Exam 1 Spring Flashcards
(458 cards)
1
Q
what is the most effective method for preventing infections?
A
vaccination
2
Q
what is the 4th modality of ca tx?
A
immunotherapy
3
Q
what is the reason immune med diseases are rising?
A
unknown
4
Q
innate immunity definition
A
def in place before infection –> rapidly respond
limit infection before adaptive imm response
5
Q
adaptive immunity
A
shaped by exposure
incr magnitude and def cap with each successive exposure to partic microbe
6
Q
features of innate immunity (6)
A
- epith barries
- present from birth
- in place prior to infections –> responds rapidly
- activated by structures shared by diff classes of microbes
- no memory - not any faster 2nd exposure
- trigger and amp adaptive imm response
7
Q
features of adaptive immunity (3)
A
- patho-sp
- memory! enhanced by repeated exposure
- uses cells/mol of innate imm sys to elim microbes
8
Q
cell meds of innate AND adaptive are derived from….
A
pluripotent hemtopoietic stem cells in bone marrow
- lymphoid stem = adaptive
- myeloid stem = innate
9
Q
neutrophil morphology
A
muiltilobed nuc
small pink granules
short-lived
10
Q
fx neutrophils
A
phago
activ bac-cidal mech
11
Q
monocyte morphology
A
bean-shaped nuc
CD14 positive
12
Q
fx monocyte
A
phago
recruit to sites of inflamm
differn –> tiss macrop
13
Q
macrophage morph
A
in tissues
ruffled memb
cytop: vacuoles and vesicles
CD14 positive
14
Q
fx macrophage
A
phago microbes and dead cells
secr cytokines
APC
15
Q
dendritic cell morph
A
found in epith tissues
long cytop arms
16
Q
fx dendritic cells
A
antigen
- capture
- txp
- present
17
Q
mast cell morph
A
found in tissues, mucosa, epith
small nuc
cytop packed with large blue granules
18
Q
fx of mast cells
A
release granules (histamine) during allergy, anti-helminth
19
Q
eosinophil morph
A
found in bloodstream, some epith
bilobed nuc
LARGE pink granules
20
Q
fx eosinophils
A
kill ANTIBODY-COATED parasites
21
Q
basophil
A
found in bloodstream
biloced nuc
LARGE blue granules
22
Q
fx basophils
A
nonphago
release active sub during allergy
23
Q
NK cells morph
A
found in: lymphoid, bloodstream
CD16, 56
LARGE cytop granules
24
Q
fx NK
A
kill
- tumor
- virus
- ab-coated target cells (ADCC)
25
lymphocyte morph
found in: bloodstream, lymph nodes, submucosa, epith
**LARGE dark nuc**
small rim of cytop
26
fx lymphocytes
B: CD 19, 20, 21 - produce Ab
TH: CD 3, 4 - reg imm responses
CTL: CD 3, 8 - kill infected, altered cells
27
plasma cell
found in: lymph nodes, spleen, MALT, bone marrow
small dark nuc - **intense staining GOLGI**
end cell of b-lymphocyte differentiation
28
fx plasma cell
prod Ab
29
types of adative immunity
humoral
* bloack infections
* elim extracel microbes
cellular
* elim phago microbes
* kill infected cells
* elim resevoirs of infection
30
humoral immunity is med by:
Ab made by B cells
* secr --\> circ/lumens of mucosal organs --\> bind extracel microbes/toxins --\> neutralization (prev int-act with host tissues)
31
cell-med immunity is med by:
T cells aga INTRA-cell microbes
32
A previously health 8 year old boy is infected with an upper respiratory tract virus for the first time. During the first few hours of infection, which one of the following events occurs?
A.A lymphocyte response rapidly controls the infection.
B.An immune response dominated by neutrophils and monocytes keeps the infection under control
C.Killer CD8 T cells destroy infected epithelial cells
D.Antibody neutralizes the virus and prevents the spread of infection
E.Memory B cells quickly become activated to secrete antibody
A.An immune response dominated by neutrophils and monocytes keeps the infection under control
33
foreign sub recog by B and T lympho are called...
antigens (epitope recog)
34
diff b/w how B and T cells recog antigens?
T = ONLY protein
B/antibodies: MANY types
35
what are naive lymphocytes?
B and T lympho not yet encountered antigen
"immun" inexperienced - inactivated state
36
protective imm aga microb induced by...
host T and B cell recog AND response to foreign antigen
37
what kinds of indiv are said to be "immune"
when lympho have responded to microbe antigens and protected from subseq exposures of THAT microbe
38
active immunity is when...
protection from prev recog microbe
induced by exposure to foreign antigen
39
what is passive immunity?
immune WITHOUT exposure NOR response to that antigen
40
how to confer passive immunity?
txf serum or lympho of sp-imm indiv
41
fxs of innate and adaptive immunity are med by...
cytokines
* soluble proteins/peptides
* concep sim to horm
* pleiotrophic: may have 2(+) unrelated effects
42
in normal indiv, primary infection is cleared by...
BOTH innate and adaptive immunity
43
A standard treatment of animal bite victimes, when there is a possibility that the animal was infected with the rabies virus, is administration of human immunoglobulin preparations containing anti-rabies virus antibodies. Which type of immunity would be established by this treatment
A.Active humoral immunity
B.Passive humoral immunity
C.Active cell-mediated immunity
D.Passive cell-mediated immunity
E.Innate immunity
Passive humoral immunity
44
key features of adaptive imm sys (7)
1. specificity
2. diversity
3. memory
4. clonal expansion - inccr # antigen-sp lymphoctytes faced with microbes
5. specialization - gen repsonse optimal for def aga diff types of microbes
6. contracftion/homeostasis
7. nonreactive to self
45
specificity means
only clones of cells with approp receptors to recog a PARTICULAR antigen becomes activated
46
antigens that adaptive imm sys can recog is...
virtually limitless due to extremely diverse repretoire of antigen receptors
47
what is the downside of having such a diverse repertoire?
cells cap of recog 1 antigen fairly small --\> clonal expansion of CURRENT infection
48
effect of clonal expansion after infection clears?
adaptive response declines (contracts) but MEMORY cells remain
* rapid more exhanced response of microbe return
49
At 15 months of age, a child received a measles-mumps-rubella (MMR) vaccine. At age 22, she is living with a family in Mexico that has not been vaccinated and she is exposed to measles. Despite the exposure, she does not become infected. Which of the following properties of the adaptive immune system is illustrated in this scenario?
A.Self Tolerance
B.Diversity
C.Specialization
D.Memory
E.Specificity
Memory
50
Is it a B cell or a T cell mophologically?
NO DIFFERENCE!
All lymphocytes are morphologically similar
51
How to tell diff lymphocytes apart?
CD - detect using antibodies
52
most common method used to detect presence of bound Ab is
flow cytometry
53
B cell CD expr
19
20
21
54
T cells CD expr
2
3
subsets:
* CD 4
* CD 8
55
NK cell CD expr
16
56
56
BCR
receptor that recog antigen
memb form of antibody
57
how to B cells med humoral immunity?
prod Ab aga EXTRACELL patho/toxins via recog soluble antigens and antigens pres on microbe surf
58
antigen recognition and T/B cell activation results in...
effector cells
59
effector cells of B cells =
plasma cells --\> secr Ab
* antigen recog induced differen B cell --\> plasma --\> prod soluble Ab with SAME sp as memb-bound Ag receptor
60
Ab combat extracel pathogens by...
neut --\> prev infection
facil destruction --\> phago or complement
61
Activated effector B cell (Plasma cell)
notice
* LOTS of cytop
* LOTS mito
* LOTS RER
62
How do T cells defect antigens?
INTRACELL
recog small frag of antigen that have been broken down and presented by APC
63
Steps to Ag presentation?
1. APC capture Ags
2. brkdown into small frag
3. present on MHC
4. recog by TCR (T-cell antigen receptor) on T cell
5. activation T cell
6. cell med immunity
64
examples of APCs
dentritic cells
macrophages
activated B cells
65
Th cells: antigen recog and effective fx
recog microbial antigen on APC --\>
* activate macrophages
* inflam
* activ prolif and diffen of T and B cells
66
cytotoxic T cells: antigen recog and effector fxs
recog infected cell expressing microb antigen --\> KILL
67
fx of regulatory T cells
what are their CDs?
SUPRESS immune response
CD4 and CD 25
68
when lymphocytes emerge from bone marrow or thymus....
they are **mature but first must find antigen recog by their receptors**
* circ from blood --\> peripheral organs (1 round a day)
69
B cell deficiency presentation
absent/reduced follicles/germ centers in lymph organs
reduced serum Ig lvls
result:
* pyogenic bac infections
* enteric bac/viral infections
70
T cell deficiency presentation
reduced T cell zones in lymophoid organs
reudced DTH rxns to common antigens
defective T cell prolif responses to mitogens IN VITRO
result:
* viral/intracell infections: p. jiroveci, atyp mycobac, fungi
* virus-assoc malig: EBV lymphomas
71
what are the most important APCS? Why?
dendritic cells (DCs)
reside in tissues most commonly used as portal of entry of pathos
* skin
* muc tissues
72
A 2 year old boy is evaluated for a immunodeficiency disease. He appears to have a normal number of CD3+ cells, however, there are no CD19+ cells found in the blood or peripheral lymphoid organs (spleen, lymph nodes). Which of the following cell types is this boy deficient in?
