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Infection and Immunity > Antibody genetics 2 > Flashcards

Antibody genetics 2 Flashcards

1
Q

What happens upon first infection?

A

Get naive B cell response (initially)
Occurs 10-12 days after exposure
Causes large amounts IgM produced + small amount IgG

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2
Q

What happens after first response?

A

Ab levels will drop + plasma cells die off

Get retention memory B cells

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3
Q

Which cell group is responsible for secondary exposure to a particular Ag?

A

Memory B cells

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4
Q

What is different about the secondary response to infection compared to the primary response?

A

Amount of Ab produce much higher 2 response
Occurs earlier - w/in 5-6 days post infection
Type of Ab dominating = IgG

Once infection over, have higher number of memory B cells remaining - .˙. next encounter will have even more cells to respond

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5
Q

Is Ag required in B cell development and why?

A

Not required for B cell development

As development occurs in bone marrow where Ag absent

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6
Q

What occurs in the bone marrow?

A

B cells rearrange genes + express surface IgM (BCR)

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7
Q

What happens once B cells enter the circulation?

A

May encounter Ag in 2 lymphoid organs
Lymphatic system helps bring Ag + Ag responding cells together

If B cell doesn’t encounter Ag, will die in a few weeks

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8
Q

What are T-independent Ag?

A

Ag don’t require T cell help to produce Ab response

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9
Q

What is a property of TI Ag?

A

Particularly resistant to degradation

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10
Q

What are the 2 groups of TI Ag?

A

TI - 1
Molecules in high concentrations cause mitogenic, polyclonal activation B cells, irrespective of BCR

Mainly bacterial cell wall components eg. LPS

TI - 2
Large polysaccharides w/ repeating Agenic determinants eg. dextran, polymeric bacteria flagellin
Thought to cross link B cells causing clustering
Req cytokine help is given by the environment

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11
Q

What do these TI Ag generate?

A

Generate IgM and don’t induce memory

Thought to activate CD5 + B cells (B-1)

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12
Q

What are the majority of B cells classified as?

A

T cell dependent

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13
Q

What are the differences in how B cells and T cells recognise Ag?

A

Recognise different parts of Ag
T cell - need peptide presented on APC (processed part protein)
APC take up protein, break into peptides + present on surface as APC - MHC 1, MHC 2

B cell - recognise conformational epitope
ie. protein or part of protein

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14
Q

What is role of T cell in B cell response?

A

Via T helper subset

CD4+ Th cells produce cytokines can allow B cells to develop into appropriate functional programme

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15
Q

Describe cell co-operation in Ab response

A
  1. Ag comes into system and can:
    directly activate B cells
    taken up by APC -> then prime T cells, only cells (DC) thought to prime naive T cells
  2. Primed T cells + B cells find each other in lymph nodes + T cells co-operation occurs
    B cells provide signals to T cell vice versa
  3. B cell induced to divide + differentiate
    majority differentiated cells become plasma cells
    minority become memory B cells -> resp. for any subsequent responses
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16
Q

What type of interaction occurs between the T helper cells and Ag. specific B cells?

A

2 way interaction - T cells get signals from B cells + vv

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17
Q

Describe the 2 way interaction between Th cells and B cells

A

Occurs because:
i. surface IgM binds Ag + internalises it
ii. Ag broken down + peptides presented MHC II to T cells
iii. TCR + MHC (on B cell) join together + polarise on cell surface
iv. Co-stimulation molecules also bind
v. Induces cytokines be produced by T cell
eg. IL-4,5,6,10,13
Determines type of B cell develops
vi. B cells then proliferate + differentiate into memory B cells or Ab forming cells (AFC)

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18
Q

What is the function of Tfh cells?

A

T follicular helper cells
Localise to germinal centre
+ produce IL-21
Critical for GC formation - where somatic hypermutation, class switching, affinity maturation occurs

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19
Q

What is the Ag receptor signalling event?

