B cells

B lymphocytes
Develop in the bone marrow
When fully developed, each B cell has a unique receptor for antigen BCR
The genes for the B cell receptor are randomly rearranged during the cells development this
can only occur once for any single B cell
o Generates unique receptors
o This process occurs millions of times a day and for each new B cell developed throughout
life
The BCR is a class of proteins known as immunoglobulins
Immunoglobulins are also released in secretory from the B cells that differentiate to form plasma
cells

BCR is a membrane immunoglobulin

The BCR has different domains C (constant), V (variable)
The variable domain is at the immunoglobulins extremity (the part that makes contact with the
antigen aka the antigen binding domain)
The variable domain is the source of uniqueness of B cells

Additional diversity is provided by junctional flexibility where the terminal deoxynucleotidyl

transferase add or remove nucleotides (up to 6) on the edges of the V, D and J segments
The precursor is now called an immature B cell.
It expresses membrane IgM at its surface

Negative selection of immature B cells in the bone marrow

Similar to T-cell education in the thymus
Immature B cells are exposed to self antigens
o B cells do not require antigen presentation to bind an antigen
o Unlike T cells, B cells undergo negative selection only
o Self-reacting clones are selected against
However they have an opportunity to have slight point modulation to decrease
their affinity and may be rescued as a result
o Non-self reacting B cells then express membrane IgD with identical antigenic specificity
(this is called receptor editing)
o Nature nave IgM+IgD+B cells leave the bone marrow, enter the blood and the secondary
lymphoid organs

B cell activation and proliferation

Occurs in the periphery in secondary lymphoid organs (lymph nodes, spleen) and requires antigen
exposure
Nave B cells have a short life span (a few weeks) this is not a big deal
Antigen driven activation and clonal selection (proliferation of a chosen B cell) of nave B cells leads
to the generation of plasma cells and memory B cells

Some B cells can be activated without the need for a T helper cell (thymus-independent)
B cells can become activated by binding to mostly complex antigens with mainly sugars
o E.g. LPS or capsular polysaccharides contains sugars that human cells do not have and it
presents the same motifs again and again
o B cell can bind many times and the same signals then add up to enable activation
o This type of activation is reasonably weak and no memory cells are formed.

o The predominant isotype produced by plasma cells is IgM, which is efficient but also has a
limited scope

Activation of B cell by thymus-dependent antigen

This applies to antigens that are proteinic in nature
o Proteins dont have many repeats they are different from different angles
o The help of a T helper cell is needed
The response is generally stronger
Memory cells are formed
Signal 1 BCR/antigen
o In the first signal, the BCR is specific for an antigen and binds to it but this is not enough for
activation
Costimulatory
o Remember the B cell is an APC
o The T helper cell then recognises the B cell expressing the antigen via an MHC2 molecule
with B7-CD28 interaction AND co-receptor CD40-CD40L (B-T conjugate)
o The T cell finalises the interaction
o This occurs in the paracortex of lymph nodes
The antigen is big, so you will have many B cells recognising different epitopes of the same antigen
On activation, the B cell expresses cytokine receptors
The T helper cell (the IL-2 needed for proliferation clonal expansion)
IL-2 binds to the B cell receptors to drive differentiation

B cells differentiate in the secondary lymphoid organs

The afferent lymphatic vessels drain the periphery numerous B cells exist with different
receptors. As soon as B cell binds an antigen, itll migrate downwards into the paracortex to get
the help of a T cell to form a B-T conjugate
The B-T conjugate then migrates to the edge of the paracortex where the B cell proliferates and
differentiates into IgM secreting plasma cells
A few days later, some B and T cells migrate further to the primary follicles in the cortex (dark zone
in the picture)
o These follicles develop and provide a suitable environment for T helper cells, follicular
dendritic cells and B cells to interact
It becomes a secondary follicle (darker outer band) with a germinal centre where the B cell
proliferates and differentiates
In the germinal centres affinity maturation and isotype switch occur

