B Cell Development

Question 1

B cell development

Answer 1

Stem Cell to
Early Pro- Heavy chain first D-J rearrangement
Late Pro- V-DJ rearrangement
Large Pre- VDJ rearranged
The H- chain has been rearranged and a surrogate chain is used to check if it is functional.
Small Pre- Light chain V-J rearrangement
Immature B cell- VJ rearranged, IgM expressed on cell surface
undergoes negative selection
Mature B cell- IgM and IgD are expressed

Rearrangements can occur from either inherited chromosome, but only one chromosome is used at a time

There are 2 light chains, kappa and lambda to choose from
The two kappa genes are used first, then the two lambda genes

This is called allelic exclusion and ensures that one B cell produces antibody of one specificity!!

Question 2

Removing B cells that recognise self

Answer 2

If self antigen is multivalent and is recognized, either B cell undergoes apoptosis or receptor editing

Soluble self antigens may be bound but not as strongly
If binding is in periphery, B cells switched off and dies of neglect- Anergy

If there is no self reaction , cell migrates to periphery takes part in immune response; this is another degree of selection called negative selection

Secondary selection- If B cell receives positive survival signals it will reside at Lymph Node (LN)

Question 3

B Cell Differentiation Pathways

Answer 3

B cells can become plasma cells and plasma cells secrete antibody

B cells can become memory B cells and memory B cells do not secrete antibody unless antigen is re-encountered

Question 4

Resting B cell to plasma cells

Answer 4

Slide 29

Question 5

Types of antibody response

Answer 5

1. T Independent antibody responses
   Extrafollicular responses where B cells differentiate to become IgM and IgG plasma cells producing antibody of low affinity.
   Short lived
   non specific
2. T Dependent antibody response
   Enter the germinal centre response that gives rise plasma cells producing high affinity, class-switched (e.g. IgG, IgA, IgE) antibody and also to memory B cells.
   Also can lead to the activation of different effector T cells
   Memory
   Long-lived
   Specific

Question 6

T-independent responses to capsular polysaccharide vaccines

Answer 6

Plasma cells producing antibody of low affinity.
Short lived
non specific
These limitations can be overcome by conjugating the TI-2 antigen to a protein

Question 7

T-dependent antibody responses require 2 signals

Answer 7

Physical interaction between specialized T cells and B cells
Soluble messengers (cytokines) to reinforce these interactions
cognate interaction

Question 8

CD4 T cells that are imp for T-dependent antibody responses

Answer 8

CD4 T follicular helper (Tfh) cells
Tfh recognise antigen (peptides) presented through MHC Class II
To positively select B cells they recognize peptide presented through MHCII by B cells
This positive selection signal to B cells is therefore through cognate interaction
B cells have a receptor called CD40 and the Tfh cells have a the Ligand CD40L
Cytokines released IL4 and IL21

Question 9

The germinal centre response

Answer 9

GC are necessary for long-lived antibody production and nearly all B cell memory
The antibody that is produced is of high affinity and class switched to IgG or IgA
To achieve this requires B cells to undergo further recombination of their Ig V genes
This has to be carefully regulated to prevent recognition of self and auto-immunity and to ensure cells leave cell-cycle
In the follicular cell
The dark zone somatic hypermutation happens
The light zone affinity maturation and class switching.

Question 10

GC are complex environments and a number of cell types are involved

Answer 10

Centroblasts (Cb) – are proliferating GC B cells that undergo somatic hypermutation – dark zone

Centrocytes (Cc) – are GC B cells that have undergone affinity maturation and are out of cell cycle – light zone

Follicular Dendritic Cells (FDC) – These are different to iDC. They have intact antigen in its native conformation bound to their surface and Cc compete to bind this antigen – light zone

Follicular T helper cells – These are GC T cells that give survival signals to Cc after they come out of the dark zone – light zone

Question 11

Affinity maturation

Answer 11

1. GC B cells mutate IgV genes
2. GC B cells compete for antigen on FDC
3. “Winners”get survival signals from GC T cells
4. GC B cells differentiate into plasma cells and memB cells