B cell Development Flashcards
Which cells produce antibodies?
Plasma cells (B cells)
What is the structure of the antibody?
It has 2 heavy chains and 2 light chains, they are held together by disulfide bonds. It has 2 antigen binding sites.
B cells
- They produce antibodies
- There is a lot of them and each B cell is unique and recognises different antigen
- Each B cell expresses many copies of B cell receptor (BCR) and each BCR on that cell recognises the same antigen
- Foetal B cells are made in the liver and after birth they are made in the bone marrow
- Majority B cells will die but if they engage their target they can differentiate either in plasma cell or memory cell
- poor control of B cell responses result in autoimmunity
- defects in antibody production lead to high susceptibility to infection and very early death
- Naive B cells express shared molecular signatures (CD19, CD20) but they differ in BCR.
What’s the key aim of vaccination?
To induce antibody production
Overview of possible life of a B cell
- B cell precursor rearranges its immunoglobulin genes in the bone marrow
- If immature B cell binds to self antigen it is removed from the repertoire (negative selection in the marrow)
- Mature B cell if binds its antigen becomes activated, it migrates to the peripheral lymphoid organs
- Activated B cell give rise to plasma cells and memory cells
How are B cells made?
- B cells arise from stem cells
- Firstly, rearrangement of heavy chain (firstly D-J then V-DJ)
- B cell with rearranged heavy chain has a pre-B receptor on their surface
- Because they don’t have a light chain yet, they use surrogate light chain to check if the heavy chain is functional
- Now rearrangement of light chain (V-J)
- Now you have immature B cells with IgM immunoglobulin on the cell surface
- B cell leaves the bone marrow and finishes its maturation. The mature B cell expresses IgM and IgD on the surface
What RAG genes do?
They are expressed on immature T and B cells. They are needed for the rearrangement of TCR and BCR.
What is allelic exclusion?
It’s a process to ensure only one allele of the gene is expressed while the other is silenced.
When it comes to BCR rearrangement:
- Rearrangement can happen from either chromosome, but only one at a time. If the gene rearrangement from the first chromosome was successful, it will stop the rearrangement from the other chromosome but if was not successful then the rearrangement from other chromosome happens
- There are 2 light chains kappa and lambda
- 2 kappa genes are used first and then 2 lambda genes (if not successful)
- This ensures that one B cell will produce an antibody of one specificity
What happens if during development B cell recognises self antigen?
It gets removed or edited. There is no AIRE in B cell development, so the antigens these B cells during development can encounter are extracellular antigens and not intracellular. Hence, the negative control for B cells is good but not perfect, and many reactive B cells get through, and they recognise dsDNA or other intracellular antigens.
Reasons for B cells to be deleted during development?
- Multivalent self molecule - if antigens are spaced closely to each other and B cell binds multiple BCRs at the same time to multiple antigens, it causes very strong signal, then its deleted or the receptor is edited,
- Soluble self molecule - strength of the signal is weaker, usually happens in periphery and it leads to cell anergy.
What happens if B cell does not recognise self?
It migrates to the periphery and matures to naive B cell
Summary of development
- Pro-B cells - heavy chain gene rearrangement
- Pre-B cells - light chain gene rearrangement
- Immature B cells - express surface IgM and exit bone marrow but if strongly binds antigen is eliminated (negative selection)
- Mature B cells - express IgM and IgD on their surface, reside in the follicles of lymph nodes and the spleen and circulate between different lymph nodes
What type of cells can naive B cells develop into after encountering their antigens?
- plasma cells - secreting antibodies
- memory B cells - do not secrete antibodies unless antigen is re-encountered
What are different types of antibodies?
- IgM - on the surface of naive B cells, are first to be released when antigen is encountered, pentamer
- IgD - on the surface of naive B cells, low level in serum
- IgG - secreted by memory B cells, there are 4 subtypes (IgG1, IgG2, IgG3, IgG4), the most numerous in serum
- IgE - are on the surface of Mast cells, low number in serum
- IgA - found in mucosa serum, there are 2 subtypes (IgA1 and IgA2)
Resting/Naive B cell
- High surface Ig as didn’t encounter its antigen yet
- High expression of MHC class 2 to communicate with CD4 T cells
- Does not secrete antibodies
- Growth
- Somatic hypermutation
- Isotype switch
Plasma cell
- Low surface Ig as it already encountered its antigen
- No MHC class 2 expression
- High rate of Ig secretion
What are 2 main pathways for generating antibody responces?
- T-independent antibody responses - extrafollicular, B cells differentiate to become IgM and IgG plasma cells producing antibody of low affinity.
- T dependent antibody responses - germinal centre responses, selective process to generate plasma cells of high affinity, class switch, leads to production of antibodies and memory B cells.
T independent responses
- purified bacterial capsular polysaccharide
- no involvement of T cells
- IgM and IgG, low affinity
T dependent responses
- Protein
- Involvement of CD4 T cells
- IgM, IgG, IgA, IgE, high affinity
- Memory
How do adaptive responses develop?
- DC recognises a foreign antigen, presents it via MHC class 2 to a CD4 T cell,
- This T cell interacts with the antigen specific B cell
- This B cell can then migrate to the red pulp of spleen or medulla of lymph nodes to form short-lived plasma cells
- Or it can migrate to the follicles and germinal centres together with T cell and it produces long-lived plasma cells and memory cells
What 2 signals are required for T-dependent antibody responses?
- Direct, physical contact between CD4 T cell and B cell
- Cytokines (IL-4 and IL-21)
What are Tfh cells?
- CD4 T follicular helper cells
- Essential for the generation of T-dependent antibody responses
- Recognise peptides through MHC class 2
- They get activated by DCs, and they recognise signals from MHC class 2 from B cells
- Co-stimulation of CD40 and CD40L
- Co-stimulation with cytokines (IL-4 and IL-21)
What happens in the absence of CD40/CD40L?
Hyper IgM syndrome where patient does not produce productive antibody responses, no class switch, greater risk of infections
T independent response
- TI-2 antigens e.g. purified bacterial capsular polysaccharide, which is a multivalent antigen (repeats over and over and over on the surface)
- not a protein, so no T cell involvement
- very important for vaccines
- Responses are rapid and peak within days, no switching to IgG
- negligible memory and no boosting effect, second vaccine will show slower response rather than faster (hyporesponsiveness)
- short lived responses, typically around 2 years
- TI-2 vaccines not effective in infants under 5 years old because of small range of B cells
