The selection and hypermutation of the B cell antigen receptor (BCR) takes place in germinal center (GCs). The presence of antigen triggers the B cell differentiation. The development of B cell includes its maturation, activation and differentiation into B plasma cells and B memory cells. The lymphoid progenitor in the bone marrow is differentiated into pro B cell. This pro B cells then undergoes a series of differentiation which includes pre B cells then immature B cells and finally mature B cells. The maturation is the product that has been achieved by the activity of of several transcriptional factors and surface markers in a series.
Thymus dependent antigen is the key factor that is responsible for the differentiation of B cells in the germinal center. After the thymus dependent antigen expresses, the development of germinal center starts in 7 to 10 days. As the development starts, Dark zones appear in the germinal center due to intensively proliferating activated B cells. These B cells which are in the state of proliferation are also called as centroblast. The centroblast are further differentiated by increased size, large cytoplasmic area and lack of surface immunoglobulin (Ig). These centroblast are then divided into centrocytes and small non dividing B cells. The surface Ig is present in centrocytes.
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The follicular dendritic cells (FDC) are present in the light zone and contains antigen antibody complex. The centrocytes migrates to this light zone and interact with the antigen of this antigen antibody complex on FDC. This interaction is specific between antigen antibody complex on FDC and membrane Ig of centrocytes. Apoptosis is the fate of other cells with low affinity and specificity and only the centrocytes with high affinity are selected to undergo the process of further differentiation. On the interaction with CD4+ T cells, these selected centrocytes are differentiated into memory cells and plasma cells. The plasma cells are responsible for the production of antibodies where the memory cells stores the information and exit from the germinal center. Light zone in the germinal center is the region where class switching and maturation takes place of the plasma and memory cells.
The selection and differentiation of centrocytes is the important step in the production of antibodies. The signals produce during the interaction of centrocytes with antigen antibody complex of FDC are responsible for the survival of selected centrocytes. Therefore, the centrocyte with weak or no interaction undergoes apoptosis.
Fig 1: The events of B cell differentiation at the cellular level.
Surface molecules and Transcription factor for the differentiation of B cell
In pro B cell stage of differentiation, the cells are not able to express heavy chains and light chains of antibodies. However, the pro B cell expresses a surface molecule i.e. CD45R present in membrane Ig-Î±/Ig-Î². In the late developmental stages CD45R shows the activity of signal transduction which is associated with antibodies. CD45R is mostly present in leukocytes and is found in tyrosine phosphatase form. The pro B cell also expresses certain other surface molecules that include CD19, Cd24 and CD43. The role of CD43 surface molecule is only in the pro B cell stage and as the cell differentiates from pro B cell to pre B cell, its role ceases. However, the activity of other surface molecules remains till the mature B cells. The pre B cell expresses another surface molecule i.e. CD25 (Î±-chain of the IL-2 receptor). Then the light and heavy chain appears on surface Ig converting pre B cell to immature B cell. The monoclonal antibodies in the progression of B cell differentiation identify the surface molecules at different stages of differentiation.
There are several transcriptional factors that play their role in the differentiation of B cell. The transcription factors responsible for the differentiation of immature B cells into mature B cells includes early B cell factor (EBF), E2A, Ikaros, BSAP, sox-4 and PU-1. These transcriptional factors are responsible for the expression of membrane Ig. The sfpi-1 gene encodes PU-1 protein in mice and it is found to be an important transcription factor in the differentiation process of b cells. The lack of this factor showed the lacking of B cell in those mice.
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The other transcription factor of great importance in the early stage development of B cells is E2A. This factor is responsible for DHJH rearrangements with the help of RAG-1 recombinase enzyme. The EBF factor also shows the similar function. Another transcription factor BSAP binds with only the specific gene mostly present in Ig heavy chains and therefore its role is in late stages of B cell differentiation.
Types of Antibodies produced by B cell
B cell produces different types of antibodies after maturation. On the interaction with CD4+ T cells in the germinal center, the selected centrocytes are differentiated into memory cells and plasma cells. The plasma cells are then capable of producing specific antibodies for the antigen. The antibodies produced by the plasma cells are IgM, IgD, IgA, IgG and IgE. The antibodies IgD and IgM surface membrane can be switched to IgE or IgG with the help of certain switch factor like interleukins. This switching is done in order to produce specific antibodies against antigen.
The heavy chain and light chain gene shuffling produces the specific antibodies against the antigen. There are 2 heavy chains and 2 light chains present in an antibody. The heavy chain posses three regions that are constant and one region that is variable where as the light chain only consist of one variable and constant region. The heavy chains constant regions are the decider that which type of antibodies are produced. These different types of antibodies production are the results of heavy chain and light chain gene rearrangements. The RAG-1 and RAG-2 recombinase enzymes are responsible for this rearrangement in the gene.