Exam 2 Spring Flashcards
(136 cards)
1
Q
humoral response revelent in…
A
- extracell bac/fungi/parasites
- helminth
- virus/intracell bac DURING spread/ADCC
2
Q
phases of b cell recognition (big pic)
A
- b cell is “born” (secr only IgM w/ some IgG2- naive and has not met ag)
- presented w/ polysacc ag
- two choices: either TI or TD
- TI: IgM
- TD: class switch to “better” ag - protein Ag (most)
- if TD: requires CD4+ (both activated each other)
- prolif
- plasma cell –> IgM
- isotype switch –> IgG, IgE, IgA
- HIGH-AFFINITY –> affinity maturation (IgG), memory B
3
Q
TI ag induced by
A
bac polysacc
lipids
repeating surf mol on viruses
4
Q
TD ags….
A
induced by ANY ag containing protein (due to CD4 help) IN GERMINAL CENTER
majority do this
5
Q
what type of cells have TI responses & characteristics
A
TI:
- marginal zone B cells (spleen)
- B1 cells (mucosa)
multiple identical epitopes –> max x-link: polysacc
can be (+) by alt C’ pathway
dom by IgM with some IgG2
- LOW affinity
- NO maturation
- NO memory
6
Q
what is the main def aga encap bac
A
humoral immunity b/c capsule is USUALLY polysacc
7
Q
what types of cells prod natural ab?
A
B1: low affinity anti-carb ab prod w/o overt exposure to pathos
- ex: ABO blood group
8
Q
what are the primary response cells to protein ags?
A
follicular B cells
Th cells
9
Q
TD response activation
A
- initial 2 separate stim
- Ag (with protein cmpts) taken up by DC –> processed –> presented on MHC
- Ag (whole ag) recog by B cell –> ingest –> present to CD4
- activated Th cell (by APC: DC) will recog B cell presented Ag (which now acts as a APC) and (+) B cell to TD response
10
Q
types of B cells
A
follicular
- follicular zone of lymph nodes
- ONLY place of TD activation
marginal zone
- marginal zone of spleen
- encap bac
- TI response: IgM (some IgG2)
B1
- mucosa
TI response: IgM (some IgG2)
11
Q
primary ab response v secondary
A
primary response : 5-10 days
secondary response: 1-3 days (due to memory cells = faster, stronger, BETTER)
12
Q
ag delivered to B cells in follicles largely thru
A
afference lymph -> subcap space –> conduits/macrophage presentation –> B follicles
13
Q
how to B cells come and go from lymph nodes
A
come:
- target via with cytokine (CXCR5) to lymph node receptor (CXCL13) –> enter via HEV (high endothelial venules)
- in contrast with Ag which enters via afferent lymph
go:
- ONLY IF NO AG TO RECOGNIZE!! –> efferent lymph
14
Q
how does a germinal center get created?
A
Ag delivered via macrophages/afferent lymph recog by B cell –> clonal expansion –> germinal center (2ndary B cell center)
15
Q
biochem pathway of B cell activation
A
- polysacc or large mol = IgM cross linking (remember naive b cells have IgM surf ag)
- (+) ITAM on Ig-alpha Ig-beta
- (P) BCR RTK complex: fyn, lyn, blk
- recruits syk TK
- (+) TK on adaptor proteins
- signal cascade
- (+) Ts factor
- b cell activation
16
Q
ag recognition by B cell induces…
A
early phase of B cell activation
- prolif and survival
- B7 ag (co-stim on CD28 on Th cells)
- IL-4R: inflammation
- CCR7: cytokine flip-flop
- ag internalization –> MHCII –> present to CD4 cells
17
Q
examples of B cells co-stim
A
- alt C’: CR2 recog of C3d on microbe
- microbe recog on TLR with Myd88 adaptor protein
- IFN-1: anti-viral
- CD4 co-activation
18
Q
what does the CR2 receptor do?
A
B cells req more than just microbe recog on BCR
CR2 (CD21) recog alt C’ pathway
- alt C’: C3d binding on microbe surface
- C3d (attached to microbe) fits into CD2 receptor at same time that microbe binds onto IgG/IgM
***co-stim ENHANCES b cell activation
19
Q
what is Myd88
A
b cells req more than just microbe recog on Ig (BCR)….
be cells have LOTS of TLR!
