adaptive immune response against extracellular bact
Antibodies... 1. neutralize microbes/toxins 2. opsonize microbes for phagocytosis 3. help NK cells w/Ab-dep cytotoxicity 4. complement (lysis, opsonization/phagocytosis, inflammation)
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Ab neutralization
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
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Ab-mediated phagocytosis
1. IgG opsonizes microbe 2. IgG binds phagocyte Fc receptor (FcgR) 3. phagocyte activation 4. phagocytosis 5. killing
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Fc receptors
FcgRI: IgG FceRI: IgE FcaRI: IgA none for IgM (pentamer-> can't bind)
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phagocyte Fc receptors
FcgRI: IgG FcaRI: IgA bind Ab-Ag COMPLEXES ONLY
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FceRI
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
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adaptive immune evasion by extracell bacteria
``` antigenic variation (Neisseria gonorrhoeae, E coli, salmonella typhimurium) inhibit complement activation (many bacteria) resist phagocytosis (pneumococcus, Neisseria meningitidis) scavenge ROI (catalase+ staphylococci) ```
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antigenic variation
helps extracellular bacteria evade adaptive immunity bacterium/virus alters surface proteins to evade host immune response ex- Neisseria gonorrhoeae, E coli, salmonella typhimurium
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complement inhibition
helps many extracellular bacteria evade innate and adaptive immunity bacterial capsules, C3 convertase decay, blocked MAC formation (vitronectin)
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vitronectin
host protein used by bacteria to block MAC formation and inhibit complement
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phagocytosis resistance
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
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scavenge ROI
helps extracellular bacteria evade innate and adaptive immunity catalase-pos pathogens deactivate peroxide radicals-> survive unharmed WITHIN host ex- catalase-pos staphylococcus
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pyrogens
``` cause fever (INNATE RESPONSE) Endotoxin/LPS (G-) LTA (G+) viruses yeast molds environment (packing materials) ```
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fever
innate response caused mostly by IL-1, but also IL-6, and least by TNFa manifestation of CK signals to hypothalamus
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bacterial pneumonia
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
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Immunological Tolerance
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)
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Remission
Occurs because Ags are removed from imm sys but NOT from the BODY

HDM (6 decks)

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