A.B cells
B.CD4 T cells
C.CD8 T cells
D.NK cells
E.Neutrophils
B cells
73
Consider the 2 year old boy in the previous case found to be deficient in CD19+ cells. Which of the following capabilities would this child’s immune system lack?
A.The presentation of antigen by MHC molecules
B.The recognition of antigen derived from an intracellular pathogen
C.The mobilization of neutrophils during the first few hours of an infection
D.The production of antibody against extracellular pathogens
E.The maintenance of the epithelial barrier
production of antibody against extracellular pathogens
74
1st line of defense of the immune sys
1. skin
2. muc memb/secr
3. normal flora
75
2nd line of defense
1. innate immune cells
2. inflam
3. complement
4. antimicobe substances
76
3rd line of defence
adative immunity: lymphocytes
77
intraepith T cells
final protective cmpt of epith
non-classical T cells -- expr only limited range of antigen receptors
78
cell mediators of innate immune sys (6)
**NENEMI**
neutrophils
epith
NK cells
eosinophils
monocytes/macrop
ILC (innate lymphoid cells)
79
soluble mediators of innate immune sys (4)
1. complement
2. cytokines
3. acute phase reactants
4. coag factors
80
biological barriers of innate immune sys
normal flora
81
most patho gain entry to tissues via
skin
respir tract
GIT
82
fx of normal flora of epith
competes for nut and oclonization
sstim secr antimicrobial sub
83
epith mechanical barriers
tight jxns
mucus (goblet cells) - prevent adherence
mucociliary elevator
84
epith chem barriers and mechanism
skin
* sweat - anti-microbe FA
muc memb
* HCl (parietal cells) - low pH
* tears/saliva - enz dig
* defensins/cathelicidins - direct toxicity
* surfantant - opsonin
85
PAMPS
limited # of microbial products recog by innate immune sys that are shared among broad groups of microbes
* structures essential for surv and infectiveness of microbes
NOT pres on host cells
86
PAMP of influenza/mumps/parainfluenze/measles
ssRNA
87
types of receptors of innate immunity
TLR
N-formyl peptide
mannose
scavenger
88
recog of PAMPS med by...
PRR (pattern recog receptors)
* TLR = major family
* NLR (nod-like) = nicrobial prod, dmg tissues
* RIG-like = viral RNA
* c-type lectin = recog mannose residues
89
types of TLRs
1. bac lipopep
2. bac pipopep/peptidoglycan
3. dsRNA
4. LPS
5. bac flagellin
6. bac lipopeptides
7. ssRNA
8. ssRNA
9. CpG DNA
90
PAMP/DAMP of NOD-like receptors
bac cell wall pep-glycans
intracel crystals
changes in ATP/ion conc
91
cytosolic DNA sensors recog what kinds of PAMP/DAMP
AIM2
* bac and viral DNA
92
c-type lectin receptors recog
mannose
* microbial mannose and fructose residues
dectin
* fungal cell wall glucans
93
scavenger receptors recog
CD36
* microbial diacylglycerides
94
innate immune receptors med
1. prod of effector molecules/cytokines --\> induce innate and adaptive immunity
2. stim phago
3. chemotactic --\> guide phago to infection site
95
NLRP-3 engagement results in...
combine with caspase 1 --\> activates IL-1 --\> fever, inflammation
**complex = inflammasome (NLRP-3 + caspase 1)**
96
sterile (non-infectious) inflam NLRP3 activators
gout: monosodium urate
alz: beta-amyloid plaq
DM2: free FA, islet amyloid polypep
atherosclerosis: ox-LDL, cholesterol
97
MyD88 deficiency
recurr, severse pus-forming/pyogenic bac infection
98
IRAK4 deficiency
recurr severe bac infections
* cellulitis
* arthritis
* meningitis
* osteomyelitis
* organ abscesses
* sepsis
99
UNC93B deficiency and TLR3 mutations
incr suscep to encephalitis caused by HSV
100
IKK/NEMO deficiency
ectodermal dysplasia
* conical/absent teeth
* sparse hair
* hypohidrosis (decreased sweat glands)
immunodefic
* recurr sinopulm infections
* mycobac
* opportunisitic org
101
Carl is a 1 month old healthy child who has not, as yet, received any childhood vaccines. He presents with his first episode of otitis media that is successfully treated with antibiotics. Which of the following immune components contributed the most to the clearing of the infectious agent during the first few days of the infection?
●
A.Antigen receptors on B lymphocytes
B.Toll like receptors on macrophages
C.Cytokines that promote antibody production
D.T cell responses to bacterial antigens
E.Memory B cells
TLRs on macrophages
102
what cells are sentinels for infectious org?
resident DCs and tissue macrophages
103
recog of PAMPS/DAMPS by resident tissues macrophages results in...
release of inflam cytokines: IL-1, TNF-alpha
* stim P and E selectin
* rolling of neutrophils due to shear forces and weak bonding
104
after rolling, what happens to neutrophils?
activated macrophages prod chemokines (IL-8/CXCL8) --\> induce HIGH AFFINITY integrins (ICAM-1, VCAM-1)
* neutrophil recog IL-8 receptor via their CXCR 1 & 2
* neutrophils bind to integrins via their Mac-1, LFA-1, VLA-4
105
how to neutrophils extravasate?
b/w endothelial cells: increased basc perm via histamine, PG, LT
106
G-CSF
granulocyte CSF
* prod @ site of infection
* incrs prod of neutrophils by bone marrow
107
inflammation is ...
accum leukocytes @ infection site
assoc vasc dila
incr leakage of fl/proteins into tissue
108
hallmark of acute inflamm
neutrophils
109
temporally distinct patterns of expr of adhesion mol/chemokines typ result in...
early neutrophil recruit
* LFA1/MAC-1 : ICAM-1
* CXCR1/2 : IL-8
later monocyte recruit
* VLA-4 : VCAM-1
* CCL2 : CCR2
110
leukocyte adhesion deficiency
auto recessive - decr mvmt leukocytes to inflam
* delated sep of umbilical cord
* recurr bac/fung infections: skin, lungs, GIT, perirectal
absent/deficient
* β2 integrins, LFA-1 and Mac-1: heterodimers of CD18 & 11
result:
* prev tigh adhesions
111
dx and tx of leukocyte adhesion deficiency
dx: CD18 flow cytometry
tx: BMT/SCT
112
It is generally thought that a limited amount of inflammation at the site of vaccination helps to stimulate a strong adaptive immune response to the vaccine antigens. Which of the following substances, if introduced with the vaccine, would best serve the purpose of attracting a neutrophil infiltrate into the area?
A.G-CSF
B.IL-8
C.Prostaglandin
D.E selectin
E.TNFalpha
IL-8
113
what are the most abundant leukocyte in blood?
neutrophils
114
neutrophil granules
specific: lysozyme, collagenase, elastase - degrade bacterial
azurophillic: defensins/cathelicidins - microbicidal
115
NETs
DNA chromatin networks --\> trap bac/fungi --\> kill via its granules
116
what is the prominent emch by which inflammation can dmg host tissue?
neutrophil granule enz and ROS
117
prod and storage of neutrophils
lifespan?
prod: G-CSF
reserve pool in bone marrow
lifespan = 6 hours : **major cmpt of pus**
118
macrophages orgin from
fetal hematopoietic organs (yolk, sac, liver)
119
fx macrophages (4)
1. ingest/kill microbes and apop host cells
2. secr cytokines --\> onto endothelial cells --\> recruit leukocytes
3. APC --\> (+) T cells
4. prom repair of dmg tiss
120
once a microbe has be engulfed by a macrophage...
killed by phagolysosome
* ROS: NADPH oxidase/MPO
* iNOS
* proteolytic enz (lysozyme)
121
CGD
mutation in NADPH phagocyte oxidase
effect:
* recurr infection with catalase --\> bac/fungi infections
* granulomas: inab to kill/phago bac
122
M1
classically activated macrophages - inflam/kill via innate inflam response
123
cytokines secr by M1
IL-1beta: vasc-endo & lymphocytes, local tiss destruction, effector cells --\> fever, prod IL-6
IL-6: fever, acute-phase proteins by hepatocytes
IL-12: activ NK cells
TNF-alpha: increase vasc perm, incr lymph drainage --\> fever, shock
CXCL8: recruit neutrophils, basophils
124
M2
activated by IL-4 & IL-13 in **absence of strong TLR signals** --\> reduce inflammation & med tissue repair
125
what are the link b/w innate and adaptive immunity?