- req Myd88 adaptor protein association
*** enhanced B cell activation
- microbe be deposited on BCR and TLR at same time
- synergized
20
Q
what is an extrafollicular focus and what happens to it?
A
when activated T & B cells meet “in the middle” (B cell out of the follicle and T cells out of its T cell zone)
- due to flip-flop of cytokines
- complex will eventually migrate BACK into follicular zone and create germinal center
- extrafoll T cells –> follicular T cell –> ab maturation
fx:
- created short lived plasma cells to produce Ag right away
21
Q
B & T cells meet up
A
once BOTH are activated
- B cell by whole ag
- T cell by T-cell (protein) epitope
cytokine FLIP-FLOP
- B: CXCR5 –> CCR7
- T: CCR7 –> CXCR5
when they meet up –> creates extrafollicular focus
- B cell will endocyt ag –> process –> present T-cell epitope on MHC II –> acts as APC to T cells
- B7
- CD40
- MORE MORE MORE MHC II
22
Q
CD40
A
expressed by B cells and macrophages
- “connects” with CD40L on T cells!!
- T cells activated B cells and macrophages the same way!
23
Q
what is the point of affinity maturation?
A
get the best Ab for BEST response to a particular ag
- occurs most ly in germinal centers and follicles
ex:
- IgG1/IgG2 = opson
- IgE = helminth, allergy
24
Q
ICOS receptor
A
binding onto ligand on B cell –> generates and (+) Tfh cells
- (+) via CD40/CD40L –> B cell affinity maturaion –> plasma cells & memory B cells & class switch (AID)
- activates T cells!
25
class switching is dependent on...
cytokines and CD40 co-stim --\> heavy-chain isotype switch
* TH1: IFN-gamma --\> IgG1/3 --\> opson, phago, classic C'
* TH2: IL4 --\> IgE, IgG4 --\> helminth, allergy
* IGF-beta, IL-5, **location:** IgA --\> mucusal def
26
IgA
dimer: protecton of mucusal surf: induced by TGF-beta and IL-5
* peyers patch: M cell endocyt fluids --\> ag recog by B and T cells --\> --\> IgA production
* IgA --\> lymph --\> blood --\> BACK to intestines --\> lumen
27
x-linked hyper IgM
can ONLY produce IgM ab
* usually due to CD40/CD40L deficiency (no T cell "help")
* also, can't activated macrophages!
immune response = NO Ig switching
* **no/reduced cell mediated response**
* incr risk of intracell microbes and opportunistic microbes
28
molecular basis of Ig class switch
CD4 cell help --\> (+) VDJ recombination: **AID**
* S(mu) (switch) region of IgM with S region of NEW constant region --\> creates loop of "extra regions" --\> extra region REMOVED --\> new strand Ts to mRNA via RNA splicing --\> T(L) --\> expr of NEW isotype
once swapped, no going back!! b/c DNA is completely changed
29
what is affinity maturation and what is the result
during prolif (after Ag recog) in germinal center...
* LOTS of pt mutations in the hypervariable Ig domains via **AID**
* creates MANY B cells with new Ig receptors
* SELECTION of the best one!!
* presentation of ag by FDCs (velco) : **positive signal**
now the best one that binds the microbe ag the best gets to leave germinal center and become a high-affinity B and eventually B mem cell
* others will apop
30
types of plasma cells
extrafollicular
* made when activated T and B cells first meet
* TI, early TD responses
* home: spleen, lymph node medullary cords
* IgM (some IgG2) - low affinity
* SHORT LIVED
high affinity
* generated in GERMINAL centers
* TI
* home: BM, gut, lactating mamm gland
* HIGH AFFINITY isotype switched
* LONG LIVED - memory --\> immed protection aga re-encounter of SAME ag/microbe
31
prop of Ab
1. prod by B/plasma cells IN lymph nodes/BM with effector fx ELSEWHERE!
2. short-lived (extrafoll) or long-lived (germinal center)
3. diff classes for diff fxs
4. ag --\> Fab --\> Ig heavy chain carries out fxs
5. class swtich --\> high affinity Ab
6.
32
IgM pentomer most important in what pathway?
classic C'
33
B cell regulation
Fc(gamma)RIIb = inhib signal
* binding of a microbe onto Ig of bcr WHO already has an ab attached to it (which will bind onto the Fc(gamma)RIIb will cause an **INHIB** signal
* b/c microbe already has an ab on it... means that there is sufficient Ab for the microbe --\> (-) B cell activation
* negative feedback
34
what Ig is most imp for neut of mucosal pathos?