Affinity maturation
Location: Occurs in the germinal centres of secondary follicles in the cortex of the lymph node
Result: Activated B cells attempt to improve their affinity for the antigen they are specific for
o The affinity resides in the BCR, specifically in the variable region sticking out on both heavy
and light chains
o Mutation in the variable region of the BCR is how these B cells improve themselves
o Outcome: Can be either an increased or decreased affinity for the antigen
Process:
o Follicular dendritic cells provide the antigen bound at their surface via Fc receptor and
complement receptors
o B cells compete for interaction with the antigen
o B cells that fail to receive sufficient interaction will die by apoptosis
o Therefore, the B cell population exiting the germinal centres will display a greatly enhanced
affinity for the antigen
Method of improving
o Could change it with an enzyme, but this is not done as it risks changing the genes
encoding the variable portion
o Instead, the processes used are somatic hypermutation and antigen selection

Somatic hypermutation
Point mutations randomly occur in the variable part of the receptor
In 99% of cases, you destroy the good affinity already present

Antigenic selection
Need the antigen itself now
Ones that have a high affinity for antigen will survive, those with weak affinity die
Isotype switch
Isotype refers to the tail Fc portion of the BCR
To change the isotype, you have to change the Fc tail
This takes place at the DNA level and involves replacing the constant region with a different type
of constant region
This provides new biological function for the Ig without changing the affinity for the antigen
o This is because affinity has more to do with shape
Isotype switch is under the control of cytokines in the microenvironment
o Sources of cytokines: T helper cells in the germinal centres

Final differentiation of B cells

The soluble immunoglobulin

Produced and secreted by plasma cells
Essentially the same as the BCR except that it does not have a membrane bound tail
Function: Binds the surface of the antigen
The biological function will depend on what isotype it is

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Biological functions of soluble immunoglobulins
Opsonisation
Activation of the classical pathway of the complement system
o Reinforces the innate immune system

Antibody-dependent cell-mediated cytotoxicity

o Macrophages, basophils, neutrophils and natural killer cells can also do this

Cross-linking and immobilisation of pathogens to prevent evasion

o IgG binds twice
o IgM binds 10 times

Antibody-mediated inhibition of extracellular bacteria and bacterial products

Blocking attachment and colonisation
o Antibody binds to bacterial receptors on fimbrae, lipoteichoic acids and some capsules to
block attachment
o Also protect mucosal surfaces
Preventing proliferation
o Blocking transport mechanisms (e.g. preventing iron chelation)
o Damaging the membranes of gram negative bacteria
Damaged membranes means that the bacteria cannot proliferate
Enhancing phagocytosis especially of encapsulated organisms

o Note that Fcs come in many families like gamma and delta
o Each Ig requires the corresponding Fc receptor
Preventing shock, toxicity, tissue damage and invasion of tissues
o E.g. neutralising toxins by binding to and disabling them
o Inactivation spreading factors suck as enzymes and hyaluronidase

Classes of secreted Ig

IgG
o Makes up 80% of all serum immunoglobulins
o Possesses a low avidity (overall strength of binding an antigen) as it only has two binding
sites
o It has a high affinity though because it comes out after affinity maturation
o Subfamilies present:
I, 3 and 4
o IgG is a small molecule and it can, therefore, pass through placenta to give passive
immunity to the foetus (IgG 1/3/4)
o IgG is a good complement activator (crosslinking and neutralising pathogens)
o It is also a good opsonin

IgM
o Makes up 5-15% of total serum immunoglobulins
o IgM comes out before affinity maturation. It therefore has low affinity but high avidity (10
binding sites)
o Due to number of binding sites, IgM is good at crosslinking and neutralising pathogens
o IgM is the first to be produced during primary immune response because the B cell receptor
itself is membrane-bound IgM
o Excellent complement activator
o Moderate role at mucosal surfaces

IgA
o Predominantly placed at mucosal surfaces
o Makes up 10-15% of total serum immunoglobulins

o Present in external secretions saliva, milk, tears and mucous

o As a dimer (two Y-shaped molecules attached by a J-chain), secretory IgA crosses epithelial
cells and carries its function on the outside
Cross-linking
Immobilisation
Prevention of attachment of species of bacteria and viruses

IgE
o
o
o
o

Only a small amount is present in serum

Found mostly bound to effector cells like mast cells, basophils and eosinophils
Involved in type 1 hypersensitivity reactions
Important in anti=parasitic immunity