DCs: capture antigen --\> bring to draining lymph nodes --\> present to naive T cells
126
types of dendritic cells
cDC (conventional) - capture antigen in perip --\> present to adaptive imm in draining lymph nodes
pDC (plasmacytoid) - circ in blood --\> recruit to inflamm sites --\> activated --\> prod IF-1 (interferon 1)
127
mast cell released things and timing: (3)
degranulation - seconds
eicosanoids - minutes
cytokines/chemokines/ GFs - hours
128
mast cell degranulations and fx
histamine - vasodil, increase perm
TNF-alpha
tryptase/chymase - proteolytic --\> kill bac & inactiv toxins
amines
129
mast cell eicosanoids
LT
PG
130
cytokines/chemokines/GFs of mast cells
TNF-alpha, IL-4/5/6/13/17, VEGF
131
true or false: NK cells express antigen receptors
**FALSE** - no antigen receptors like T and B cells
132
how do NK cells recog target cells?
absence of MHC I
"stress signals"
133
how do NK cells induce apop of target cells?
perforin/granzyme
Fas/FasL
134
NK cell receptors: inhib v activating
inhib:
* KIR: bind MHC I
* KLRG-1
* NKG2/CD94
activating:
* CD16 (FcR) - ADCC (Ab-dep cell-med cytotoxicity): kill Ab-coated cell
* NKG2D
135
NK cell cytokines
IL-12: prod INF-gammy
IL-15: dev/mat
IF-1: enhance killing fx
136
what fxs together to kill intracell microbes?
activated macrophages prod IL-12 --\> activ NK to --\> IFN-gamma --\> activ macrophages
137
viruses and the immune sys
1. Virus infects host cells
2. CD8 T cells recognize viral antigen:MHC complex. Kill host cell
3. Viruses evolve to evade the CD8 T cell response by suppressing MHC class I expression
4. Natural killer cells develop to recognize cells that have decreased MHC class I expression
5. Viruses encode decoy MHC class I molecules that cannot present Ag, but suppress NK cell activation!
138
Lymphocytes with Limited Antigen Receptor Diversity
features of both innate and adaptive immune sys: **considered part of innate sys**
1. gamma-delta T cells: somatically rearrange Ag recept
2. NK-T cells: T-cell antigen receptors (TCRs)
3. B-1 cells: expr Ag receptors, secr Ab (usually prod natural Ab that recog carbs on cell walls of bac)
4. marginal zone B cells: Ag receptors
139
main functions of complement
140
3 pathways of complement activation
classic: IgG/IgM Ab - humoral adaptive immunity
alt: microbal surf proteins - innate
lectin: lectin mannose binding - innate, but requires time gain strength
141
C3 cleavage
**central to all C' pathways**:
* later in classic/lectin
* activates alt
a - chemoattractant: mast cells --\> vasoactive
b - opsonin (coval binding)
142
activation of alt C' pathway
C3 spont hydrolyzed in plasma in low lvls --\> iC3 (C3 tickover)
fac B (serine protease, active enq of C3/C5 convertases) + iC3 --\> C3b --\> readily bind to microbe surf
* cleavge of fac B by fac D
* stby by properdin
--\> activation alt path
143
C' lectin pathway
MBL - acute phase reactant (liver) during periods of inflamm
* innate immunity: bc init by microbial prod
bind MBL to microbe --\> bkdwn C4 & C2 --\>
* C4b + C2a --\> complex --\> C3 convertase
* C3b binds complex --\> C5 convertase
* init late steps of C'
144
C' classic pathway
init by bindning Ab to Ag: adaptive
* C1 bind to Fc portions of 2 IgG or IgM --\> cleave C4 & C2 --\> C4b2b complex = C3 convertase
* C3b binds to complex --\> C5 convertase
145
all 3 C' pathways lead to...
coat of convalently attached C3b = opsonin
146
last steps of C'
C5 convertase cleaves C5
remaining C6-C9 bind seq to C5b
C9 polymerizes --\> MAC --\> pokes hole
147
C' deficiencies
C3: recurr severe bac infections --\> usually fatal
C5-C9: incr suscept to Neisseria (thin cell wall - esp suscep to MAC)
148
regulation of C'
mammal cells can reg, microbes cannot
* overwhelming C' --\> coat with antibody --\> C' target
149
Factor I
proteolytically cleaves C3b and C4b
150
Factor H
dissoc alt pathway C3 convertase
co-fac for Fac I med cleavage of C3b
151
C4BP
dissoc classic C3 convertase
co-fac for Fac I med cleavage of C4b
152
DAF
dissoc c3 convertase
153
CD59
blocks C9 binding --\> inhib MAC
154
MCP
membrane cofactor protein
cofac for Fac I for proteolysis of C3b into inactive frag
155
C1 INH
stops activation of classic path: interferes with C1q cmpt
* prev C1 r2s2 from activating
156
hereditary angioedema
inherited: deficiency in C1 INH
* excessive C1 activation --\> subseq activation of kinin sys (C2b)
unpredictable/recurr episodes of periodic swell in subQ/submuc
157
in the innate immune response, the principal sources of cytokines are...
macrophages
mast cells
dendritic cells
158
major proinflamm cytokines
TNF
IL-1
IL-6
159
local effects of proinflam cytokines
vaso-dil: marginalization of leukocytes
activates endothelium - adhesion mol
incr vasc perm - diapedesis/extravasation
160
sys effects of inflam cytokines
liver: acute-phase proteins --\> C', opsonin
bone marrow, endothelium: neutrophil mob --\> phago
hypoT: incr body temp --\> decr microbe replication
fat/M: get more E --\> decr microbe replication
161
pyrogens
ab to induce fever: IL-1, IL-6, TNF-alpha
elev temp
* slows patho growth: most grow & replic optimally @ temps below human body
* actively seques iron --\> lim bac growth
162
acute-phase proteins
IL-6
* MBL --\< incr phago, trigger lectin C'
* CRP - binds PL-choline --\> incr phago, trigger classic C'
* SAA
163
early clinicla and patho manifestations of septic shock are caused by...
very high levels TNF-alpha due to systemic bac infection
164
IL-8
recruits neutrophils
165
IL-12
prod by activated macrophages and DCs --\> NK & CD4 T cells --\> IFN-gama --\> bidirectional activation
166
major innate cytokine prod in response to viral infection is...
IFN-I
* host cells recog via viral PAMPS (dsRNA) by PRRs (Rig-1)
secr by virally infected cells and leukocytes to protect surr cells from infection
* activ JAK-STAT sig pathway
167
fnal role of innate immune response
alert adaptive immune response
* signal 1: antigen recog by lymphocytes
* signal 2: moles induced during innate imm response
168
evasion of innate imm: pneumococci
cap polysacc --\> inhib phago
169
evasion of innate immunity: staphylococci
produces catalase --\> resists ROS
170
evasion of innate immunity: neisseria meningitidis, streptococci
sialic acid --\> inhib C3/C5 convertase
M protein --\> blocks C3 fx
**resists alt C'**
171
evasion of innate immunity: pseudomonas
synth mod LPS --\> resists antimicrobial peptides
172
bone marrow
common lymphoid progen cell
* precursor: T, B, NK
* most steps B cell mat in BM --\> finals events @ 2ndary lymphoid organs, particularly spleen
common myeloid progen cell
* RBCs, platelets, granulocytes (N, E, B), monocytes (most DCs)
173
thymus
3rd parayngeal pouch
* flat, bilobed
* 2 compartments:
* outer cortex = thymocytes
* inner medulla = T cell maturation
* DCs and macrophages help with mat
174
thymic cortical epith cells
secr IL-7: GF req for early T cell dev
175
thymic medullary epith cells
remove self-reactive T cells
176
thymus through time
enlarges during childhood
involutes after puberty
177
DiGeorge syndrome
mutations in genes for thymus dev
* T cell deficiency
also effects parathyroid & heart dev due to 3rd pharyngeal pouch origin
* hypocalcemia
178
•A 52 year old man who receives radiation therapy and cytotoxic drugs for treatment of cancer sustains significant damage to his bone marrow. Which of the following changes will most likely occur?
•
A.Decreased production of monocytes but not B lymphocytes
B.Decreased production of B lymphocytes but not T lymphocytes
C.Decreased production of neutrophils and monocytes but not B lymphocytes
D.Decreased production of B and T lymphocytes, monocytes, neutrophils, and red blood cells
E.Normal production of all red blood cells due to compensatory extra medullary hematopoiesi
A.Decreased production of B and T lymphocytes, monocytes, neutrophils, and red blood cells
179
•In DiGeorge syndrome, the thymus fails to develop. Which of the following characterizes the immunodeficiency state in this syndrome?
A.Low numbers of neutrophils and monocytes in the blood.
B.Deficiency in antibody production in response to bacteria polysaccharides
C.Deficiency in cell mediated immunity in response to an intracellular infection
D.Normal T cell numbers, however, defective T cell activation
E.Deficiency in B cell maturation
A.Deficiency in cell mediated immunity in response to an intracellular infection
180
peripheral lymphoid organs fx
collect/cencentrate antigens --\> gives oppor for naive lymphocytes to recog
181
lymph contains (3)
debris from dying cells
antigens
DCs with captured antigen
182
celephantiasis
interstitial fluid collected by not drained by lymph
183
paracortical area of lymph node
DCs present captured Ags to T cell
184
primary lymphoid follical
B cell zone
contains FDCs
* forms meshwork to present antigens to **B cells**
185
secondary follicle of lymph nodes
with germinal center --\> intense B cell prolif
186
medullary cords of lymph nodes
macrophage and plasma cells
187
188
how do lymphocytes wind up in the correct regions of lymph nodes?
chemokines
189
spleen basic fxs
drains bloodborne antigens
removes aging and dmged blood cells/particles (immune complexes and opsonized microbes)
190
red pulp of spleen
macrophages remove microbes and old/dmged RBS
blood --\> central splenic A --\> vasc sinusoids (open circulation) --\> splenic sinus --\> vein --\> portal circ
191
indiv lacking spleen...
highly suscep to infections with encap bac norm cleared by opsonization and phgo of splenic macrophages
192
white pulp of spleen
lymphocyte rich
org around central arteries: sep from red pulp via marginal zone
* contain marginal zone B cells
* site of immune response targ bloodborne antigens
193
segregation in the spleen
T cells
* PALS (around central arteries)
B cells
* follicles
**sim to LNs**
194
SALT AND MALT
sp-L tissues found inder skin and epith of GIT, RT, UGT
* lymphocytes
* macrophages
* DCs
site of immune responses to antigens that breach epith
195
examples of MALT
pharyngeal tonsils
peyer's patches
196
cells of SALT
keratinocytes
Langerhan's cells - immature DCs
* forms con't epith mesh --\> capture Ag --\> mig to draining LNs --\> APC
intraepithelial T cells
melanocytes
197
•A 5 year old boy with recurrent infections is discovered to have a genetic defect that impairs B cell development. Which of the following abnormalities is most likely to be found in this patient?