IgA
35
what Ig is most importnat aga helminths
IgE
36
most neut ab:
IgG: blood
IgA: mucosal surf
37
how do most effective vacc avail today work?
stim production of neut Ab
38
mech of neut....
1. Ig binds microbe to prevent entry into cell
2. Ig prevents binding of SAME microbe onto NEW cells once microbe detaches from infected cell
3. Ig prevents binding of NEW microbe onto NEW cells once microbe-infected necrosis of infected cell, releasing NEW microbe
4. bind toxins released by microbes
39
how do Ab cause opsonization?
IgG1/3
* IgG has **high affinity** for BOTH microbe --\> opson
* Fc for neutrophils and macrophages --\> phago
* binds to Fc(gamma)RI of neut and macrop
* production of ROS and proteolytic enz
40
what is the major mech of def aga encap bac
where does it happen?
ab-med phago: IgG1/3 onto Fc(gamma)RI of macp and neutp
* opson bac
* phago
spleen
41
FC(gamma)RIIIA
CD16
(+) ADCC by NK cells
* released protein granules --\> kill opsonized targets
important for viral cell with surf glycoproteins
42
\_\_\_\_\_\_ response to helminths dom by...
humoral (b/c it is extracell)
TH2:
* IL-4: Ig class switch to IgE
* IL-5: (+) eosp --\> IgE binds onto Fc(**epsilon**)RI
rxn causes dmg to host --(can)--\> hypersens
43
IgE
Fc(**epsilon**)RI on eosp AND mast cells
* mast cells: can become sens after initial exposure (arms outstretched)
* IgE will sit and wait on mast cells so there is a HUGE dumping of inflam mediators when allergen appears again and **x-links on IgE con't bound on Fc(epsilon)RI**
44
why is IgM good at activating the classic C'
pentomer = lots of Fc portions to grab onto ag
* **not opsonizer though!!**
IgG needs couple of IgG super close to each other
45
classic C' pathway is most closely related to what other C' pathway? What is the difference?
lectin
difference in activation
* classic: IgM, IgG3
* lectin: mannose binding lectin - binds mannose on patho
46
what can be bad about neonatal immunity
Rh- mom can mount ab response aga Rb+ baby
* due to RBC txf during 1st birth
* now there are anti-Rh+ ab in mom
* can affect NEXT fetus if Rh+ --\> lysis of RBC
47
IgA production and txp to lumen
IgA produced in lamina propria of intestine cells form IgA class switched plasma cell
* dimer conneted by a J-chain
* secreted out of plasma cell into lamina propria
attached to **poly-Ig receptor**
* helps with txp across mucosal epith cell --\> lumen
48
how is IgA not digested and neut by self?
secretory cmpt of **poly-Ig** remains attached to IgA and protects from degradaton
* some of receptor stays on epith cells
* \*\*\***proteolytic cleavage**
49
how does baby get IgA?
change in horm lvls during preg allows ACTIVATED IgA to home to mamm glands --\> milk --\> baby --\> baby's intestions --\> mucosal IgA Ab neut
* ONLY what mom has been exposed to!!
50
IgA deficiency
most common primary imm-defic
makes sense!! --\> if missing --\> no mucosal protection --\>
* INCR respir, GI, UG infections
51
why is Ig replacement not indicated in IgA deficiency?
if there is no production of IgA in body....
* no presentation to dev B cell
* IgA not recog as self
when Ig therapy (which still contains SOME IgA) gets introduced....
* body will ATTACK IgA as non-self --\> immune response
52
neonatal immunity
maternal IgG txp via **FcRn** across placenta to fetus via pinocytosis into syncytotrophoblast --\> PASSIVE immunity
* mostly during 3rd trimester
* duration around 3-4 mo (~5 IgG half-lives)
* \*\*\*after 6mo, protecton essentially gone
* only good aga pathos mom has been protected aga
* **more IgG in BABY at time of birth than mom**
* so there are vacc SPECIFICALLY targ for preggos
53
BTK
b cell deficiency
neonatal immunity is reason why this does not get noticed until around 6mo old
54
is FcRN present in adults?
if so...why?
