Bloque 3: B cell ontogeny Flashcards
Definition of B cell ontogeny
B cell ontogeny is the process through which precursor cells develop into mature B lymphocytes.
This process is produced due to phenotypic changes and consists in the association between differentiation processes, specificity and tolerance.
B cell development, general features
B cell development begins in the bone marrow and it’s completed in the periphery.
The process begins in the bone marrow with the asymmetric division of an hemaotpoyetic stem cell (HSC). Then it continues through a series of progressively more differentiated progenitor stages to the production of common lymphoid progenitors (CLPs), which can give rise to B cells (remain in bone marrow), T cells (go to thymus) or innate lymphoid cells.
As differentiation proceeds, developing B cells express a precisely controlled sequence of cell-surface receptors and adhering molecules. Signals may induce differentiation of developing B cells, trigger their proliferation at particular stages or direct the movement of B cells through bone marrow environment.
B cell development in the bone marrow
The bone marrow contains microenvironments or niches populated by hematopoyetic cells and various bone marrow stromal cells (provide support and growth factors).
At various points of their development, precursors of B cells must interact with stromal cells expressing particular proteins that induce the developing cells to differentiate and move in an orderly progression from different locations of the bone marrow.
B cell development stages are defined by:
- Cell-surface markers: Adhesion molecules and receptors of chemokines and cytokines
- Transcription factor expression: Determine which genes are expressed at each step in the developmental process
- Immunoglobulin genes rearrangements
B cell developmental stages
Earliest steps:
In this step, HSC develop into CLP. In order to do so, HSC express: C-Kit (receptor for stem cell factor) and Sca-1 or Ly6D. Depending on wether it is more expressed one or the other, HSC will develop into one cell type or another one.
The interaction between C-kit and receptor for stem cell factor, induces the differentiation of HSC to multipotent progenitor cells.
Pro-B cells:
In early pro-B cells, the combination between the diverse genes (D) and the joining genes (J) of the heavy chain is completed.
Late pro-B cells express Pax5 transcription factor, which promotes the initiation of D-J complex with the variable segment (V) and the expression of CD19. Pax5 also produces Ig-alpha and Ig-beta, which help receptors in B-cells to transport signals into the cell.
In this step there is a significant cell death due to unproductive rearrangements (2/3 of cells).
Pre-B cells:
In this step there is NO cell death.
Early pre-B cells express pre-B cells receptors at early stages. The heavy chain rearrangement is finalised and complexed with VpreB and lambda5 surrogate light chains.
CD25 is expressed at this stage and IL-2 is produced by T cells
Pre-B-cell expression causes: RAG inhibition and allelic exclussion, cell survival and cell proliferation.
Late pre-B cell stage is characterised by the beginning of light-chain gene rearrangement and completion.
The IgM receptor expressed on the cell surface provoques the transition from pre-B cell into a mature B cell stage.
Positive multivalent high-avidity recognition of autoantigens in the bone marrow or spleen causes receptor editing or cell death (negative selection)
B-cell maturation:
B cells that leave bone marrow are functionally immature, they express IgM on their surface but not IgD. Pre-B cells mature as they progress through the spleen
There’s a recirculation of B-cells between blood and spleen.
Earliest steps in B cell development
In this step, HSC develop into CLP. In order to do so, HSC express: C-Kit (receptor for stem cell factor) and Sca-1 or Ly6D. Depending on wether it is more expressed one or the other, HSC will develop into one cell type or another one.
The interaction between C-kit and receptor for stem cell factor, induces the differentiation of HSC to multipotent progenitor cells.
Pro-B cell stage in B cell development
In early pro-B cells, the combination between the diverse genes (D) and the joining genes (J) of the heavy chain is completed.
Late pro-B cells express Pax5 transcription factor, which promotes the initiation of D-J complex with the variable segment (V) and the expression of CD19. Pax5 also produces Ig-alpha and Ig-beta, which help receptors in B-cells to transport signals into the cell.
In this step there is a significant cell death due to unproductive rearrangements (2/3 of cells).
Pre-B cell stage in B cell development
In this step there is NO cell death.
Early pre-B cells express pre-B cells receptors at early stages. The heavy chain rearrangement is finalised and complexed with VpreB and lambda5 surrogate light chains.
CD25 is expressed at this stage and IL-2 is produced by T cells
Pre-B-cell expression causes: RAG inhibition and allelic exclussion, cell survival and cell proliferation.
Late pre-B cell stage is characterised by the beginning of light-chain gene rearrangement and completion.
The IgM receptor expressed on the cell surface provoques the transition from pre-B cell into a mature B cell stage.
Positive multivalent high-avidity recognition of autoantigens in the bone marrow or spleen causes receptor editing or cell death (negative selection)
B cell maturation
B cells that leave bone marrow are functionally immature, they express IgM on their surface but not IgD. Pre-B cells mature as they progress through the spleen.
There’s a recirculation of B-cells between blood and spleen.
Positive multivalent high-avidity recognition of autoantigens in the bone marrow or spleen causes receptor editing or cell death (negative selection)
Positive and negative selection of B cells
Negative selection is a process in which B-cells that recognise self-antigens are either destroyed or their receptors are edited. This process takes place in both the bone marrow and the spleen while the maturation process of B cells takes place.
Positive selection is the process in which those cells able to recognise antigens survive and proliferate and those cells unable to provide a signal against antigens die by neglect.
B-cell development and phenotypic markers
Pro-B cells: CD19, CD10, CD24 and TdT
Pre-B cells: CD19, CD10, CD20
Immature B-cell: CD19, CD20, IgM
Mature B-cell: CD19, CD20, IgM and IgD
