B Cell Maturation

The maturation of B cells occurs within the bone marrow of higher vertebrates (with the exception of the Bursa of Fabricius in birds and the role of the Peyer's Patches in B cell maturation in some vertebrates).

It has been estimated that ~ 5 X 10^7 B cells are produced each day. However, only ~ 5 X 10^6 (10%) survive in the bone marrow to eventually enter the peripheral circulation.

Experimental evidence suggests that the cross-linking of membrane-bound immunoglobulin with antigen on immature B lymphocytes in the bone marrow triggers the cell to undergo apoptosis. This is a type of negative selection by which B cells bearing Ig which is specific for self antigen can be eliminated in the bone marrow.

Interestingly, there is also evidence that at least some immature B cells can be rescued from apoptosis by editing of light chain genes.

In such cells, an maturation of the cell is arrested and the RAG-1 and RAG-2 genes are reactivated. Lambda chain genes are triggered to rearrange, and a non-self reactive lambda light chain can replace the original self-reactive kappa light chain.

Within the bone marrow, under the influence of the hematopoietic micro-inducing environment provided by stromal cells, the differentiation of B lymphocytes occurs in the sequence diagrammed below:

Pluripotent Stem Cell--->Lymphoid Stem Cell--->Progenitor B Cell--->Precursor B cell--->Immature B cell--->Mature B cell

The progenitor B cells (termed pro-B) proliferate and fill the extravascular spaces of the bone marrow. Within these cells, heavy chain genes begin rearrangement. DH-JH rearrangement occurs and tDt (terminal deoxynucleotidyl transferase) is active. [Recall that tDt is the enzyme responsible for N-region diversification at the DH-JH and VH-DHJHjunction.]

A truncated mu heavy chain is produced at this time and is associated with two distinct polypeptides which form a "surrogate light chain". One of the polypeptides has a conformation similar to the variable region of light chain while the second polypeptide has a conformation similar to the constant region of the light chain. The truncated mu heavy chain in association with the "surrogate light chain" can be detected on the surface of the pro-B cells. Even in this early form, the structure is also associated with the heterodimer Ig-alpha/Ig-beta [explained below]

The rearrangement of the VH gene segments with DHJH and the appearance of the IL-7 receptor signals the transition from pro-B to precursor B cell (pre-B). These cells proliferate and produce a complete mu heavy chain still associated with the surrogate light chain and the Ig-alpha/Ig-beta heterodimer (together termed the pre-B cell receptor).

Continued maturation of the pre-B cell to an immature B cell requires light chain gene rearrangement. Once a functional light chain is produced, the immature B cell is now committed to a particular antigenic specificity determined by the antigen binding site formed by the VH and VL domains. The immature B cell, therefore, expresses the mu heavy chain + either a kappa or lambda light chain. It is the immature B cell which is subjected to the process of negative selection. Further development of immature B cells which survive negative selection leads to the co-expression of IgD and IgM on the membrane, which is a characteristic of mature B cells.

Following the release of mature B cells from the bone marrow, the subsequent steps in B cell development--activation, proliferation, and differentiation occur in the periphery and require the presence of specific antigen.

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