During early human life, B cell development begins in the fetal liver. From 12 weeks onwards, B cell development continues in hematopoietic stem cells in the bone marrow throughout our lives.
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The plasma cell, which is the terminally differentiated B cell, is the only cell type that can produce antibodies in our body. B cells are the cellular basis of the humoral immune response, and they play an important role in maintaining the normal immunologic functions of the human body.
Generation of B Cells
The human fetal liver is the place where B cell development starts. Then, the process continues in hematopoietic stem cells in the bone marrow where the stromal cells supply cytokines and chemokines like C-X-C motif chemokine 12 and interleukin (IL)-7, which are needed for early-stage B cell development.
The signals from the stromal cells facilitate hematopoietic stem cells to differentiate into common lymphoid progenitor cells, which express c-kit and IL-7 receptors to bring the survival and proliferation signals for common lymphoid progenitor cells once they come into contact with the ligands.
The expression of the transcription factors, E2A and early B-cell factor helps in the development of common lymphoid progenitor cells into pro-B cells, which can undergo a sequential genetic rearrangement of heavy-chain and light-chain immunoglobulin genes, the V(D)J recombination, leading to the production of the IgM-expressing immature B cells.
Then, these immature B cells travel from the bone marrow to the spleen, the site where they will differentiate into T1 and T2 stages. The final stage in maturation to mature B cells is when they co-express IgD and IgM so they are ready to be activated by foreign antigens.
Differentiation of B cells
In the peripheral lymphoid organs, mature B cells require two signals to be activated and differenced into antibody-secreting plasma cells. Signaling through antigen-coupled B cell receptors is the first one, whereas the second one is a T cell-dependent or T cell-independent manner.
Lipopolysaccharides and glycolipids are triggers of T cell-independent pathways that generally lead to short-lived plasma cells producing low-affinity antibodies. T cell-dependent responses, initiated by antigen encounter and interaction with follicular helper T cells, facilitate B cells to either rapidly turn into short-lived plasma cells or go to the germinal centers (microanatomical niches where B cells proliferate) for differentiation into plasma cells or memory B cells with a higher affinity toward the antigens.
There are two zones in the germinal center: the dark zone and the light zone. In the dark zone, B cells are subjected to somatic hypermutation at the variable regions of the B cell receptors genes and clonal expansion. In the light zone, B cells undergo affinity maturation through interaction with follicular helper T cells and follicular dendritic cells to choose B cell clones having high-affinity B cell receptors.
The ability of B cells to differentiate into antibody-secreting cells is the basis of the humoral adaptive immune system. This process is performed with an ideal balance to ensure sufficient specific humoral immunity with simultaneously eschewing the production of autoantibodies. There are various subpopulations of mature B cells with specific functions and predispositions to differentiate into antibody-secreting cells. When B cells come into contact with foreign antigens, they are activated in either a T-cell independent or T-cell dependent manner.
In T-cell dependent pathway, researchers found that there is an establishment of germinal centers. This results in the production of antibody-secreting cells, and also memory B cells that allow for rapid secondary responses upon re-exposure to the same antigen. Aberrant expression of germinal center transcription factors is usually reported in B cell malignancies.
References
- Asma, G.E., van den Bergh, R.L. and Vossen, J.M., 1984. Development of pre-B and B lymphocytes in the human fetus. Clinical and experimental immunology, 56(2), p.407.
- sai, D.Y., Hung, K.H., Chang, C.W., and Lin, K.I., 2019. Regulatory mechanisms of B cell responses and the implication in B cell-related diseases. Journal of Biomedical Science, 26(1), p.64.
- Bhattacharya, M., 2018. Understanding B lymphocyte development: a long way to go. In Lymphocytes. IntechOpen.
- LeBien, T.W., and Tedder, T.F., 2008. B lymphocytes: how they develop and function. Blood, 112(5), pp.1570-1580.
- Schmidlin, H., Diehl, S.A., and Blom, B., 2009. New insights into the regulation of human B-cell differentiation. Trends in immunology, 30(6), pp.277-285.
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