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Immuno Year 1 > Exam 2 Spring > Flashcards

Exam 2 Spring Flashcards

1
Q

humoral response revelent in…

A
  1. extracell bac/fungi/parasites
  2. helminth
    1. virus/intracell bac DURING spread/ADCC
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2
Q

phases of b cell recognition (big pic)

A
  1. b cell is “born” (secr only IgM w/ some IgG2- naive and has not met ag)
  2. presented w/ polysacc ag
  3. two choices: either TI or TD
    • TI: IgM
    • TD: class switch to “better” ag - protein Ag (most)
  4. if TD: requires CD4+ (both activated each other)
  5. prolif
    • plasma cell –> IgM
    • isotype switch –> IgG, IgE, IgA
    • HIGH-AFFINITY –> affinity maturation (IgG), memory B
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3
Q

TI ag induced by

A

bac polysacc

lipids

repeating surf mol on viruses

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4
Q

TD ags….

A

induced by ANY ag containing protein (due to CD4 help) IN GERMINAL CENTER

majority do this

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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
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6
Q

what is the main def aga encap bac

A

humoral immunity b/c capsule is USUALLY polysacc

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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
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8
Q

what are the primary response cells to protein ags?

A

follicular B cells

Th cells

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9
Q

TD response activation

A
  1. 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
  2. activated Th cell (by APC: DC) will recog B cell presented Ag (which now acts as a APC) and (+) B cell to TD response
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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)

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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)

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12
Q

ag delivered to B cells in follicles largely thru

A

afference lymph -> subcap space –> conduits/macrophage presentation –> B follicles

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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
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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)

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15
Q

biochem pathway of B cell activation

A
  1. polysacc or large mol = IgM cross linking (remember naive b cells have IgM surf ag)
  2. (+) ITAM on Ig-alpha Ig-beta
  3. (P) BCR RTK complex: fyn, lyn, blk
  4. recruits syk TK
  5. (+) TK on adaptor proteins
  6. signal cascade
  7. (+) Ts factor
  8. b cell activation
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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
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17
Q

examples of B cells co-stim

A
  1. alt C’: CR2 recog of C3d on microbe
  2. microbe recog on TLR with Myd88 adaptor protein
  3. IFN-1: anti-viral
  4. CD4 co-activation
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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

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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
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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
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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
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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!
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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
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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!
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25
Q

class switching is dependent on…

A

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
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26
Q

IgA

A

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
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27
Q

x-linked hyper IgM

A

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
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28
Q

molecular basis of Ig class switch

A

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

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29
Q

what is affinity maturation and what is the result

A

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
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30
Q

types of plasma cells

A

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
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31
Q

prop of Ab

A
  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.
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32
Q

IgM pentomer most important in what pathway?

A

classic C’

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33
Q

B cell regulation

A

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
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34
Q

what Ig is most imp for neut of mucosal pathos?

A

IgA

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35
Q

what Ig is most importnat aga helminths

A

IgE

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36
Q

most neut ab:

A

IgG: blood

IgA: mucosal surf

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37
Q

how do most effective vacc avail today work?

A

stim production of neut Ab

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38
Q

mech of neut….

A
  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
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39
Q

how do Ab cause opsonization?

A

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
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40
Q

what is the major mech of def aga encap bac

where does it happen?

A

ab-med phago: IgG1/3 onto Fc(gamma)RI of macp and neutp

  • opson bac
  • phago

spleen

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41
Q

FC(gamma)RIIIA

A

CD16

(+) ADCC by NK cells

  • released protein granules –> kill opsonized targets

important for viral cell with surf glycoproteins

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42
Q

______ response to helminths dom by…

A

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

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43
Q

IgE

A

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
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44
Q

why is IgM good at activating the classic C’

A

pentomer = lots of Fc portions to grab onto ag

  • not opsonizer though!!

IgG needs couple of IgG super close to each other

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45
Q

classic C’ pathway is most closely related to what other C’ pathway? What is the difference?

A

lectin

difference in activation

  • classic: IgM, IgG3
  • lectin: mannose binding lectin - binds mannose on patho
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46
Q

what can be bad about neonatal immunity

A

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
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47
Q

IgA production and txp to lumen

A

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
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48
Q

how is IgA not digested and neut by self?