YES!
fx: protect IgG from degradation --\> **recycling**
* endothelial cells constantly endocyto
* proteins are degraded BUT! FcRn binds IgG
* IgG-FcRn complex gets recycled back to lumen
* **reason why IgG half-life is so long (3 weeks)**
advantageous: therapeutic agents fuse to Fc regions of IgG
55
examples of mech of immune evasion
1. antigenic variation
2. inhib C' activation
3. resistance to phago
56
features of extracellular bac
replic outside host cells
induce disease through 2 mech
1. inflammation
2. toxins
* endotoxin: LPS (gram -): potent activator of macp
* exotoxin: secr from bac --\> cytotoxic
57
innate immunity to extracel bac
alt C'
* activation:
* peptidoglycan/LPS (+) alt C'
* mannose binding ligant bind mannose residents on bac surf (+) lectin C'
* outcome:
* C3b opson --\> phago
* C5-9: MAC
* C5a (+) neutp, C3a/C5a (+) mast cells
PRRs
* activation:
* TLRs, mannose receptors, scav receptors on PAMPs
* outcome:
* secr IL-1, TNF, IL-6 --\> induce infiltration @ site of infection
* fever
* acute phase proteins
* (+) phago
* (+) ROS, NO
58
humoral immunity to extracellular bac
**main protection!!!!**
TI: polysacc capsule by marginal B cells
* IgM, IgG2
* activates CLASSIC C' --\> opson & phago
TD: proteins --\> class switch to IgG
* CD4 Th1:
* IgG --\> opson, phago, activates C'
* high affinity IgG and IgA --\> neut bac and toxins
59
cellular immunity to extracell bac
CD4:
* Th1: (+) macp
* Th17: (+) neut
60
injurious effects of immune response to extracel bac
PAMP: LPS induced
* septic shock!
* systemic TNF release --\> vasc collapse
humoral
* protective Ab can self-react (ex: strep throat --\> RF)
* ag-ab complex can deposit into issues --\> inflamm
cellular:
* septic shock!
* super-ag (+) LARGE T cell response --\> cytokine storm
61
LPS-induced septic shock
1. LPS on TLRs/PAMP release G-CSF --\> incr release of neutp from BM --\> dmg endothelium --\> reduce blood flow
2. prod of acute phase proteins (CRP, IL-6, SAA) by liver
3. PAF, LT, arach-acid --\> fever
4. TNF-alpha, IL-1 --\> pro-coag tissue factor --\> suppress anti-coag properties of endothelial cells --\> disseminated intravasc coag (DIC)
62
mechanisms of immune evasion by extracel bac
1. inhib alt C'
2. capsule evades phago (REQ phago)
3. catalase+ bac removes ROS
4. surf ag variation evades humoral imm
63
what is the key feature of intracell bac?
able to survave and replicate within phagosome
ESCAPE from humoral imm --\> REQ cellular immunity
64
innate immunity to intracell bac
1. phagocytes
* able to gobble up bac BUT bac can live in phago!!
2. NK cells
* IL-12 prod by activated DC/macp --\> potent NK cell activator --\> prod IFNgamma --\> INCR killing ability of macp
65
adaptive imm to intracell bac
**major protection!**
IL12 --\> TH1 --\> IFNgamma and CD40L --\> (+) macp to e better killers
bac that escape into cytop --\> (+) presentation on MHC I --\> (+) CD8 --\> kill infected cell
66
what differentiates CD4 into Th1 or Th2?
cytokines!
Th1: IFN-gamma, IL-1
Th2: IL-10, IL-4 --\> (-) macp activation
67
injurious effects of immune sys to intracell bac
CHRONIC intracell infection --\> CONSTANT ag (+) Th1 --\> CHRONIC (+) of macp:
* since macp cannot seem to get rid of it, it'll form a **granuloma** --\> "walls off bac" --\> lead to fibrosis and necrosis
68
immune evasion by intracell bac
inhib formation of phagolysosome
69
what is the most sig factor in fungi infections
immunocompromised:
* can be intracell or extracell
70
what are the main cmpts in imm aga fungal infections
neutp and macp
* phago for intracell killing
* neutp: ROS intermeds and lysosomal enz
pts with neutropenia EXTREMELY SUSCEPTIBLE to fungal infections
71
what is the major mech of fungal infection immunity
cell med!