A

Ag taken up by BCR, broken down
presented on cell surface via MHC - II
Which can present to TCR on corresponding T cell

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20
Q

What are the co-signals?

A
  1. interaction between CD40 L + CD40 (crucial)
  2. CD80/CD86 w/ CD28+CTLA4
    Increase levels CTLA4, displacement CD28 from CD80/CD86 causes T cell switch off (like -ve feedback loop)
21
Q

List some adhesion molecules

A

LFA-1 (T cell) w/ ICAM -1, ICAM-3 (B cell)
CD2 (T cell) w/ LFA 3 (B cell)
Hold complex together whilst interaction are occurring

22
Q

What is the main cytokine response for B cells?

A

Th2 cytokines

23
Q

List the Th2 cytokines and their effects

A

IL-4 - induces actvn + differentiation B cells
IL-5 - “ + additional effects on eosinophils
IL -5 - induces B cells become AFC (also prod by other cell types)
IL-10 - growth + differentiation B cells, blocks Th1
IL-13 - directs response to IgE

Combo cytokines w/in env where B cell being activated which results in functional outcome B cell differentiation

24
Q

What are the 2 outcomes of B cell actvn?

A
  1. prod Ab forming cells -> secrete Ab to clear Ag
    mostly die w/in 2 hrs
  2. prod memory B cells -> long lived + resp for long term Ab prod
    Circulate after infection + resp any subsequent exposure
25
Q

Where does B cell actvn?

A

Occurs in GC of 2 lymphoid tissue, spleen, lymph nodes, PALS - periarteriolar lymphatic sheath

26
Q

Describe the seq of events of B cell actvn

A
  1. Ag taken up by DC -> DC can present to T cells but need to be activated
    eg. pattern recognition ligation TCR on surface
  2. DCs activate Th cell in lymph node
    DC - only active naive T cell
  3. B cells in lymphoid tissue activated by soluble Ig
  4. B cells take up Ag, process + present to T cells
    get some Ig prod = extra follicular actvn - before lymphoid follicles formed
    as low levels somatic mutation - rudimentary response
  5. Some T cells develop Tfh cells -> T cells move to follicles - give help to B cells in follicles
  6. B cells move to follicles
7. T+B cells co-operate and form GC - where get extensive hypermutation, 
affinity maturation - to select for useful hyper-mutated cells for Ig class switching 
Here have interaction between follicular DC, Tfh, B cell, generates long lived response - plasma cells, memory B cells, proliferation, isotype switching + somatic mutn
27
Q

Describe GC

A 
W/in secondary lymphoid tissue 
Lymph node zones - 
i. mantle
ii. follicle 
iii. light zone 
iv. dark zone
Light + dark zone - what makes up GC
28
Q

What happens in the germinal centre?

A

large amount of proliferation w/in GC
proliferating cells undergoing somatic hypermutation + then go through FDC - holding Ag + allowing selection B cells that bind Ag at better affinity

Ig class switching occurs - order unknown

Heavy chain isotype can switch from u->gamma, alpha, epsilon

29
Q

When does class switching occur?

A

Occurs in secondary response in germinal centre

Adds functional plasticity to response generated against the Ag

30
Q

What determines the functionality of an Ab?

A

Ig class which is determined by cytokines in the env

31
Q

What is cytokine control?

A

Cytokines produced direct way in which class switching goes

eg. Th1 cells activated by viruses + bact produce IFN-g
Causes class switching to IgG (main complement fixing isotype) - most appropriate for viral response
32
Q

What cytokines does a helminth infection induce production of + what are its effects?

A

Induce IL-4 from Th2
Directs B cell prod IgE which target eosinophils to helminths
imp in allergic response (IgE)
causes mast cell degranulation + immediate hypersenisitivity

33
Q

What type of cytokines are produced at the mucosal surface?

