Lecture 19: Early Lymphocyte Maturation - B cells Flashcards
What does it mean if there are low levels of IgA and IgM and there are normal levels of IgG?
there is an issue with isotype switching
this is because IgG is the isotype which all other isotypes originate from
What leads to issues in isotype switching?
deficiency of B cells
Where do B lymphocytes develop?
in the bone marrow
What does engagement of BCR allow for activation of?
plasma cells / antibody secreting cells (ASC)
memory B cells
What is the BCR capable of?
secretion of soluble forms of BCR (antibodies) which are important for opsonization, complement activation, and neutralisation
What do BCRs recognise?
antigen
What does allelic exclusion ensure?
only one type of antibody / BCR is produced per B cell
What is vital to diversity of B cells?
V(D)J recombination
What does B cell development start from?
uncommitted progenitors
initiation of differentiation from hematopoietic stem cells into multipotent progenitors
What do interactions with molecules such as FLT3 allow differentiation to?
common lymphoid progenitors (CLP)
What are common lymphoid progenitors (CLPs)?
a heterogenous population that commits to
different fates depending on their multipotent potential
How are B cells generated throughout life?
generation of new B cells is continuous throughout life (in contrast to T cells)
What is B cell development dependent on?
interactions with bone marrow stromal cells
What does transitioning of B cells through developmental stages require?
each stage requires positive signals
cells require these signals to be rescued -> the default is death
What happens after each progression of a premature B cell?
each progression decreases the cell’s potential and commits it further to its fate
What is important for B cell commitment?
E2A and EBF
What happens when a stem cell enters the bone marrow and starts committing to become a B cell? What is required in order for the cell to progress?
starts as an early pro-B cell which starts rearranging its D fragment with the J fragment -> requires successful heavy chain recombination in order to progress
What is required for transition to large pre-B cells?
expression of pre-BCR using the successful μ chain
What does formation of a large pre-B cell involve?
use of a surrogate light chain consisting of λ5, VpreB with signalling components Igα, Igβ -> signalling is antigen independent and requires dimerization / oligomerization
What does signalling through pre-BCR enforce?
allelic exclusion and halts recombination
What happens before commencing rearrangement of light chain?
expansion of the successful cell 30-60 fold
What is light chain rearrangement also subject to?
allelic exclusion once successful
two types of light chain (kappa or lambda) and only one type is used (isotypic exclusion)
How is IgM formed?
through successful light chain and μ heavy chain signals transition into an immature B cell
What does ratio of kappa to lambda expression correlate with?
the number of functional gene segments in the genome -> implications on dominance of segments when it comes to order of expression
What is the progression of a hematopoietic stem cells to an immature B cell?
HSC -> MPP -> CLP -> pro-B cell -> large pre-B cell -> small pre-B cell -> immature B cell
How is pre-BCR formed?
using a surrogate light chain by pairing with VpreB and λ5 and if successful goes on to the large pre-B cell
How does antigen independent pre-BCR stimulation occur?
via Bruton’s tyrosine kinase which halts heavy chain rearrangement and induces a burst of proliferation
What occurs after antigen independent pre-BCR stimulation?
light chain rearrangement occurs in in the small pre-B cell
What does successful pairing of a heavy chain and light chain result in?
an immature B cell that is able to leave the bone marrow
What happens when recombination of gene segments results in unintended consequences?
some events might lead to cancer and autoreactivity is a major concern (various mechanisms in place to overcome this)
What is central tolerance? What is it dependent on?
acts as the first checkpoint and is dependent on the how strongly interaction occurs between the BCR and self-antigen
What are the four main outcomes of central tolerance?
no self reaction, multivalent self molecule, soluble self molecule or low-affinity non-cross-linking self molecule
What is the role of receptor editing?
potentially rescues self-reactive B cells from clonal deletion
What is still active at the receptor editing stage?
RAG expression and is able to continue light chain rearrangements
What can defects in receptor editing contribute to?
diseases such as lupus and rheumatoid arthritis
What is peripheral tolerance?
second checkpoint
similar to central tolerance
Why doesn’t receptor editing occur in peripheral tolerance?
since these cells are somewhat more mature and can no longer rearrange the light-chain loci
Where does maturation of B cells occur? What is required for maturation to occur?
in the spleen where immature B cells enter follicles to receive survival signals (requires the molecule BAFF and weak BCR interactions)