* IL12 --\> Th1 --\> IFNgamma & CD40L --\> (+) macp to be better killers
* CD8 --\> ADCC
* Th17 --\> recruit neutp and monocytes
\*\*\***very similar to intracell bac immunity**
72
injurious effects of fungal infections to immune sys
**granuloma**
\*\*\*very similar to intracell response
73
mech of immune evasion by fungi
cryptococcus neoformans
* (-) TNF, IL-12
* (+) IL-10 --\> drives Th2 response --\> (-) macp activation --\> no killing!
74
innate immunity to viral infections
PRR of viral RNA/DNA --\> IFN-1 --\> inhib viral replic --\> CD8 kill
(+) NK
75
adaptive immunity to viral infections
1. Ab during extracell stage: early in fection or when released from infected cells and spread --\> neut (IgG in blood, IgA at mucosal surf)
2. anti-viral vaccines
3. CD8: intracell viral presentation on MHC I cells
76
how do viruses get into cells?
hemoglutinin --\> interacts with sialic acid on host cells
77
kinetics of anti-viral response
innate response helps CONTROL virus: IFN-1, NK
adaptive response: **major CLEARANCE of virus via CD8**
78
injurious effects of immune response to viral infections
1. virus-ag complex can deposit on/in tissues
2. CD8 eractication (b/c it kills cells) can cause injury to normal tissues
* ex: hep B --\> liver injury
3. molecular mmicry: can turn host immune sys on SELF
79
how do viruses evade imune sys?
1. antigenic variation
2. prod IL-10 --\> (-) macp --\> no killing
3. cytokine receptor decoys
4. can shut down MHC I or II, (-) TAP transporter, (-) proteosome
5. infect immune cells directly: CD4, T cells (HIV)
80
immunity to parasites
account for GREATER morbidity/mortality than other other class of infectious organism
MOST = CHRONIC
* weak innate immunity
* ab of org to evade/resist adaptive
81
innate immunity to parasites
NOT VERY EFFECTIVE
1. protozoa: phago by macp
2. helminth: secr microbicidal substances (too large to be phago)
3. (+) alt C'
82
adaptive immunity to parasites
depends GREATLY on the parasite
* protozoa can surv in macp --\> STRONG Th1 response --\> IFN-gamma --\> better killing ability of macp
* malaria has different stages --\> CD8 aga hepatic stage of infection
* extracell helminths --\> Th2 --\> IL4 (IgE) , IL5 (eosp)
83
injurious effects of parasites
* parasite-ag complex deposit on tissues
* **eosinophil** **granuloma: Th2**
* ****schistosomas
* DIFFERENT than intracell and fungal which do TH1 macp granulomas
84
mechanisms of parasite evation
1. resist C'
2. antigenic variation of surf proteins (can shed surf ag's)
3. "hide" in host cells or intestinal lumen
4. (+) Treg --\> (+) IL-10, TGF-beta
* leishmania
85
Overview of importance of antimicrobial defenses for infectious agents
86
a successful primary imm response purpose:
1. clear infection
2. temp gives immed protectiong against reinfection
3. imm mem
87
how do you get immed protection aga re-infection?
pre-formed circ ab formed from 1st infection do that clear away immed --\> several months of high lvl ab aga that particular ag --\> no re-infection
* usu infection is cleared by innate and circ ab = no clinical signs of infection
* virus: IgG/IgA
* bac: opson via IgG1/IgG3, C'
* parasites: IgE mast cells, eosp
88
immeidate protection usu drops off after..
what happens if the person if infected after that time?
4 mo
now re-infection dep on secondary (mem) response = stronger and faster (and almost immediate)
89
mem response med by...
expanded clones of long-lived mem B and T cells formed during **primary** response
90
new ab prod during 2nd response from? why?
long lived mem cells:
* makes sense!
* naive B cells suppressed!
* mem cells aga that partic ag already prod the BEST ab in a stronger and faster way --\> when naive B cells "see" ag on their BCR, there already is an ab attached (which co-binds @ the Fc(gamma)RIIB portion)
91
2ndary response is dom by what ab?
high affinity IgG: due to mem cells!
v 1maryresponse = IgM
92
how do memory T cells dev?
how long do they last?
