Lecture 11 - Development of the B cell repertoire Flashcards
What are the principles of clonal selection?
- Each lymphocyte has a single type of receptor with a unique specificity
- Each lymphocytes bears multiple (thousands) of the same receptor.
- Cells that have receptors for self molecules are deleted from the repertoire
- Interaction between a foreign molecule (antigen) and a lymphocyte receptor
leads to activation of that lymphocyte - The daughter cells derived from the activated cell has receptors that are
identical to those of the parental cell
Process of finding correct immune cell with right receptor known as clonal selection
Describe B cell development in the bone marrow
regulates construction of an antigen receptor
ensures each cell has only one specificity
checks and disposes of self-reactive B cells
exports useful cells to the periphery
provides a site for antibody production
Describe the role of B cells
Neutralize toxins and virsues
Help in the Phagocytosis of pathogens
Destruction of Bacteria and virus
Can also act as an antigen presenting cell to activate T cells
Describe the two forms in which antibodies exist
As a membrane receptor (B cell receptor [BcR]) that binds antigen
As a secreted, fluid phase molecule that directs a specific immune function
1. complement fixation
2. opsonisation 3. neutralisation
Describe immunoglobulin structure
B cell receptor composed of two identical heavy chains and two identical light chains which are held together by disulphide bonds - the hinge region which gives the molecule flexibility to move and transmit signals
Chains are divided into domains - variable and constant regions
Constant - amino acid sequence doesn’t vary
Variable region - amino acid sequence varies from one B cell receptor to another
Antigen binding is always at variable region
How is diversity obtained in immunoglobulin molecules at the protein level?
High levels of amino acid variability in Hyper Variable Regions (HV) of both the heavy and light chains
The sequence of amino acids in the
HV regions will define the shape of the antigen binding site.
How is diversity encoded in the genome?
Adult humans have an immunoglobulin repertoire of about 10,00000000000 different immunoglobulins
The total human genome only encodes for ~ 30,000 genes
This is a very significant genetic problem, how is it possible to encode for 1011 different possible proteins
Immunoglobulins compensate for limited number of genes in the genome by making sure
that the variable (Hv) regions in the immunoglobulin result from the random rearrangement
of defined gene segments.
Variable regions of Heavy chains are composed of V segments, D segments, J segments
Variable regions of Light chains are composed of V segments and J segments
Variable region composed of individual segments - multiple copies of each segment, which are randomly rearranged
IgM heavy chain (IgmH) is always rearranged first, followed by the light chain
The first BCR made and expressed on a B cell is therefore of the IgM isotype
How is diversity of the immunoglobulin repertoire generated?
1) The power of combinatorial diversity, and heavy and light chain pairing
2) Junctional diversity – TdT (Terminal deoxynucleotidyl transferase)
How does recombination happen?
The 23-12 rule!
Utilizes binding of RSS 23 base pair spacer with RSS 12 base-pair spacer
Each V, J and D segments in heavy chains and V, J segments in light chains has a RSS
A RSS 23 base-pair spacer can not bind to a 23 base-pair spacer
Important for evolution because otherwise variability would be decreased and so would the number of pathogens targeted
Why does recombination only occur in lymphocytes?
Recombination activation genes 1 and 2 (RAG1 and RAG2) facility the recombination of RSS upstream
of the appropriate gene segment i.e. V, D, or J. Only B cells (and T cells) express both RAG1 and RAG2
Both RAG1 and RAG2 must be active for recombination
Binding leads to the DNA forming a hairpin loop bringing the 2 sequences that need to recombine together
The endonuclease complex cuts between the heptamer and nonamer and RSS
Describe how quality control of B cells is carried out in the bone marrow during development
1) Surrogate light chain complexes with the IgM heavy chain to test whether a function IgM heavy chain
has formed. Failure to do so results in death of the cell.
2) The reactivity of the newly formed BcR for host antigens is tested. Sources of host antigens; molecules on the surface of stromal and immune cells, dying cells that pass through bone marrow in the blood, dying cells that are brought to the bone marrow by innate cells.
What happens to autoreactive B cells that express an autoreactive receptor?
a)Re-initiate rearrangement of the Light Chain V region segments to form a new
shape in the antigen binding site (called receptor editing)
b) Die if the new receptor still has autoreactivity for self antigens