A

secretory cmpt of poly-Ig remains attached to IgA and protects from degradaton

  • some of receptor stays on epith cells
  • ***proteolytic cleavage
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49
Q

how does baby get IgA?

A

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!!
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50
Q

IgA deficiency

A

most common primary imm-defic

makes sense!! –> if missing –> no mucosal protection –>

  • INCR respir, GI, UG infections
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51
Q

why is Ig replacement not indicated in IgA deficiency?

A

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
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52
Q

neonatal immunity

A

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
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53
Q

BTK

A

b cell deficiency

neonatal immunity is reason why this does not get noticed until around 6mo old

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54
Q

is FcRN present in adults?

if so…why?

A

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

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55
Q

examples of mech of immune evasion

A
  1. antigenic variation
  2. inhib C’ activation
  3. resistance to phago
56
Q

features of extracellular bac

A

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
Q

innate immunity to extracel bac

A

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
Q

humoral immunity to extracellular bac

A

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
Q

cellular immunity to extracell bac

A

CD4:

  • Th1: (+) macp
  • Th17: (+) neut
60
Q

injurious effects of immune response to extracel bac

A

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
Q

LPS-induced septic shock

A
  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
Q

mechanisms of immune evasion by extracel bac

A
  1. inhib alt C’
  2. capsule evades phago (REQ phago)
  3. catalase+ bac removes ROS
  4. surf ag variation evades humoral imm
63
Q

what is the key feature of intracell bac?

A

able to survave and replicate within phagosome

ESCAPE from humoral imm –> REQ cellular immunity

64
Q

innate immunity to intracell bac

A
  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
Q

adaptive imm to intracell bac

A

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
Q

what differentiates CD4 into Th1 or Th2?

A

cytokines!

Th1: IFN-gamma, IL-1

Th2: IL-10, IL-4 –> (-) macp activation

67
Q

injurious effects of immune sys to intracell bac

A

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
Q

immune evasion by intracell bac

A

inhib formation of phagolysosome

69
Q

what is the most sig factor in fungi infections

A

immunocompromised:

  • can be intracell or extracell
70
Q

what are the main cmpts in imm aga fungal infections

A

neutp and macp

  • phago for intracell killing
  • neutp: ROS intermeds and lysosomal enz

pts with neutropenia EXTREMELY SUSCEPTIBLE to fungal infections

71
Q

what is the major mech of fungal infection immunity

A

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
Q

injurious effects of fungal infections to immune sys

A

granuloma

***very similar to intracell response

73
Q

mech of immune evasion by fungi

A

cryptococcus neoformans

  • (-) TNF, IL-12
  • (+) IL-10 –> drives Th2 response –> (-) macp activation –> no killing!
74
Q

innate immunity to viral infections

A

PRR of viral RNA/DNA –> IFN-1 –> inhib viral replic –> CD8 kill

(+) NK

75
Q

adaptive immunity to viral infections

A
  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
Q

how do viruses get into cells?

A

hemoglutinin –> interacts with sialic acid on host cells

77
Q

kinetics of anti-viral response

A

innate response helps CONTROL virus: IFN-1, NK

adaptive response: major CLEARANCE of virus via CD8

78
Q

injurious effects of immune response to viral infections

A
  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
Q

how do viruses evade imune sys?

A
  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
Q

immunity to parasites

A

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
Q

innate immunity to parasites

A

NOT VERY EFFECTIVE

  1. protozoa: phago by macp
  2. helminth: secr microbicidal substances (too large to be phago)
  3. (+) alt C’
82
Q

adaptive immunity to parasites

A

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
Q

injurious effects of parasites

A
  • parasite-ag complex deposit on tissues
  • eosinophil granuloma: Th2
    • ​schistosomas
    • DIFFERENT than intracell and fungal which do TH1 macp granulomas
84
Q

mechanisms of parasite evation

A
  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
Q

Overview of importance of antimicrobial defenses for infectious agents

A
86
Q

a successful primary imm response purpose:

A
  1. clear infection
  2. temp gives immed protectiong against reinfection
  3. imm mem
87
Q

how do you get immed protection aga re-infection?