2 options:
* naive --\> divergent --\> effector T OR mem T
* naive --\> effector --\> mem
93
cytokine differences b/w naive v effector v memory T cells
CD25 = IL-2
* lo on naïve AND memory
* HI in effector
CD44 =
* low in naïve
* HIGH in effector AND memory
CD45RA+ for naïve --\> CD45RO+ on effector AND memory
94
feat of mem T cells
1. surv in quiescent state after init ag elim --\> mount larger, more rapid response (like B cells)
2. # mem cells specific for ag \> naive (like B)
3. maint dep on cytokines
* memCD4 = IL-7
* memCD8 = IL-7, IL-15
4. mem cells can be committed or uncommited Th1/Th2
95
types of mem T cells
effector:
* home to perip tissues (esp mucus) --\> RAPID EFFECTOR RESPONSE
* low expr of CD62L (L selectin) and CCR7
* IFN-gamma = CD4
* CD8
central:
* home to T zones of 2ndary lymph organs --\> RAPID PROLIF OF EFFECTOR CELLS
* high expr of CD62L (L selectin) and CCR7
* very little effector ability but good at clonal expansion
96
ult goals of preventative vacc
induction of mem T and B cells for rapid response to re-infection
97
why is the current measels vacc ineffective in tropical countries?
heat sens
98
passive immunization
IV admin of Ig
* prevent disease after known exposure (needlestick)
* **post-exposure prophylaxis**
* soothe disease symptoms
* protect imm-defic pts
* block actions of bac toxins --\> (-) diseaes they cause
99
active immunization
stim of host to prod 1mary reponse so "re-exposure" induces 2ndary response
100
how to assess immune response to vacc?
ELISA: measure serum lvl of ag-specific ab
1. sat amt vacc ag attached to plastic plate
2. add pt's serum (if ab prod by host, it'll bind to vacc ag on bottom)
3. peroxidase (anti-human Ig ab) added --\> attaches to pt's ab that is attacehd to vacc ag
4. substate added that changes color in presence of peroxidase
* amt of color DIRECTLY PROPROTIONAL to amt of pt ab
101
adjuvants
cmpds added to vacc to incr expr of costim mol and cytoines that stim T cells growth/differentiation
* some vac (pure protein) do not have PAMPS (like LPS) to activate APCs which in turn (+) T cells
Alum is commonly used: aluminum salt adjuvants in US
cervarix: prevent cerv-ca caused by HPC 16/18
* ASO4 = alum-OH + monophosphoryl lipid A (MPL)
* lipid A: bio-active portion of LPS = strong imm-stim properties
102
what is the double-edged sword of a highly diverse ag repertoire?
good: blanket protection aga a LOT of microbes
* immunogenic
bad: random recombin may prod high-affinity ag aga SELF
* normally protected v self-ag by tolerance by ACTIVE process req exposure to self ag
103
tolerance induced when...
presented with self ag in central (negative selection) or periphery
104
fates of T and B cells when they recog self...
B:
* can have 1 round of receptor edited via RAG1/2 VDJ recomination
* then: anergy, apop, suppresion
T:
* apop
* chnage to Treg for imm suppression
105
central tolerance of T cells
thymus:
* AIRE: Ts factor that turns on tiss-RESTRICTED (does not leave) self-ag presentation to **immature** T cells
* negative selection: strong interaction with self-ag displayed by self MHC by T cells alpha/beta chains
106
APS1
autoimm polyendocrine syndrome 1
* monogenic mutation in AIRE
major cmpts:
* chronic mucocut candidiases
* autoimmune addison's disease (AAD): autoimm adrenalitis
* autoimm hypoparathyroidism
107
positive selection in thymus depends on....
LOW-AFFINITY MHC I/II recognition
108
peripheral tolerance of T cells
induced when **mature** T cells recog self-ag in peripheral tissues --\> negative selection
* anergy
* death
* supression by Treg
important for preventing T cell response to self-ag not presented in thymus
109
mech of peripheral T cell tolerance
T cells require co-stim:
* signal 1: CD and TCR
* signal 2: B7
results in:
* anergy: no B7 --\> surv but INCAPABLE of responding to ag
* via inhib signal from APC presenting self-ag: CTLA-4 onto B7, PD-1 binding onto PDLigand
* Treg:
* apop
110
what would happen to an indiv with loss of fx of CTLA-4
autoimm
111
why CTLA-4 needs to be manually blocked?