•
A.Small thymus
B.Absence of follicles in lymph nodes and spleen
C.Enlarged tonsils
D.Diminished parafollicular zones in the lymph nodes
E.Hypocellular bone marrow
Absence of follicles in lymph nodes and spleen
198
trafficking requirements for adaptive immune response
what is actually first (innate immune response)
recruit neutrophils & monocytes (innate)
Ag "carried" to perip L organs
naive lymphocytes circ through
activated lymph go to site of infection
199
Ag presentation by DCs to T cells takes place
paracortical area of LN
200
Major DCs
surface markers: CD11c, CD1C, dectin 1/2
TLRs: varios
Ts: IRF4
maj cytokine prod: IL-12
fx:
* innate immunity - souce of inflam cytokines
* adative imm: APC mostly to CD4 T cells
201
Cross-Presenting DCs
surf markers: CD11C, CD141, CLEC9A, XCR1
TLRs: various
Ts: IRF8
maj cytokines prod: IL-23
fx:
* adaptive imm: APC to CD8 T cells
202
plasmacytoid DCs
surf markers: BDCA 2/4, CD123
TLRs: 7/9
Ts: E2-2
maj cytokines prod: IFN-1
fx:
* antiviral: early innate response
* prime antiviral T cells
203
how are immature DCs activated?
DC TLRs bind to microbe cmpts
DC stim by inflamm cytokines induced by microbe
204
how to ag-bearing DCs leave perip tissue --\> LNs?
1. activation: TLRs or inflamm cytokines
2. change cell type form ag uptake --\> APC
* incr MHC/antigen complexes: provides 1st signal of T cell activation
* incr costimulatory mol: prov 2nd signal for T cell activation
205
activated DCs incr expression of...
CCR7 (chemokine for T cell zone of LN)
* binds CCL19 & 21 (T cell zones of LN)
* also expr by naive T cells
206
how do B cells get to LNs?
naive B cells expr CXCR5 --\> binds CXCL13
* produced only in follicles by FDCs
207
208
lymphocyte homing
activated effector lymphocytes selectively enter LNs (reverses previously just recirc)
209
naive T lymphocytes delivered to 2ndary lymph tissues via _______ and leave circulation and migrate into the stroma of LNs via \_\_\_\_\_\_\_\_\_\_
arterial blood flow
HEV (postcap venules) - lined by plump endothelial cells
* rich adhesion mol & chemokines for naive T cells
210
T cell homing
naive T cells: L-selectin (CD62L) ---\> PNAd (endothelial cells of HEV) = rolling
T cell zones of LN (CCL19 & 21) bind CCR7 --\> allows expr of high affinity integrins (LFA-1/VLA-4) --\> allow naive T cells bind ICAM-1 --\> firm adhesion --\> migration to T zone
211
true or false: T cell homing is similar to B cell migration (homing)
TRUE
212
egress (leaving) from a LN is controlled by...
expr of receptors for S1P
213
what happens after naive T cell activation?
must reduce expr of adhesion mol that init targeted it to the LN
* L-selectin, CCR7: no longer directed to LN
upreg adhesion mol & chemokine receptors
* typ present on endothelial cells @ perip inflam sites
* activated by inflam med
* recruitment no Ag specific: **but** only T cells that see their cognate Ag @ infection site become reactivated
* held @ site
* contrib to killling
* ex: skin = E-selectin, CLA-1
214
engineered Abs aga integrins or endothelial adhesion mol do...
block migration of effector T cells to tissue in diseases like MS and inflam bowel
215
Fingolimod is a drug used to treat autoimmune diseases, which blocks the function of sphingosine-1 phosphate (S1P), by binding to its receptor S1PR1 and downregulating it’s expression. Patients treated with this drug become lymphopenic, ie, they have low number of lymphocytes in the blood. Why?
S1P binding to S1PR1 on lymphocytes is required for exit of lymphocytes from lymphoid tissues
216
A group of researchers is studying the effects of the CXCL13 gene by knockout mice experiments. Which of the following might you expect to see upon examination of the animal’s lymph nodes?
A.Hypocellular paracortex
B.Hypercellular paracortex
C.Hypocellular follicles
D.Hypercellular follicles
Hypocellular follicles
217
compare and contract innate and adaptive immunity: receptors
innate:
* germline encoded
* limited diversity
* \<100 different types of invarient receptors
Ig/TCR:
* somatic recombin of gene segments
* greater diversity
* only Ig and TCR with millions of variations of each
218
compare and contrast innate v adaptive immunity: distribution of receptors
innate = nonclonal - identical receptors on all cells of same lineage
adaptive = clonal - clones of lymphocytes with distinct specificites expr different receptors
219
Ab-mediated effector fxs (5)
1. neutralization of microbes/toxins
2. activate classic C'
3. opsonizattion
4. cell-med cytotoxicity
5. mast cell activation
220
antigen definition
any structure bound by Ag or TCR
* binding portion = determinant/epitope
* typ larger than the region
multivalent: multiple DIFFERENT epitopes
polyvalent: multiple IDENTICAL epitopes
221
compare and contrast B v T cell antigen recognition: antigen-binding site
b = 3 CDRs in VH & VL
t = 3 CDRs in V-alpha and V-beta
222
B cell vs T cell antigen recognition: nature of bound antigen
B = macromol & small chemicals
T = peptide-MHC complexes
223
immunogen definition
substance that acitvates lymphoytes & stim immune respnose
antigen is **not necessarily** an immunogen
224
T-independent antigen
polysacc cross-link multiple B cell antigen receptors --\> strong activation signal --\> activate B cell **indep** of Th cell
225
T-dependent antigen
**protein** antigen allow B cell to elicit help from activated CD4 T cells
* conformational epitope --\> endocytosis --\> digest and present the protein part of the antigen that was previously "hidden"
226
T cells can only recognize
linear peptide epitode in context of MHC
227
haptens versus carriers
hapten = binding onto B cell
carrier = what a T cell can bind
binding on hapten on B cell causes endocytosis and presenting of carrier which binds T cell
228
DNP and pcn in relation to haptens and carriers
antigenic but NOT immunogenic --\> must fuse with protein to work
* does not have correct linear seq to stimulate T cell initially
229
antibodies may be directed again...
hapten
carrier
or the conjugate
230
pcn MOA
1. pcn (hapten) binds to RBC --\> creates new antigens on surface
2. forms Ab specific for conjuguate of drug (hapten) and cell surf protein (carrier)
3. binding of pcn-mod RBCs --\> C' lysis or phago by macrophages in spleen
* via IgG
4. immune mediated hemolytic anemia
231
newborn vaccines
newborns = poor response to bac capsule polysacc T-indep antigens
soln: improve vaccine by fusing polysacc (hapten) to protein (carrier)
* bind to B cell --\> present protein on MHC II --\> recog by T cell --\> mount STRONGER Abs (versus weak IgM)
232
adjuvants definition
substances that themslves are not immunogenic but can enhance the immunogenicity of other substances
233
how to adjuvants work?
create antigen depot --\> slowly release antigen
induce Ag aggregation --\> eaiser to phago, proc, present to T cells
induce inflammation --\> induce expr costimul mol
234
Alum
alum-salt adjuvants:strong responses to Ag
235
vaccines that contain alum (7)
DTP/DTaP (diphtheria-tetanus-(acell)-pertussis)
HiB (hemophilus influenzae type b)
pneumococcal
hep A & B
HPV
anthrax
rabies
236
cross-reactivity
Ab or TCR can recog 2 sim but non-identical Ag
* share 1 or more epitopes: tetanus toxoid & tetanus toxin
* structurally sim: bac & auto Ags
237
rheumatic fever
streptococcus pyogenes antigen similar to self-antigens of heart valves - jones criteria
* fever
* rash
* carditis
* arthritis
* subQ nodules
* syndeham chorea
238
•A 3 year old male who is small for his age presents with a history of pyogenic infections. A culture of purulent discharge from an abscess grows out Staphylococcus aureus. Protective immunity against this organism requires an immune response which targets the polysaccharide chains of the bacterial capsule. Which of the following cell types is most important for the adaptive immune response to this type of antigen?
A.CD4 T cells
B.B cells
C.CD8 T cells
D.Antigen presenting cells
E.Natural killer cell
b cells
239
•A patient treated with penicillin presents with fever associated with kidney damage from complement-mediated hemolysis of red blood cells (RBC). What is the role of penicillin in this disorder?
•
A.Carrier
B.Hapten
C.Polyvalent antigen
D.Autoantigen
E.Immunogen
hapten
240
•A 41 year old patient visits a physician for a physical. She recalls to her physician that in childhood, she experienced two bouts of fever, headache and sore joints following severe sore throats. Although she appears to be well at the present, which of the following sequelae of her childhood illness is most likely to present as a chronic disease in her later years?
•
A.Anemia
B.Myocarditis
C.Glomerulonephritis
D.Mitral valve disease
E.Neurological disease
•
•
Mitral valve disease
## Footnote
**rheu-MITRAL fever**
241
how do the majority of T cells recog peptide antigens?
bound and displayed by MHC
* TCR recog residues of peptide Ag AND of the particular MHC that is displaying it
242
MHC restriction
TCR can only recog peptide antigens when displayed on **OWN** MHC molecules
243
why do most T cells only respond to protein antigens?
