B cell development & Ab maturation (1/3) Flashcards
What are teh 2 locations that B cells develop?
Marrow and lymph nodes (including spleen)
What is allelic exclusion?
That one B cell expresses only one antibody
How is immunological tolerance generated
By deleting self-reactive clones
What is the order of rearrangement of Ig genes during B cell development in the marrow?
First, heavy chain arrangement occurs
Then the light chain develops
What occurs during heavy chain rearrangement?
First, VDJ recombination creates a variable region
If it’s a funcitonal heavy chain (no stop codons, frame is ok), it’s expressed with a surrogate light chain
Signals tell the cell that it has a functional heavy chain
1/9 generate a functional heavy chian; it’s a limiting step
What is a pre B cell receptor?
Proteins that resemble a light chain
includes membrane lambda 5 (like a constant region) & VpreB(similar to variable region), two proteins that bind miu heavy chains in a way that mimics a light chain
Once the the heavy chain has done VDJ rearrangement & assembled a preBCR, then what happens?
Heavy chain rearrangement stops & light chain rearrangement begins
How many light chain recombinations occurs?
There are three VJ recombinations in the light chain at the same locus (can lead to rescue of nonproductive rearrangements)
There is a higher chance of generating a funcitonal light chain: 1/3 (as compared to 1/9 for making heavy chain)
How many checkpoints are there for B cells? When do they occur?
2 checkpoints: one at the pre B cell receptor before light chain rearrangement. A second at the end after light chain rearrangement (BCR)
How is regulation at these checkpoints accomplished?
Changes in levels of proteins involved in rearranging the Ig genes i.e. RAG 1/2 expression is reduced, access of the HC locus to the recombinase machinery is reduced
There’s also testing of the quality of Ig chains
What is the BTK gene?
It’s downstream of the BCR and is required for B cell development
What are the 2 types of B cell tolerance and where do they develop?
Central tolerance: to self antigens. Occurs in lymphocytes in central lymphoid organs i.e. marrow. Clonal deletion is the main mechanism (cell death)
Peripheral tolerance: to self antigens. Occurs in lymphocyt4es in the peripheral tissues i.e. spleen/lymph nodes. Clonal deletion, anergy (nonresponsive to signals), and clonal ignorance (cells don’t die)
What is the GC reaction?
Germinal center reaction: antigen-dependent B cell development
3 main steps:
- T cell dependent activation of antigen specific naive B cells (the precursor cells of GC rxn)
- Somatic hypermutation & Ig class switch –> high-affinity antigen-specific B cells with specialized effector functions
- Differentiation of antigen-selected GC B cells into memory B cells & plama cells, the carriers of antibody-dependent immunity
What 3 processes occur in 3 specific compartments of the GC?
- T cell zone = T-cell dependent activation
- GC dark zone = somatic hypermutaiton (SHM) & proliferation
- GC light zone = class switch recombination (CSR) & memory cell/plasma cell differentiation & selection for high-affinity B cell clones/against newly generated self-reactive B cell clones
What is somatic hypermutation (SHM)?
random mutagenesis, mostly single bp changes
limited to V(D)J regions (not C)
hypermutation is 10^6 more than normal mutation rate
Occurs only in mature, antigen-activated B cells
Combined with selection, results in clones making Ab’s with increased affinity for antigen (affinity maturation), particularly prominent in memory immunizations
What is class switch recombination? (CSR)
A DNA rearrangement that allows the same VDJ to be expressed with different heavy chain constant regions
Allows you to have a particular V region but a different effect/use of it
What are the two mechanisms of CSR’s?
- RNA processing: IgM to IgD
- DNA rearrangement: IgM to IgG, IgA, or IgE
What are the 2 differentiated B cell states that result following the GC reaction?
Memory B cell: no Ig secretion, but rapid response to renewed Ag encounter w/high affinity & switched isotypes. Circulate b/w lymphoid tissues through the blood
Plasma cell: Ig secretion of high affinity and switched isotypes; home to the bone marrow
What is X-linked agammaglobulinemia?
A human immunodeficiency syndrome caused by loss of Btk tyrosine kinase –> no B cells
Pt’s are susceptible to extracellular bacteria & viruses
What is hyper IgM syndrome?
Human Immunodeficiency syndrome caused by deficiency of: AID, CD40 ligand, CD40, or NEMO (IKK). Result is no isotope switching and/or no somatic hypermutation. Susceptible to extracellular bacteria, pneumocystis carinii, and cryptosporidium parvum
What is common variable immunodeficiency?
A human immunodeficiency syndrome caused by ICOS deficiency. It causes defective IgA and IgG production & leaves patients susceptible to extracellular bacteria
What causes most B cell lymphomas?
Most derive from GC somatic mutations. You can tell because the cancer cells have undergone the class switch. Many GC-derived lymphomas are characterized by reciprocal balanced chromosome translocations i.e. follicular lymphoma is due to t(14;18) and affects the BCL2 gene