blcok inhib to INDUCE immune response when imm-suppressed
* attack tumors which are self tiss
* good for killing tumor
* bad b/c non-specific so can result in autoimm inflamm
112
Treg
differen and fx require Ts Foxp3 and prod of IL-2 (and TGF-beta)
* MOST commonly IDed by ALWAYS expr of CD4 and alpha chain of IL-2 receptor (CD25)
* norm CD4: CD25 expr only when ACTIVE
113
Identification of Tregs by
flow cytometry
Before x axis line = cells that do not expr CD4
1st box: low expr of CD4 à probs activated CD4 cells
2nd box: expr LOTS of CD4 = Treg (b/c they ALWAYS ALWAYS ALWAYS expr CD25)
114
IPEX syndrome
mutation in Foxp3 --\> absence/dysfx Treg
* x-linked
* OVERWHELMING autoimm:
* DM1 dev around 2 days of age
tx: BMT
* cannot tx with imm-suppress agents since amt needed would be toxic to baby
115
Treg mechanisms
inhib activation and differen of T cells
* **IL-10**
* **TGF-beta**
expr CTLA-4 that block/deplete B7 from APCs --\> (-) co-stim
high lvls CD25 (IL-2 alpha chain) may bind IL-2 --\> (-) T cell activation
116
AICD
activated induced cell death
* apop due to recog of self-ag
defect --\> autoimm lymphoprolif syndome (signally defects downstream of Fas)
117
importance of IL-2
IL-2 (+) bcl-2 = antiapop --\> survival
* absence/inhib of IL-2 --\> tips cell in favor of pro-apop
Fas/FasL engagement --\> 2 cells bind together --\> BOTH apop
118
mech of central B cell tolerance
high self-ag recog:
* RAG1/2 receptor editing --\> non-sefl reactive B cell
* apop
low self-ag recog:
* anergy
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perip B cell tolerance
**mature** B cells that recog self in periphery --\> anergy, apop, reg by inhib receptors
* NO T cell help b/c no co-stim from self-ag
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what will regulate immune response and bring it down after infection is cleared?
CTLA-4/PD-1
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allergy/autoimmunity and infectious diseases
seems to be a tradeoff: decr in infectious disease --\> incr in autoimm disease
* **Treg** may be key
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principle factors in dev of autoimmunity
inherit susceptibility genes
environ triggers
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genes that may contrib to genetically complex autoimm diseases (5)
1. PTPN22 --\> RA
2. NOD2 --\> crohns
3. CD25 (IL-2Ra) --\> MS, DM1
4. C2, C4 --\> SLE
5. Fc(gamma)RIIb --\> SLE
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single-gene defects that cause autoimmunity (mendelian) (3)
1. AIRE --\> APS1 = defic in presentation of self-ag to T cells
2. FOXP3 --\> IPEX: defic in Treg
3. FAS --\> ALPS: unable to apop self-reactive T and B cells in periphery
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mech by which microbes may promote autoimmunity
1. self-tolerance
2. APCs that have both a harmful microbe ag and self-ag
* when presented to self-reactive T cell, the co-stim released from the microbe ag will provide the B7 signal on self-T --\> autoimmunity
3. molecular mimicry:
* cross-reactive T cell due to similar looking microbe and self ag
* ex: RF: pharyngitis (strep throat) and mitral heart valves
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type I hypersens
genetic predispose to dev strong Th2 response to environ triggers --\> IL-4 --\> B class swtich to IgE --\> binds to Fc(epsilon)RI on mast cells --\> sensitize
* disreg of **T-bet**: Ts that drives Th1
* overexpr of **GATA-3**: Ts that drives Th2
mast cells important due to location: CLOSE to surfs that 1st encounter ag --\> FAST AND POWERFUL response to IgE
* immed release of lots of histamine
* coated with a range of IgE mol of different ag-specificities -\> multiple ag from same allergen can stim strong response
* prod inflam mediators: IL-3, IL-4, TNF-alpha
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most imp mediated prod by mast cells
vasoactive amines (histamine)
* H1 on endothelial cells:
* incr permeability --\> inflam-med recruit and edema
* contraction of smooth M cells --\> diff breathing
* prod mucus in airway
proteases
prod of arachidonic acid: PG, LT
* LT: longer response than histamine and 100x more potent
* PGD2: bv dilation and neutrophil chemoattractant