MHC Ag can only bind peptides from PROTEIN antigens
* can display peptides from foreign proteins AND self proteins
244
human v mouse MHCs
human = HLA: human leukocyte antigens
mouse: H-2 antigens
245
MHC I
present ag to CD8+ (CTL)
## Footnote
**all nucleated cells expr this**
246
MHC class II
present antigen to CD4+ (Th)
expressed by **APCs**
* macrophages
* DC
* B cells
247
MHC class III
complement
TNF
lymphotoxin
248
which MHC classes are structually similar to txmemb proteins?
I & II
249
MHC I structure
alpha chain (of 3 domains) noncovalently attached to b2-microglobulin (b2-M)
amino term alpha 1 & 2 form peptide binding cleft: peptides 8-11 aa in length
250
MHC II structure
2 chains: alpha and beta
* cleft = peptides 10-30aa in length
251
HLA are encoded...
multiple loci on short arm of chr 6
class III = genes for C' and some cytokines
252
MHC I loci encodes
MHC class 1 alpha chains:
* HLA-A & -b & -C
beta-2-M is encoded on **chr 15**
253
MHC II loci encodes
MHC class II alpha and beta chains
* HLA-DP & -DQ & -DR
254
MHC haplotype
complete set of MHC alleles inherited on each chr
* each individual has 2
255
MHC genes are the most ___________ genes in the genome
highly polymorphic: different alleles for each MHC gene are present among different individuals in population
* so great that any 2 people are EXTREMELY unlikely to have exactly same MHC genes and molecules
* accom a different complement of peptides presented to T cells
256
alleles of MHC mol are ________ expressed
co-dom: from both chr
* max diversity --\> allows wider array of peptide ag presented to T cells
257
multiple MHC alleles benefits to indiv and gen pop?
indiv: greater diveristy of patho-derived peptides presentduring infection --\> improves strength of immune response by incr # of patho-specific T cells
gen pop: always someone able to present any particular microbial protein ag --\> will not succumb to newly encountered mutated microbe
258
structure of MHC I receptor domains and binding
peptide binding cleft: alpha 1 & 2
* floor = peptide antigen
* walls = TCR
T-cell CD8 co-receptor: alpha 3
* does **not** interact with CD4
CD8 T cells can only respond to antigen presented by MHC I
259
structure of MHC II receptor domains and binding
peptide binding cleft: alpha 1 and beta 1
* floor - peptide antigen
* walls = TCR
T-cell CD4 co-receptor: alpha 2 and beta 2
CD4 can only respond to antigen presented by MHC II
260
successful antigen recognition involves
binding of TCR to peptide-MHC complex
binding of CD8 **OR** CD4 co-receptor to MHC I or II
261
what kind of specificity do MHC mol have?
broad - many diff peptides can bind to same MHC mol
262
how many peptides can each MHC mol display at one time?
**ONE** - each T cell responds to single peptide
263
MHC molecules can bind ONLY \_\_\_\_\_\_\_
peptides: protein ag
## Footnote
**no other chemicals**
264
how to MHC molecules acquire peptides?
intracell assembly
265
stable surf expr of MHC mol requires...
bound peptide: empty MHC is disassembled
266
lenght of time of MHC presentation
very slow off-rate: display long enough to be located by T cell
can be days
267
autosomal MHC I deficiencies
decreased CD 8 T cell numbers and fx
necrotizing granulomatous skin lesions & RT infections
**not viral infections -** b/c virus is intracel
268
bare lymphocyte syndrome
defective expr of MHC II --\> decr CD4 T #s and fx
impaired: cell-med immunity & B cell response to T-dep antigens
**lethal** unless BMT
269
what is the most important genetic factor in detm suscep to autoimmune disease
MHC - but not the only factor
* vast maj of people with HLA disease associated allele never dev disease
* still not completely known why
270
how can particular MHC alleles contribute to dev of autoimmune diseases?
1. ineffective @ displaying self antigens in thymus --\> defective removal of autoreactive T cells
2. peptide antigens presented by these MHCs fail to stim immunosuppressive reg T cells
3. VERY efficient at presenting self-peptide in periphery --\> incr likelihood of activating autoreactive patho T cells
271
CD1
surface glycoprotein that can present lipids/glycolipids to T cells
* expressed in associated with beta-2 microglobulin
non-classical ag presentation
* non-MHC endcoded
* non-polymorphic
272
how does CD1 work?
binds hydrophobic regions of lipids --\> expose polar region for alpha-beta or gamma-delta T cells & NK cells
273
what is the key presenter of ag to naive T cells?
DC cells --\> migrate to T-cell zone of LN to present
274
how do APCs display antigens that are recognized by specific lymphocytes?
T cells:
* MHC-associated peptides: cytosolic for I, vesicular for II
B cells:
* native antigens
* APCs = macrophages, FDC in germinal centers
275
how do APCs activate T cells?
costim & cytokines induced by microbes act as "second signals"
ensure that T cells respond BEST
276
why are DCs most efficient APCs for initating immune responses?
1. location
* @ sites of microbe entry
* receptors that recog inflamm cytokines
2. receptors for capturing microbes
* PRRs with very active endocytosis
* mannose, c-type lectin, TLRs
3. migration
* CCR7
* co-localize in peripheral L tissues with naive T cells
4. mature while migrating
* incr lvls of MHC: induce costim & decr endocytosis
* convert from ag capture --\> APC and T cell activation
277
immature DCs are activated when:
DC TLRs bind microbal cmpts
stim via inflam cytokines from microbe
278
what are the signals that DCs provide to activate T cells?
1. increase MHC/antigen complexes
2. increase costim molecules
**programmed change that DC undergoes upon activation in peripheral tissues**
279
fxs of different APCs: DCs
naive T cell activation
clonal expansion
differentiation into effector T cells
280
fxs of different APCs: macrophage
effecgtor T cell activation
activation of macrophages: cell-med immunity
281
fxs of different APCs: B cells
effector T activation
B cell activation
antibody production
**humoral immunity**
282
Which of the following cell types is best equipped for the activation of naïve T cells?
A.B cells
B.Macrophages
C.Eosinophils
D.Neutrophils
E.Dendritic cells
DCs
283
antigen processing and presentation means:
how APCs and normal cells break down larger proteins --\> small polypeptide epitodes --\> present to T cells on MHC I or II
284
sources of protein antigen for APC?
extracell: internalized by specialized APCs
intracell: cytosolic proteins (microbial or self) from cell's OWN protein prod machinery
285
difference b/w extracell and intracell antigen presentation?
extracell = MHC II
intracell (cytosolic) = MHC I
286
antigen processing
conversion of native antigen (globular protein) into peptides cap of binding to MHC
* loaded in same cell compartments where MHC are synth and assembled
287
MHC II processing of protein antigens
1. endocytose extracell protein
2. biosynth MHC: with invarient chain Ii
3. association
4. present on surf for CD4 cell
288
MHC I processing of protein antigens
1. cytosolic protein --\> proteasome
2. enter ER via TAP
3. attachment to MHC
4. presentation on surf for CD8 CTL
289
before an ag can be processed via MHC II pathway....
exogenous ag must be bound & internalized
different APCs bind protein ag
* DC & macrophages recog structures shared by board groups of microbes: TLF, MBR
* macrophages - Fc & C3b --\> opsonizing ab and C'
* B cells: specific! = high affinity
290
Class II MHC pathway of processing and presentation of peptide ags
1. extracel protein ingested into endosomes/lysosomes
2. brkdown --\> peptides
3. MHC II mol constantly produced in ER with Ii to block ER loading
4. MHC/Ii complex targeted to late endosome/lysosome vesicles
5. CLIP removed by HLA-DM and extracel peptide Ag takes its place
6. presentation
7. recog by CD4
291
The class I MHC pathway of processing of endogenous cytosolic protein antigens
1. cytosolic proteins ubiquitin tagged --\> proteosome
* most = endogenous derived (self, virus, tumor)
* some = proteins of phago microbes that enter cytosol
2. peptides --\> ER via TAP
3. load onto empty tapasin-anchored MHC I complexes
* holds MHC in place
4. complex stab & released from TAP
5. txp to cell surf
6. recog by CD8 T cells
7. activates CTL that destroy cells infected with intracell microbes & eradicate reservoirs of infection
292
what is the problem for CD8 cells?
only ag presented by activated DCs can activate naive T cells
soln: some DCs can capture infected cells --\> txp ag to cytosol --\> enter class I pathway
* explains how non-prof APCs can lead to init of CD8 cell response
293
what is the significance of segregating class I and class II MHC pathways?
respond in diff ways --\> find BEST way to combat microbes
294
protein antigens of microbes that live in cytoplasm of infected cells enter what pathway?
MHC I --\> cells recog by CD8 --\> kills infected cell
295
protein antigens of microbes endocytosed from extracel environment enter what pathway?
MHC II --\> recog by CD4 Th cells --\> activate macrophages to destroy phago microbes **&** activate B cells to prod antibodies aga extracell microbes
296
what does immunodominance of peptide epitopes mean?
not all peptide epitopes presented equally
"determinant selection"
* unique set of MHC alleles select best MHC-binding peptides --\> select immunogenicity of individual = immunodominat!