A

TGF-B
directs Ab response to IgA (secretory)
APRIL - A proliferation induced ligand
BAFF - B cell activating fx - also causes B cells to prod IgA
Dimeric form IgA transported through epithelium into lumen of gut

34
Q

What does the ligation of CD40 to CD40L cause?

A 
Induces expression of actvn induced deaminase (AID)
Incolved in class switching + somatic hypermutation .˙. crucial for development Ab response

If don’t have then don’t get maturation B cell response - most Ig = IgM/G

35
Q

What is required for class switching?

A

Switch recombination

36
Q

Describe what occurs during class switching

A

Rearranged VDJ exon (normally bound Cu - IgM), which encodes heavy chain V domain, must recombine with diff C region

Intervening DNA is deleted

Are switch regions in introns between J + each Ch region u

Upstream switch (s) have initiation seq (I)

Transcription will occur along the strand but then strand breaks occur at switch region

Su strand breaks + recombines w/ selected downstream switch region, determined by cytokines

Then get translation protein composed of original VDJ + new C region

Eg. iL-4 mediated IgE production
take IgM molecule, splice out info that makes it IgM
.˙. now IgE producing B cell

37
Q

What is AID?

A

Activation induced deaminase

38
Q

How is AID activated?

A

By CD40 signal (actvn by CD40L on T cell)

39
Q

How does AID work?

A

Converts C->U in single strand DNA

Switch region V rich in C+G bases

C’s now Us
AID removes Us forming abasic DNA - unstable

Endonucleases cleave DNA @ site, forming nicks on both strands -> double stranded breaks

Then get somatic hypermutation + affinity maturation

Generates point mutation in Ig variable regions (V genes) using AID
Specific for a particular Ag

Selects for increased affinity Ab (any Ab with lower affinity, due to point mutation, gets deleted)

Occurs in dark zone GC (req. T cell help to induce AID)

40
Q

Why is it hypermutation?

A

Point mutations occur at 1000x spontaneous rate

accumulate in progeny, every time cell divides get more mutation

41
Q

How does AID cause hypermutation and cause diversity of affinity?

A

Not well understood - but it’s important
Converts C–>U
upon DNA replication can convert C–>T (have C->T mutation)
Get strand breaks - repair of which can also cause errors
Randomised process to generate lots of point mutation

42
Q

What is the significance of point mutations?

A

Generate varying binding affinities
Most mutations reduce binding/ affinity for Ag
Some will increase affinity for Ag (high affinity Ab) - needs to be selected

43
Q

What occurs as time goes on and after successive infections?

A

Can see increase in number of point mutations in B cells
get increased affinity + lower dissociation constant
= higher affinity interaction by Ab for Ag

44
Q

What is the first step of B cell selection?

A

FDC express large no Ag + complement receptors

Present Ag bound to these structures + display to B cell
Allows B cell to interact w/ Ag on cell surface

45
Q

What is the role of TFH in B cell selection?

A

TFH produce IL-21 drive B cells into apoptosis UNLESS are rescued by Ag recognition (via stimulation BCR)
BCl2 induction, further CD40 interaction Tfh

46
Q

What enables selection of high affinity Ab once maturation is underway?

A

The concentration of Ag decreases .˙. only selecting for those B cells w/ highest affinity Ab on their surface

47
Q

What is the product of B cell selection?

A

Get plasma cells (bone marrow where survive for long time prod Ab)
+ Memory B cells express high levels Bcl2

48
Q

Describe memory B cells

A

Contribute to the long life span B cells + stop cells undergoing apoptosis
Some stay in lymph nodes, some recirculate in blood system

49
Q

How are 10^8 B cells generated from 35000 genes?

A

Ab made up of 2 chains - heavy + light are randomly associated

Multiple VDJ segments - chosen from many libraries

Combo VDJ = junctional diversity (massive variation)

secondary response get somatic hypermutation - causes point mutation in Ab binding region
allows maturing of response

C region switching - class Ab develops w/ response

Infection and Immunity (8 decks)

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