A

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
Q

immeidate protection usu drops off after..

what happens if the person if infected after that time?

A

4 mo

now re-infection dep on secondary (mem) response = stronger and faster (and almost immediate)

89
Q

mem response med by…

A

expanded clones of long-lived mem B and T cells formed during primary response

90
Q

new ab prod during 2nd response from? why?

A

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
Q

2ndary response is dom by what ab?

A

high affinity IgG: due to mem cells!

v 1maryresponse = IgM

92
Q

how do memory T cells dev?

how long do they last?

A

2 options:

  • naive –> divergent –> effector T OR mem T
  • naive –> effector –> mem
93
Q

cytokine differences b/w naive v effector v memory T cells

A

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
Q

feat of mem T cells

A
  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
Q

types of mem T cells

A

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
Q

ult goals of preventative vacc

A

induction of mem T and B cells for rapid response to re-infection

97
Q

why is the current measels vacc ineffective in tropical countries?

A

heat sens

98
Q

passive immunization

A

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
Q

active immunization

A

stim of host to prod 1mary reponse so “re-exposure” induces 2ndary response

100
Q

how to assess immune response to vacc?

A

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
Q

adjuvants

A

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
Q

what is the double-edged sword of a highly diverse ag repertoire?

A

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
Q

tolerance induced when…

A

presented with self ag in central (negative selection) or periphery

104
Q

fates of T and B cells when they recog self…

A

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
Q

central tolerance of T cells

A

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
Q

APS1

A

autoimm polyendocrine syndrome 1

  • monogenic mutation in AIRE

major cmpts:

  • chronic mucocut candidiases
  • autoimmune addison’s disease (AAD): autoimm adrenalitis
  • autoimm hypoparathyroidism
107
Q

positive selection in thymus depends on….

A

LOW-AFFINITY MHC I/II recognition

108
Q

peripheral tolerance of T cells

A

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
Q

mech of peripheral T cell tolerance

A

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
Q

what would happen to an indiv with loss of fx of CTLA-4

A

autoimm

111
Q

why CTLA-4 needs to be manually blocked?

A

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
Q

Treg

A

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
Q

Identification of Tregs by
flow cytometry

A

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
Q

IPEX syndrome

A

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
Q

Treg mechanisms

A

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
Q

AICD

A

activated induced cell death

  • apop due to recog of self-ag

defect –> autoimm lymphoprolif syndome (signally defects downstream of Fas)

117
Q

importance of IL-2

A

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
Q

mech of central B cell tolerance

A

high self-ag recog:

  • RAG1/2 receptor editing –> non-sefl reactive B cell
  • apop

low self-ag recog:

  • anergy
119
Q

perip B cell tolerance

A

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
120
Q

what will regulate immune response and bring it down after infection is cleared?

A

CTLA-4/PD-1

121
Q

allergy/autoimmunity and infectious diseases

A

seems to be a tradeoff: decr in infectious disease –> incr in autoimm disease

  • Treg may be key
122
Q

principle factors in dev of autoimmunity

A

inherit susceptibility genes

environ triggers

123
Q

genes that may contrib to genetically complex autoimm diseases (5)

A
  1. PTPN22 –> RA
  2. NOD2 –> crohns
  3. CD25 (IL-2Ra) –> MS, DM1
  4. C2, C4 –> SLE
  5. Fc(gamma)RIIb –> SLE
124
Q

single-gene defects that cause autoimmunity (mendelian) (3)

A
  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
125
Q

mech by which microbes may promote autoimmunity

A
  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
126
Q

type I hypersens

A

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
127
Q

most imp mediated prod by mast cells

A

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
128
Q

cytokines prod by mast cells

A

TNF: sticky endothelium and lymphocytes recruitment

IL-3: mast cell prolif

IL-4: Th2

IL5: eosp activation

***late phase of allergy response

129
Q

biphasic allergy response

A

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
130
Q

location effects of type I sens

A

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
131
Q

type II sens

A

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
132
Q

type III hypersens

A

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)
133
Q

arthus rxn

A

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
134
Q

both type II ad III hypersens mech depend on…

A

classic C’ pathway

135
Q

type IV hypersens rxn

A

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
136
Q

T cell med diseases

A

Immuno Year 1 (4 decks)

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