297
MHC I v II: composition of stable peptide-MHC complex
I: polymorphic alpha chain of MHC, beta-2-microglobin
II: polymorphic alpha and beta chains of MHC
298
MHC I v II: cells that express MHC
I: all nucleated cells
II: DC, mononuc phagocytes, B lymphocytes, endothelium, thymic epithelium
299
MHC I v II: responsive T cells
I: CD8
II: CD4
300
MHC I v II: source of protein antigens
I: cytosolic proteins - mostly synth in cell (can have ones that are phagoed)
II: endosomal/lysosomal proteins - internalized from extracell environ
301
MHC I v II: enz responsible for peptide generation
I: cytoplasmic proteasome
II: endosome/lysosome proteases (cathepsins)
302
MHC I v II: site of loading of MHC
I: ER
II: specialized vesicles
303
MHC I v II: molecules invovled in txp and loading of peptides onto MHC
I: TAP
II: Ii & DM
304
causes of MHC I deficiencies
mutations
* TAP
* tapasin
absense --\> failure to produce stable MHC I mol --\> expr fewer
305
what kinds of viruses evade CD8 T ecll response and how?
inhib proteasomal activity:L EBV, human CMV
block TAP txp: HSV
block MHC synth and/or ER retention: adenovirus, human CMV
removal of MHC I from ER: CMV
interfere with CTL recog with "decoy" viral class I-like mol: murine CMV
306
Ag displayed by FDCs are...
coated by ab and complement (C3b, C3d) --\> target for activated B cells
* selects B cells that bind ag with **high affinity**
307
Cytomegalovirus (CMV) is a common infection that often produces no clinical symptoms, however, can be quite dangerous in immunocompromised patients. CMV has a number of mechanisms by which it evades the immune response. One mechanism involves blockade of the TAP molecular complex. Which of the following is the most likely outcome of this blockade?
A.Reduced humaral immunity
B.Impaired neutrophil recruitment
C.Reduced activation of helper T cells
D.Impaired cytolytic destruction of infected cells
E.Reduced expression of costimulatory molecules by infected cells.
impaired cytolytic destruction of infected cells: CD8
308
BCR v ab
basic structure is similar aside from transmemb region in cell-bound form
* soluble Ig produced by effector B cells
309
different stages of B cells
will express ag either as cell surf receptor or secreted as ab
310
what class of glycoproteins are Ab?
gamma-globulin
311
composition of ab
4 polypep chais: 2 heavy and 2 light
held together by disulfide bonds
312
secreted IgG versus membrane IgM
IgM has extra Ch4 portion close to PM of B cells with transmemb tails
313
what makes up the antigen binding pocket
fx?
variable regions of light and heavy chain - 2 indentical
determines antigen specificity
314
fx of constant region of ab?
detms isotype: IgG, IgM, IgD, IgE
C' deposition
Fc receptor binding
transcytosis
315
regions of antibody are classified by....
proteolytic frag
* papain --\> 2 Fab frag and 1 Fc frag
* pepsin --\> 1 F(ab)2 frag: digestion occurs below hinge region = 2 arms are attached
316
CDRs
antigen-binding site: aa seq variably concentrated in short, hypervariable stretches
* each region = 3 CDRs
317
isotypic v allotypic v idiotypic differences in Ab
isotypic: constant regions due to usage of diff c-region genes
allotypic: different allesles of SAME C GENE (polymorphic)
idotypic: variable portion differences
318
IgA isotype
mainly dimer
fx: mucosal immunity
319
IgD
trace amts in serum
monomer
fx: naive B cell antigen receptor
320
IgE isotype
monomer
fx: helminth parasite def, immediate hypersense
321
IgG isotype
most abundant in serum
monomer
fx:
* opsonization
* C' activation
* antibody-dep cell-med cytotoxicity (ADCC)
* neonatal immunity
* feedback inhib of B cells
322
IgM isotype
pentamer
fx: native B cell antigen receptor (monomeric form), C' activation
323
relationship b/w valency of interaction and avidity of interaction of Ab on cells
higher valency = high avidity of interaction
324
fx of hinge region of ab
loc b/w Fab and Fc portions --\> allow indep mvmt
325
what is affinity
strength of binding b/w single antigen binding surf on ab and one epitope of ag
326
what is antibody avidity?
total strength of binding b/w compelx antigen (multi-epitope) and dimer/pentamer ab complex
327
change in ab affinity and avidity over course of immune response
IgM (pentamer) early when ab affinity low
as immune response con't --\> antibody affinity improves
* + class switching = uses smaller molecules (G, E, A)
increased affinity compensates for decreased in # of binding sites for maintaining overall avidity for antigen
328
Changes in Antibody Structure During the Humoral Immune Response
329
clone
population of lymphocytes with identical antigen receptors
330
monoclonal
derived from single cell clone --\> will be specific for SAME epitope on SAME antigen
331
polyclonal
derived from multiple clones --\> specific for MULTIPLE epitopes or ag
332
how to produce a monoclonal ab?
1. immunize mouth with ag X
2. boost days later to incr # of ag-sp B cells
3. remove spleen --\> isolate B cells
4. fuse B cells with immortalized myeloma cell line
5. culture in medium that allows only fused cells to grow
6. isolate SINGLE clones of ab-prod immortal B cell
7. you've made a hybridoma
333
so what's the point of mAb's (monoclonal antibodies)
1. ID pheno markers on particular cell types
2. imm-dx
3. tumor ID
4. therapy
5. fx analysis cell surf and secr mol
334
TCR structure
surf ag receptor on T cell that recog MHC ag-present
similar to Ig
2 types:
* α β: predominant in lymphoid tissues
* γ δ: predominantly at mucosal surfaces
335
Features of the TCR (αβ)
memb-bound heterodimer
* anchored: **not prod in secreted form** (like ab)
each variable region contains 3 CDRs with CDR3 being MOST variable
short cytoplasmic tail: no transduction of activation signal - requires CD3 complex which can transmit some signals
no class switching --\> no effector fx
336
each T cell has TCR for how many specificities?
ONE - αβ TCR recog ag only in context of MHC
* low affinity --\> str by addn cell surf adhesion mol: LFA-1 to ICAM-1
337
how to compensate for short cytoplasmic tails of TCRs?
T cell co-receptors (CD4 and CD8) recog nonpolymorphic regions of MHC --\> transmit activating signals
338
non-traditional T cells
recog wide variety of ag: many are non-protein
* NOT MHC restricted
339
Comparison of antigen-recognizing molecules of the adaptive immune system: chart
340
flow cytometry findings of different CDs
341
most diverse CDR
CDR3 --\> key for determining ag specificity
* spans jxn of V and C regions
342
how is enormous diversity of ag receptors created?
somatic recombination
formation of antigen receptors take place during B and T cell dev: random rearragement of antigen receptor gene seg
343
IL-7
critical for init prolif and survival or earliest lymphocyte precursors
rearragement process is random & error prone --\> high lvls of precursor cell death
344
somatic recombination
randomly joining of gene seg
345
Steps of Ig heavy chain somatic recombination
1. D pairs with J
2. V joins DJ
3. Ig heavy chain Ts
4. VDJ RNA spliced into 1st heavy chain C RNA (mu)
5. RNA T(L) to produce M heavy chain
6. if heavy chain recomb successful, light chain gene recombined next
346
germline configuration of T cell antigen receptor loci
D gene seg not part of TCR-alpha chain locus
during som-recomb:
* 1 V + one of many D and J and one of C regions
347
The germline configuration of B cell antigen receptor loci
many different C region gene segments - extracellular and transmembrance/cytoplasmic domains
348
when does Ig som-recomb happen? What does that mean?
during lymphocyte dev: B in bone marrow, T in thymus
* **indep of antigen**
each lymphocyte will be DIFFERENT from seg combining in neighboring cell
349
VDJ recombinase
lymphoid sp-enz: combosed of RAG1 and RAG2 proteins (same name genes)
fx:
* recog DNA signal seq that flank all V, D, and J gene seg --\> brings those together --\> cleaves --\> ligased to be V-J or V-D-J exon without intervening DNA seg
350
where odes the diveristy of hte B and T cell antigen receptor repertoire come from?
combinatorial diversity: diff combos of V, D, J seg
junctional diversity: addn/removal of nt seq @ jxns
351
mechanism of diversity in ag receptors
exonucleases removed nts from VDJ seg during recomb --\> TdT adds random nts to the region --\> overhanging DNA seg created and filled on (P nts)
352
what is the price paid for tremendous B and T cell antigen receptor diversity?
recomb can prod seq that do not recog antigen
soln: multple pts of regulation to select for fx ag recep
353
SCID
severe combined immunodeficiency
defects in both T cel land B cell arms of adaptive immune response
* IL-7R
* ADA
* RAG
354
IL-7R mutation --\>
blocks T cell maturation
B cell mat intact b/c they CAN use other GFs
355
ADA mutation --\>
ADA = salvage pathway of purine synth
loss --\> accumulate toxic purine metabolities --\> kill lymphcyte prolif during maturation --\> decreased B, T, NK cells
356
RAG mutation --\>
RAG1/2 mutation --\> blocks VDJ recomb --\> absence of T and B cells
357
processes invovled in maturation of lymphocytes from BM precursors
1. prolif immature cells
2. expr of ag receptor genes
3. selection that expr useful receptors
358
what chain gene is 1st to be expr which results in the expression of IgM?
