4 Antibody Diversity II Flashcards
B cell activation
B cell development does not require Ag
B cells rearrange their genes and express surface IgM (BCR) in the bone marrow
B cells then enter the circulation where they may encounter Ag in the secondary lymph organs
If they don’t encounter Ag they die within a few weeks
T-independent Ag
These are antigens that cause B cells to produce loads of antibodies without the need for a T cell interaction.
These antigens do not cause B cell maturation (no class switching /affinity maturation), just IgM production
TI Ag are particularly resistant to degradation
2 groups
TI-1: mainly bacterial cell wall components eg LPS. In high concentrations they can polyclonally activate B cells
TI-2: predominantly large polysaccharides with repeating antigenic determinants eg dextran, polymeric bacterial flagellin.
Thought to x-link B cells causing clustering. Need cytokine help.
Generate IgM and don’t induce memory
Tend to activate CD5+ B-cells (B-1)
T dependent response
T cells and B cells recognise different parts of the antigen
B cells see epitope, T cells see processed peptide fragment.
T cells need peptide presented on APC
T helper cells
T helper cells
There to provide cytokines for other cells to respond
when is a T cell response first initiated?
when antigen is taken up by APC’s - dendritic cells are the only APCs that can present to naiive T cells
T and B cell interaction
Complex 2 way interaction between a Th cell and an Ag specific B cell
Surface IgM binds Ag and internalizes it
Peptide presented on MHCII
TCR and MHC polarise on cell surfaces to form an immunological synapse
Co-stimulatory molecules bind
Cytokines produced by T cell (IL-4, 5, 6, 10 & 13)
B cell proliferate and differentiate into memory cells or AFC
T-follicular helper cells, localise to germinal centres and produce IL-21 (critical for germinal centre formation) and direct Ig class switching
Co stimulatory signals
CD28 and CD80 - 2 strong signals you get between T and B cell
CD28 is on the surface of most T cells, binds to CD80 on B cells
CTLA-4 can also bind to CD80/CD86, interferes with the immune response
As the interaction goes on, the CD28 becomes less important and CTLA-4 becomes more expressed on the surface of the cell
The affinity for CTLA-4 for CD80/CD86 is much higher than CD28 for CD80/CD86, hence it displaces CD28 to cause a negative signal to switch of T cell response (function)
Some tumours have the ability to ligate CTLA-4 to inhibit T cell response, but if you can stop this interaction then T cells may carry on to target tumour cells.
The other interactions such as LFA-1 ICAM-1 and CD2 with LFA-3 are adhesion interactions that holds the cells together
CD40 and CD40L important in the B cell undergoing class switching and somatic hypermutation
Th2 cytokines in B cell response
IL-4: Induces activation and differentiation in B cells
IL-5: Similar effect but additional effects on eosinophils
IL-6: Also produced by other cell types, induces B cells to become AFC
IL-10: Growth and differentiation of B cells, blocks Th1
IL-13: Directs response to IgE
B cell activation
Two outcomes
Production of antibody forming cells, secrete Ab to clear Ag, mostly die within 2 weeks
Production of memory B cells, long lived and responsible for long term Ab production
Occurs in the germinal centres of the secondary lymphoid tissue, spleen particularly in (PALS- periarteriolar lymphatic sheath) and lymph nodes.
Sequence of events (B cell activation)
Ag taken up by DCs (TLR etc)
DCs activate Th in Ln (DC only cell to activate naïve T cells)
B cells in the lymphoid tissue activated by soluble Ag
B cells present to T cells and get some Ig production-extrafollicular activation, low level somatic mutation.
Some T cells develop into TFH and these cells move to follicles
B cells move to follicles
T and B cells cooperate to form germinal centres where extensive somatic hypermutation, affinity maturation and Ig class switching takes place
DC’s role
The DCs sit in the tissue mopping up debris, proteins, viruses etc
They are activated by Toll like receptors – pattern recognition molecule that is expressed on some immune cells
Germinal centres
The T helper cells can go to the germinal centres to become follicular T helper
Here the follicular dendritic cells and B cells are present, causes B cell to undergo affinity maturation and somatic hypermutation generating long lived plasma cells and memory B cells
Ig Class switching
Heavy chain isotype switches to γ, α, ε
Occurs in the secondary response
Happens in the germinal centre
Adds plasticity to the response
Determines the functionality of the antibody
Determined by cytokines
What happens first, class switching or somatic hypermutation?
Unknown
role of cytokines in immune response
direct the way in which class switch goes e.g.:
Th1 cells are activated by viruses and bacteria to produce γIFN. This causes switch to IgG- main complement fixing isotype.
Helminths produce IL-4 from Th2, IL-4 directs IgE production which target esoinophils to helminths.
Mucosal tissue results in the switch to IgA under the influence of TGFβ
