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PM3 - Infection and immunity > B cells - adaptive immunity > Flashcards

B cells - adaptive immunity Flashcards

1
Q

BCR
genetic composition

A

LC (kappa or lambda)
HC (IgM, IgE, IgG, IgA, IgD)

each chain: VR (V(D)J) and CR

soluble (first poly A splice site) or membrane bound (second poly A splice site

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2
Q

BCR
activation model

A

cross-linkage model questionabel

DISSOCIATION MODEL: BCR clusters in unstimulated state, ligand breaks clusters appart -> signalling

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3
Q

affinity

A

binding strengh of one receptor-ligand interaction

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4
Q

avidity

A

strength of protein-complex - protein interaction
even low affinity Ab can have high avidity when they are polyvalent (e.g. IgM)

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5
Q

Valency

A

numbr of binding elements -> Ig usually bivalent (two paratopes), IgM molecule can be polyvalent via complex formation

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6
Q

antigen-indipendent B cell development

A

multipotent HSC in fetal liver or bone marrow
production of CPL
B cell committment -> pro B cells, driving TF is Pax5 (inhibits Notch 1)
Early pro-B cell: initiation of D-J recomination in HC
Late pro-B cell: V-DJ recombination in HC

PRE-B CHECKPOINT: VDJ HC forms pre-B receptor by binding lambda5 -> VpreB inducs receptor dimerization -> signalling

Large pre-B cell: passes/passed checkpoint, signalling induces prolifration, shut down of preBCR expression and allelic excluison
Small pre-B cell: IgL recombination (V-J), first kappa than lymbda genes if unsuccessful

Immature B cell: VJ LC rearranged, IgM expression -> signal induction then receptor editing (autoreactive)

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7
Q

receptor editing

A

on LC of BCR
signalling after LC recombination -> receptor editing by combining new V and J segments
prevents autoreactivity

if still autoreactive when lambda and kappa segments are used -> deletion (ev. HC contributes significantly to autoreactivity)

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8
Q

Early pro-B cell

A

initiation of somatic recombination
D-J recombination
one chromosome!

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9
Q

Late pro-B cell

A

DJ recombined
V-DJ somatic recombination

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10
Q

Pre B Checkpoint

A

between/in late pro and large preB cell
VDJ recombined
binds lambda5
lambda binds VpreB and causes dimerization
induces signalling (positive selection)

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11
Q

Large preB cell

A

positive selection -> signalling
induces shutdown of preBCR expression
induces alelic inclusion
initiates IgL rearrangement

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12
Q

small pre B cell

A

V-J recombination of LC
first kappa gene rearrangement (later if necessary lambda)

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13
Q

immature B cell

A

VJ rearranged
if autoreactive then receptor editing
if autoreactivity persists (sgements of lambda and kappa used up, HC contributes to autoreactivity) than deletion

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14
Q

mechanism of somatic recombination in BCR

A

LC encoded in two loci (k and l), HC in one
segments contain a RSS (recombination signal sequence) -> 23 or 12 RSS

RAG1/2:
- alligns with RSS, captures the other (opposing!)
- Signal joint: ku70:80 binding, DNA ligase IV and XRCC4 form PRECISE JOINT
- Coding joint: ku70:80 binding, DNA-PK and Artemis open covalently closed hairpins, TdT randomly adds or deletes nts, pairing and ligation via DNA ligase IV and XRCC4 -> IMPRECISE JOINT

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15
Q

RAG in BCR recombination

A

RAG1/2:
- alligns with RSS, captures the other (opposing!)
- Signal joint: ku70:80 binding, DNA ligase V and XRCC4 form PRECISE JOINT
- Coding joint: ku70:80 binding, DNA-PK and Artemis open covalently closed hairpins, TdT randomly adds or deletes nts, pairing and ligation via DNA ligase IV and XRCC4 -> IMPRECISE JOINT

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16
Q

RSS

A

recombination signal sequence
23 and 12 RSS
only sequences with heterologoue RSS are paired

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17
Q

Signal joint BCR

A
  • ku70:80 binding
  • DNA ligase IV and XRCC4
  • PRECISE JOINT
18
Q

Coding joint BCR

A
  • ku70:80 binding
  • DNA-PK and Artemis open covalently closed hairpins
  • TdT randomly adds or deletes nts
  • pairing and ligation via DNA ligase IV and XRCC
    -> IMPRECISE JOINT
19
Q

Imprecise joint

A

coding joint

  • ku70:80 binding
  • DNA-PK and Artemis open covalently closed hairpins
  • TdT randomly adds or deletes nts
  • pairing and ligation via DNA ligase IV and XRCC
    -> IMPRECISE JOINT
20
Q

precise joint

A

signal joint

  • ku70:80 binding
  • DNA ligase IV and XRCC4
  • PRECISE JOINT
21
Q

RAG regulation

A

TRANSCRIPTIONAL: no RAG activity in mature cells

CHROMATIN & LOCUS ACCESSIBILITY: open chromatin structure and epigenetic modifications necessary for RAG binding -> RAG2 binds H3Kme3 -> required