μ (Mu) heavy chain gene
359
significance of rearragement of 2nd chr?
successful --\> VDJ recomb will move forward
unsuccessful --\> cell = apop
**2 alleles allows for multiple chances for successful rearrangement**
360
what is the surrogate light chainn
placeholder to stabilize expr of pre-B cell receptor
* inhib futher heavy chain rearrangement
* if both alleles used, then no problem
* if 1st allele was successful --\> prevent using 2nd allele to redo recomb
* further prolif of pre-B cells
* lost a bunch of cells during failed recomb so need to replace
* stim of K light chain recomb
* indep of heavy chain recobin
361
allelic exclusion
produtivec rearrag on one chr --\> turns off further rearrag
* Ts RAG stopped & RAG proteins degraded
ensures that all ag receptors expressed will have SAME ag specificity
362
light chain rearragement of pre-B cell
cells with light chain success combine with heavy chain --\> selecgted to surviv e nad prolif
363
XLA
x-linked agammaglobulinemia
* def in B cell dev: BTK gene
* males over 6mo
result:
* low to absenb B cells
* low serum Ig
* underdev L tissues - no germinal centers
* absent plasma cells
* recurr RT infections by extracel bac & viruses norm neut by Ab
* bac: strep, h.influenzae
* virus: polio, coxsackievirus
364
BTK
enq that signals for light chain rearrag
req for B cells to dev beyound pre-B cell stage in bone marrow
365
selection of B lymphocytes is _____ selection
negative - screen via binding of self antigen with high affinity
if binding occurs:
* reactivate RAG to gen 2nd light chain --\> change specificity (receptor editing)
* apop
366
receptor editing
gen new light chain - ONLY if there is an allele yet to be rearranged
ONLY IN B CELLS
367
final step of B cell dev
in periphery - spleen: expr IgM and IgD
368
chart of steps in maturation of T cells
369
allelic exclusion in T cell development
2 attempts to rearragement for both beta and alpha gene
* success @ 1st attempt turns off any further attempts for other allele
* success of beta signals rearragemetn of alpha gene
370
selection for T cells
positive
* recog of self-MHC
* class I --\> retains CD8, loses CD4
* class II --\> retains CD4, loses CD8
negative
* del double-positive T cells that strongely recog MHC-self peptide complexes
371
what does the process of negative selection in the thymus require?
presentation of self ag/MHC complexes in thumus
Ts AIRE - allow expr 100s of different tissue specific genes to be presented
* so T cells can recognize self and not react
* rxn --\> apop
372
APS-1
autoimmune polyendocrine syndrome type 1
* monogenic disorder caused by AIRE mut
* triad
* mucocutaneous candidiasis
* autoimm addison's
* autoimm hypoparathyroidism
373
Congenital immunodeficiencies caused by defects in lymphocyte development chart
374
A B cell tumor is isolated from a patient. If two separate DNA probes with different sequences (Probe 1 and Probe 2) show that the immunoglobulin genes of one B cell tumor are in the conformations shown below, at what stage did the B cell become a tumor?
A.A pro B cell
B.A pre B cell
C.An immature B cell
D.A mature B cell
E.A memory B cell
A pre B cell
375
376
T cell activation and accessory molecules
molecules other an ag receptors involved in T cell response
ligang-receptor int-act:
* ag-recog
* adhesion
* signal (activate, supress)
invarient amoung ALL T cells
377
factors that impact T cell activation
TCRs engaged by Ag/MHC - requires 2 or more TCRs
* **low affinity!**
length of engagement: req several min to gen enough signals to activate
378
fx of adhesion molecules for T cell activation
productive activation requires stabilization
* integrins: LFA-1 (bind to ICAM-1)
naive T cells have low affinity integrins --\> high affinity integrins
* via Ag recog
* cause clustering --\> allows strong binding to APCs
379
best defined costim for T cells
B7-1(CD80) & B7-2 (CD86) --\> recog by CD28 (on virtually all T cells)
* **essen for activation of naive T cells**
****ICOS: CD28-like molecule expressed by CD4 cells
* provide help to B cells in follicles (follicular Th cells)
380
significance of costim requirement
ensures naive T cells only activ FULLY by microbial ag
* NOT by harmless self or foreign ags
381
vaccines and B7
vaccines = only pure microbial proteins
require adjuvant to induce B7 expr by APCs to offer sufficient co-stim to T cells specific for vacccine Ags
382
anergy
T cells that get Ag receptor stim but NOT costim signal
* **need BOTH signals to proceed**
makes cell unresponsive/quiescent --\> death
383
other fx of CD28 constim receptor?
can be inhib and limit or terminate an immune response
* CTLA-4 can also bind B7 but it's singal = suppression
* like PD-1: inhib receptor that recog idfferent but related ligands on many cell types
384
CTLA-4 and PD-1 engaged on their ligands --\>
inhib T cell activation/effector fx:
* supress response to self antigens
* term responses upon clearance of ag
385
CTLA-4 blockage
tumor regression via enhancing of tumor-sp immune responses
autoimune inflam
386
what is the TCR-CD3 complex for?
intraacyto region of TCR is too short to transduce activation signal
* requires CD3 chains!
* ITAMS regions that require (P) to signal
387
activation steps of T cell signalling
1. TCR bind to MHC-peptide complex and CD4/8 binds to nonpolymorphic regions of MHC I/II
2. binding of CD4/8 brings Lck (tyrosine kinase) to ITAMS
3. activate Lck --\> (P) tyr residues in ITAMS
4. docking site for Zap-70 --\> getts (P) by Lck --\> activates
5. several signally pathways
388
Zap-70 activation via _____ activates....
(P)
Nuclear factor of activated T cells (NFAT) pathway
PKC-NF-kB pathway
Ras/Rac-MAP Kinase pathway
PI-3 Kinase pathway
389
Calcium-NFAT pathway
ZAP-70 --\> (+) PLC (phospholipase C) --\> IP3 --\> ER --\> release Ca2+ --\> (+) calcineurin (phospatase) --\> (+) NFAT --\> nuc --\> (+) expr for IL-2 & IL-2 receptor
390
Protein Kinase C (PKC)-NFkB
PLC --\> IP3 + DAG
DAG --\> PKC --\> recreuit to TCR --\> (P) IkB-NFkB (bound together ) --\> IkB + NFkB
* (P) causes IkB to be destroyed
* NFkB --\> nuc
391
RAS/Rac MAP Kinase pathway:
ZA-70 (P) adaptor proteins in PM --\> recruit RAS & RAC inter-med --\> activate via GDP-GTP exchange --\> enz cascade --\> MAP kinase ERK/JNK --\> induce expr c-Fos & (P) c-Jun --\> dimer --\> AP-1 --\> activates T cell genes
392
Phosphatidylinositol-3 (PI-3) kinase pathway
trigger TCR, CD28, IL-2 receptor --\> PI3 kinase --\> (P) PIP2 --\> PIP3 --\> Akt/PkB (ser-thr kinase) --\> anti-apop proteins --\> surv ag-stim T cells
393
mTOR
kinase similar to Akt
promotes cell surv & growth
target for **rapamycin** - used to tx graft rejection
394
Ts factors activated due to T cell stim drive expr of genes for...
T cell prolif
cytokine production
effector mech
395
clonal expansion of T cells is due to
IL-2:
* induced within 1-2 hours after T cell activation
* alongisde high affinity form of IL-2 receptor
396
IL-2 is produced by... and then fxs to?
ag-stim T cells
**acts on same T cell**
induces prolif and surv
INDUCED BY ACTIVATION OF **NFAT**
397
cyclosporin
blocks IL-2 via inhib of NFAT
398
which cells prolif the most?
CD8
most during anti-viral response
399
superantigens
bac/viral toxins --\> (+) T cells in **antigen-nonspecific way**
* bind simultaneously to MCH II & TCRs (particular beta chain variable region)
binds to wide array from TCR --\> EXCESSIVE polyclonal response --\> can invovle CD4 T cells
**massive** release of inflam cytokines (IL-1/2, TNF-alpha) --\> septic shock
400
staph aureus enterotoxins
exotoxins prod by gram positive
most common cuase of food poisoning in humans
401
TSST
toxin related to stap enterotoxin --\> causes toxic shock synd
* mass of activated T cells --\> TNF --\> fever, disseminated intravasc coag --\> CV shock
assoc with tampon use and sx wounds
402
403
most important cell surf protein involved in T cell effector fx of CD4 cells is...
CD40L
404
during mycobacterium infectons, what does CD4 T cells do/
req to activate macrophages --\> destroy intraell bac (cell-med immunity)
405
anti-helminth and CD4 cells
involves CD4 T cells
**BUT**
dominated by B cell prod of IgE --\> (+) eosinophils & mast cells
406
different T cell subsets defied by capa to...
produce different sets of cytokines
* Th 1, 2, 17
dev in response to types of microbes BEST at eradicating - influenced by innate immune response
407
Th1 cells critical for
stim phago-med killing of intracell microbe: IFN-gamma
408
effects of IFN-gamma
1. activate macrophages
2. amp CD4 response: expr of MHC II & B7 on macrophages and DCs
3. production of opsonizing IgG ab from B cells
4. differen CD4 --\> Th1 subset --\> inhib dev of Th2 and Th17
409
differentiation of Th1 cell is driven by...
