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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
Where does B cell actvn?
Occurs in GC of 2 lymphoid tissue, spleen, lymph nodes, PALS - periarteriolar lymphatic sheath
26
Describe the seq of events of B cell actvn
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
Describe GC
``` 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
What happens in the germinal centre?
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
When does class switching occur?
Occurs in secondary response in germinal centre | Adds functional plasticity to response generated against the Ag
30
What determines the functionality of an Ab?
Ig class which is determined by cytokines in the env
31
What is cytokine control?
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
What cytokines does a helminth infection induce production of + what are its effects?
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
What type of cytokines are produced at the mucosal surface?
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
What does the ligation of CD40 to CD40L cause?
``` 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
What is required for class switching?
Switch recombination
36
Describe what occurs during class switching
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
What is AID?
Activation induced deaminase
38
How is AID activated?
By CD40 signal (actvn by CD40L on T cell)
39
How does AID work?
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
Why is it hypermutation?
Point mutations occur at 1000x spontaneous rate | accumulate in progeny, every time cell divides get more mutation
41
How does AID cause hypermutation and cause diversity of affinity?
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
What is the significance of point mutations?
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
What occurs as time goes on and after successive infections?
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
What is the first step of B cell selection?
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
What is the role of TFH in B cell selection?
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
What enables selection of high affinity Ab once maturation is underway?
The concentration of Ag decreases .˙. only selecting for those B cells w/ highest affinity Ab on their surface
47
What is the product of B cell selection?
Get plasma cells (bone marrow where survive for long time prod Ab) + Memory B cells express high levels Bcl2
48
Describe memory B cells
Contribute to the long life span B cells + stop cells undergoing apoptosis Some stay in lymph nodes, some recirculate in blood system
49
How are 10^8 B cells generated from 35000 genes?
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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