3D LOCI ARCHITECTURE: segmnt genes loop around recombination center, formation of COHESIN LOOPS (CTCF mediated segment chosing)

22
Q

BCR central tolerance mechanism

A

immature B cells causing signalling -> receptor editing

23
Q

immediate effect of B cell activation

A

B cell activation by Ag binding with co-stimulatory signals
- upregulation of survival proteins and proliferation
- Ag and B7 expression elevated -> interaction with CD4 (CD40!)
- cytokine receptor expression changes
- upregulation of CCR7 -> migration to T cell area

24
Q

antigen-dependent B cell development

A

Ag binding in LN
migration to T cell zone (CCR7 upregulation)
interaction with CD4 T cells (CD40!)
T and B cell migration to follicle
d4 early GC formation in follicle

GC for diversification (SHM), selection and class switch initiation
not all B cells enter GC -> some proliferate into short-lived plasma cells for faster response

memory B cell formation

25
Q

GC cells

A

T-FH cells: produce BCl6, essential for GC formation, mediate expansion via competition of B cells for T cell help
FDCs: long term Ag storage, concentration and presentation, involved in selection process (affinity to FDC)

26
Q

diversification of B cells
location and mechanism

A

somatic hypermutation
“faulty” repair mechanisms
in dark zone of GC
AID expression induced by CD40:CD40L

AID = deaminase, ususally repair via base-excision (UNG) or mismatch repair (MSH2/6)
in SHM translation over apyrimidinic site or repair with mistake-prone low-fidelity DNA polymerase

27
Q

Selection of higher affinity B cells
models

A

in light zone of GC
2 models: either apoptosis when affinity is low or proliferation when affinity is high
affinity measured towards Ag presented by FDC
cells enter aapoptosis, reenter the dark zone for SHM or proliferate
proliferation/expansion dependend on T cell help T-FH

28
Q

class switch

A

cytokine-mediated activation of switch region promotor
induces transcription
AID active
UNG removes generated U and causes apyrimidinic residue
APE1 removes ribose and induces ssB
in repair mechanisms dsB is initated
DSBR machinery joins the switch regions and excises intervening sequences (Cm)

29
Q

AID

A

deaminase
induces SHM and CSR

30
Q

IgA

A

protects epithelial barriers
neutralizes pathogens and their toxins

31
Q

IgG

A

neonatal immunity
opsonization
ADCC (bind FcgRIII on NK cells)
feedback inhibition of B cells
activates complement (C1q binds)

32
Q

IgM

A

pentamer in soluble form
naive B cell receptor
complement activation (binds C1q)

33
Q

Magnitude of neutralizing Ab response

A

massive in cytopathic viruses -> fast and effective, prevents excessive host damage, CTL response later and reduced

minimal in non-cytopathic viruses -> strong CTL response responsible for clearance, Ig mor opsonizing and less neutralizing

34
Q

IgD

A

naive B cell receptor

35
Q

IgE

A

defence against helmiths
immediate hypersensitvity
bind FceRI on mast cells -> sensitizing

36
Q

B1 cells
compared to B2, types and activation

A

restricted BCR reservoir (no SHM) compared to B2 cells (follicular B cells)
only IgM (no CSR)

MARGIAL ZONE B cells: T indinpendent short lived plasma cells
INNATE-LIKE B1 cells: T independent, short lived plasma cells

ACTIVATION: BCR signalling and TLR signalling

37
Q

immunogenicity of microbes

A

dependend on several factors
acessibility of important sites for e.g. entry
organisation -> e.g. abundancy of epitopes
B cell repertoire -> e.g. corresponding paratope not often encoded

38
Q

Ab function

A

neutralizing (surface coating)
complement activation
opsonization (ADCC)

39
Q

Immunecomplexes
effect

A

formation of Ag:Ab complex, can have several effects

ANTIVIRAL: complex mediates macrophage recognition (FcgR), phagocytosis and degradation, cytokine release promoting clearing immune response

ADE: antibody-dependent enhancement, complex mediates phagocytosis but viral entry strategy, cytokine release more immunopathological

COMPLEMENT ACTIVATION: Fc of IgG binds C1q -> triggers cascade, phagocytosis, cell lysis and immune recruitment

PHAGOCYTOSIS: macrophages or DC
ADCC
T CELL ACTIVATION: phagocytosis, processing -> Ag presentation on APCs

40
Q

viral persistance strategies

A

HIGH TITER REPLICATION: requires non-cytopathic virus, or target cell with high replenishing potential

LATENCY: non-replicative mode until re-activation

LOW TITER REPLICATION: continous low level replication and immune response

41
Q

High titer replication

A

ineffective immune clearance due to tolerance, immune complex formation, viral variations etc
virus must be non-cytopathic or target cell with high replenishing potential

TOLERANCE: absence of viral-specific immunity
- deletion of naive T cell clones
- exhaustion of CTLs (low pathology despite high viral load)
- absence of specific Ab response

PM3 - Infection and immunity (9 decks)

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