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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
GC cells
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
diversification of B cells location and mechanism
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
Selection of higher affinity B cells models
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
class switch
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
AID
deaminase induces SHM and CSR
30
IgA
protects epithelial barriers neutralizes pathogens and their toxins
31
IgG
neonatal immunity opsonization ADCC (bind FcgRIII on NK cells) feedback inhibition of B cells activates complement (C1q binds)
32
IgM
pentamer in soluble form naive B cell receptor complement activation (binds C1q)
33
Magnitude of neutralizing Ab response
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
IgD
naive B cell receptor
35
IgE
defence against helmiths immediate hypersensitvity bind FceRI on mast cells -> sensitizing
36
B1 cells compared to B2, types and activation
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
immunogenicity of microbes
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
Ab function
neutralizing (surface coating) complement activation opsonization (ADCC)
39
Immunecomplexes effect
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
viral persistance strategies
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
High titer replication
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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