* inactivated by asa/NSAIDS = (-) COX
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cytokines prod by mast cells
TNF: sticky endothelium and lymphocytes recruitment
IL-3: mast cell prolif
IL-4: Th2
IL5: eosp activation
\*\*\*late phase of allergy response
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biphasic allergy response
immediate: histamine
* minutes --\> vasodil, congestion, edema
* **wheal (swell) and flare (accumulation of RBC)**
* prostacyclin and NO contribute
late: cytokines: TNFalpha, IL-3/4/5
* 2-4 hours after immed with MAX at 12-24 hours
* recruitment of lymphocytes --\> tissue dmg
* **eosp = KEY!**
* ****release MBP and esop-cationic-protein --\> toxic to helminths, bac, AND normal tissue
* Th2 = exaerbate rxn
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location effects of type I sens
allergen injected IV --\> systemic mast cell activation --\> sys histamine release --\> sys vasodilation --\> shock & sys anaphylaxsis
wheal and flare = local
rhinitis (hay fever) = upper airway
astham = lower airway
ingestion --\> diarrhea, vomit
* rapid absorption --\> systemic --\> uticaria, anaphylaxis
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type II sens
Key word: **Ab binding to TISSUE-BOUND ag**
* C'
* C3a/C5a --\> neutrophils --\> inflammation
* C3b/C5b --\> opson & phago by macp
physio type II sens:
* graves: autoab bind TSH
* myasthenia gravis: autoab binds ACh receptors @ post-synaptic NMJ --\> (-) activation --\> M atrophy, droppy eyelids
* goodpasture's: autoab bind type IV collagen (BM) in pulm and glom --\> (+) classic C' --\> C5a recruits neutp --\> releases proteases and ROS --\> destroy BM --\> cough up blood or blood in urine
medicine type II sens:
* pcn, quinidine, methyldopa
* haptens that bind surf proteins on RBCs/platelets and create new antigenic epitopes --\> IgM, IgG SPECIFIC for conjugate of drug-tissue protein
* result: hemolytic anemia, thrombocytopenia due to C'-mediated lysis or phago in spleen
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type III hypersens
Key word: **ab binding to SOLUBLE ag** (immune complex!!)
3 phases:
1. formation of immune complexes: ab in blood react with ag still present in circ
2. **DEPOSIT** (needs to deposit to cause harm since we prod complexes all the time which are cleared away efficiently)
* _patho detm by site of DEPOSIT_
3. acute inflamm rxn:
* C'
* (+) neutp thru Pc and C3b receptors
\*\*\*high in kidneys since they filter
physio type III rxns:
* SLE: autoab v dsDNA
* chr hep B (tx with antivirals will solve type III rxn)
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arthus rxn
experimental: can induce a type III hyersens rxn in pts who make IgG aga a soluable protein via subQ injection of ag
* positive = HARD swelling, platelet accumulation may cause occulsion and possible bv rupture --\> erythema
* C5a (+) mast cells --\> histamine LOCAL
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both type II ad III hypersens mech depend on...
classic C' pathway
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type IV hypersens rxn
Key word: **T cell mediated!! (CD4 or CD8)**
* CD4: inflamm cytokines and lymphocyte recruit
* Th1 --\> IFN-gamma --\> (+) macp
* Th17 --\> IL-17 --\> recruit neutp
* macp & T-cells --\> TNF-alpha and chemokines --\> lymophocyte recruitment and (+)
* CD8: kill via MHC I assoc ag
**DTH: DELAYED-TYPE HYPERSENSITIVITY**
* directly activated by Th1 cytokines
* major tiss injury due to macp and neutp
* (+) macp --\> IL-12 --\> (+) Th1 --\> IFNgamma --\> (+) macp .... CYCLE
* CHRONIC: **granuloma****:** epitheliod cells "wall off"
* typ dev 24-48 hours AFTER ag challenge
* **TB**
* depends on MEMORY Th1 cells
* diffen from type I b/c type I is immediate
* **ACD**: allergic contact dematitis to specific environ ag
* poison ivy/oak/sumac = HAPTENS
* after init contact (itching), 5-7 days later, the activated T founds recirc back to skin to quickly react if encountered again (clinically sig symptoms)
* **viral hepatitis**
* CD8 type IV response: MHC I --\> kills virus AND liver
* loss of DTH to univeraslly encountered ag --\> indicated of deficient T cell fx
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T cell med diseases