IL-12 - DC & macrophages via stim through TLR & other PRRs
INFgamma - NK (in combo with IL-12) --\> (+) Ts --\> INF-gamma by Th1 CD4 T cells
usually prod during innate immune response to bac
410
what is an example of cell-med immunity directed by Th1 CD4 T cells?
mycobacterium Tb
primary Tb = early, uncontrolled prolifand spread of bac in the pulm alveoplar macrophages (lasts 3 wks)
@ 3 wks: CD4 response aga Tb mounted via high lvls IL-12 --\> Th1 differen & IFN-gamma prod --\> (+) infected macrophages to better kill Tb
* form intracell phagolysosome
* NO/ROS
* granulomas
411
activation of macrophages by Th1 CD4 effect T cells requires...
1. Th1 specific for ag presented by macrophage @ infection site
2. prod IFN-gamma by Th1 --\> bind to IFN-gamma of macrophage
3. int-act b/w CD40L b/w Th1 and macrophage
4. macrophage activated = classically activated
## Footnote
**bidirectional int-act b/w cells of innate & adaptive immune sys**
412
Th1 effector fx
activate macrophages
secr TNF-alpha --\> (+) adhesion of endothelium & (+) chemokines --\> inflam
CD4 --\>
* CD8 --\> CTL
* helper B --\> plasma cells
413
cytokines of Th2
IL4: (from Th2 & Tfh) --\> class switch to IgE --\> opson helminth & bind Fc of mast cells and eosinophils
IL5: (+) eosinophiles --\> MBP & major catonic protein --\> kil helminth
IL13: (+) mucus secr & intestinal peristalsis
414
how do cytokines from Th2 differ in their effect on macs than Th1?
Th1 --\> INF-gamma --\> (+) classic mac --\> kill, cytokine secr
Th2 --\> IL-4, IL-13 --\> inhib mi-cidal of macs & (+) fibrosis via incr collagen synth
415
what are M2?
alt-activated macs via IL4 anad IL13 in **absence** of strong TLR signals
reduce inflamm & prom tissue repair
416
how do ______ cells differentiate into Th2 cells?
CD4 (in presence of IL-4 and **absence of IL12**) --\> Th2
source:
* (+) CD4 prod small amts of IL4 when (+) in absence of IL-12
* (mast cells)
* (basophils)
417
Th17 cells
prod only:
* IL-17
* recruit neutrophils and monocytes
* defensins
* IL-22
* maint integrity of epith barriers
418
Th17 cells destroy...
but can be implicated in..
destroy: extracel bac & fungi
implicated in: inflam disease --\> MS, IBD, RA
419
dev req for Th17
IL-1, 6, 23 **+** TGF-beta
TGF-beta = usually inhib immune response but prom dev of Th17 in PRESENCE of IL-6 or IL-1
420
CD4 effector subsets on themselves and other subsets
amp themselves and INHIBT others
421
mycobacterium lepra
bac in macs --\> leprosy
2 clinical forms:
* tuberculoid
* dom Th1 response --\> poor growth in macs
* low infectiveness
* loc infection
* normal serum Ig
* lepromatous
* dom Th2 response --\> florid growth
* mac killing inhib by Th2 response
* high infectivity
* disseminated
* hypergammaglobinulinaemia
422
A major function of ____ cells is to activate macrophages. Which CD4 T cell subset activates macrophages and what molecules are essential for this function?
A.Neutrophils, IL-1 and TNFa
B.Th17, IL-17 and IL-22
C.Th2, IL-4 and CD28
D.CD8, IL-2 and IL-12
E.Th1, IFNg and CD40L
Th1, IFNg and CD40L
423
Activated macrophages (classical or alternative) perform all of the following functions except:
A.Inhibition of fibroblast proliferation and angiogenesis within damaged tissues
B.Production of lysosomal enzymes and reactive oxygen species that kill phogocytosed microbes
C.Presentation of antigen to helper T cells
D.Secretion of inflammatory cytokines such as TNFa and IL-1
E.Production of NO
Inhibition of fibroblast proliferation and angiogenesis within damaged tissues
424
Which type of T cell is most likely to promote acute neutrophilic inflammatory responses that defend against extracellular bacteria and fungi?
A.Th1
B.Th2
C.Th17
D.CD8+ CTL
E.T follicular helper cell
A.Th17
425
naive CD8 cell activation depends on...
cross presentation of ag by DCs
virus-infected cell destroyed --\> frags endycyto up by host DC (has MHC II) --\> present on MHC I alongside costim B7 --\> activates virus-sp CD8 --\> prolif --\> kills infected cells
426
how do CD4 cells "help" (+) naive CD8 cells?
DC can present ag to CD4 and CD8
DC with high levels of B7 --\> (+) naive CD8 --\> IL-2 --\> self prolif and differentiation
APC --\> (+) CD4 --\> (+) APC (DC) --\> expr B7 --\> co-stim naive CD8
APC --\> (+) CD4 (to make IL-2) & CD8 to expresss IL-2 receptors --\> IL-2 sec by activated CD4 will (+) CD8 IL-2 receptor --\> (+) CD8
427
co-stim of CD8 T cell
required during stim
CD8 can self-prolif and differentiate but secr IL-2 that self acts
effector phase does **not** need co-stim --\> allows targeting of non-APCs --\> kill
428
CTLs kill target cells via
apoptosis
* perforin/granzyme
* Fas/FasL
429
All of the following are associated with immune responses to intracellular bacteria except:
A.Interferon gamma production by bacterial-antigen specific CD4 T cells
B.Opsonization of infected cells by complement
C.IL-12 production by macrophages
D.Granuloma formation
E.Cytotoxic T cell killing of infected macrophages
Opsonization of infected cells by complement
430
how can mycobac evade cell immunity?
inhib phagolysosome fusion --\> survs in phagosome
431
how does HSV evade cell immunity?
inhib TAP txper (into ER) --\> no ag presentation
432
how does CMV evade immunity?
inhib proteosome activity
remove MHC I from ER
--\> **no ag presentation**
433
how does EBV evade immunity?
inhib proteosome activity --\> no ag presentation
prod IL-10 --\> inhib mac and DC activation
434
how does the pox virus inhib immunity
prod soluble cytokine receptors --\> bind extrcel cytokines --\> decreased cytokine binding onto effector cells --\> decreases activation
435
T cell exhausion
virus --\> (+) inib receptors like PD-1 (sim to CTLA-4) --\> (-) CD8 --\> prematurally terminated response to virus --\> chronic infection -- T cell exhausion
436
which cells contritube to hypersense?
CD4
* Th1: RA
* Th2: asthma - IL4 + IL13 --\> (+) IgE, IL-5 --\> (+) eos --\> chronic asthma
* Th17: crohns - neutrophil recruit to gut --\> lyso enz + ROS
CD8
* DM I --\> beta cell lysis
437
general properties of cytokines (4)
prod transient response to ag: TCR signal and costim
autocrine/paracrine - T cell activation induces expr of cytokines and high-affinity receptors for this cytokines
pleiotropism - each cytokine has mult actions
redundancy - mult cytokines share same/sim actions
438
compare and contrast innate v adaptive immunity: cytokines
innate: TNF, IL-1, 12, IFN-gamma
adaptive: IL-2, 4, 5, IFN-gamma
439
compare and contrast innate v adaptive immunity: major cell source
innate: macs, NK
adaptive: T cells
440
compare and contrast innate v adaptive immunity: prinicple physio fxs
innate: med inflam (local and sys)
adaptive: reg T ells growth and diffen, (+) effector cells (mac, eos, mast)
441
compare and contrast innate v adaptive immunity: stimuli
innate: LPS (endotoxin), bac pep-glyc, viral RNA, T cell derived cytokines (IFN-gamma)
adaptive: protein ag
442
compare and contrast innate v adaptive immunity: amounts produced
innate: high - detectable in serum
adaptive: low - usulaly undetectable in serum
443
compare and contrast innate v adaptive immunity: local or stim effects, roles in disease
innate: both --\> septive shock (sys diseases)
adaptive: usually local only --\> local issue injury (granulomatous inflam)
444
compare and contrast innate v adaptive immunity: inhibitors
innate: corticosteroids
adaptive: cyclosporine, FK-506
445
TNF effects (6)
1. endothelium - inflam, coag
2. neutrophil - activ
3. hypoT - fever
4. liver - synth acutep phase
5. M/fat - catabolism (cachexia)
6. apop
446
IL-1
endothelium - inflam, coag
hypoT - fever
liver - acute phase prot
447
IL-12
T cells --\> Th1 diffen
NK/T cells --\> IFN-gamma, incr cytotoxic activity
448
chemokines are most important for...
leukocyte: chemotaxis, activation, migration to tissues
449
IL-12
produced by...
effect?
prod: macs, DC
effect:
* stim NK & CD4 --\> INF-gamma --\> bidirectional stim and incr cytotoxic activity
* Th1 differen
450
IFN-1
prod:
* alpha - mac
* beta - fibroblasts
effect:
* (+) anti-viral state
* incr MHC I
* activates NK
451
IL-10
main prod by reg T cells
inhib --\>
* IL-12 production
* expr costim
* MHC II
452
IL-15
prolif NK
prod memory CD8 cells
453
IL-18
stim INF-gamma prod from NK & T cells
454
IL-23
(+) Th17 cells --\> Th17 production
455
TGF-beta
inhib T & B cells and mac
(+) IgA
angiogenic
(+) fibroblastss --\> (+) collagen synth
456
IL-13
isotype switch B cells --\> IgE
increase musuc prod in epithelium
increase collagen synth in fibroloasts and M2
457
lymphotoxin
prod by T cells --\> recruit neutrophils & lymphoid organogenesis
458
IL-4
B cell isotype swithc to IgE
(+) Th2
inhib IFN-gamma med activation of macrophages --\> (+) M2
mast cell prolif
