IgGene Rearrangment Produces Immature B Cells

B-cell maturation depends on rearrangement of the immuno-globulin DNA in the lymphoid stem cells. The mechanisms of Ig-gene rearrangement were described in Chapter 5. First to occur in the pro-B cell stage is a heavy-chain DH-to-JH gene rearrangement; this is followed by a VH-to-DHJH rearrangement (Figure 11-3). If the first heavy-chain rearrangement is not productive, then VH-DH-JH rearrange ment continues on the other chromosome. Upon completion of heavy-chain rearrangement, the cell is classified as a pre-B cell. Continued development of a pre-B cell into an immature B cell requires a productive light-chain gene rearrangement. Because of allelic exclusion, only one light-chain isotype is expressed on the membrane of a B cell. Completion of a productive light-chain rearrangement commits the now immature B cell to a particular antigenic specificity determined by the cell's heavy-chain VDJ sequence and light-chain VJ sequence. Immature B cells express mIgM (membrane IgM) on the cell surface.

As would be expected, the recombinase enzymes RAG-1 and RAG-2, which are required for both heavy-chain and light-chain gene rearrangements, are expressed during the pro-B and pre-B cell stages (see Figure 11-3). The enzyme terminal deoxyribonucleotidyl transferase (TdT), which catalyzes insertion of N-nucleotides at the DH-JH and VH-DH-JH coding joints, is active during the pro-B cell stage and ceases to be active early in the pre-B-cell stage. Because TdT expression is turned off during the part of the pre-B-cell stage when light-chain rearrangement occurs, N-nucleotides are not usually found in the VL-JL coding joints.

The bone-marrow phase of B-cell development culminates in the production of an IgM-bearing immature B cell. At this stage of development the B cell is not fully functional, and antigen induces death or unresponsiveness (anergy) rather than division and differentiation. Full maturation is signaled

Bone marrow antigen-independent

Surrogate light chain of pre-BCR

Periphery antigen-dependent

Surrogate light chain of pre-BCR

LYMPHOID STEM CELL

PRO-B CELL

PRE-B CELL

IMMATURE B CELL

NAIVE B CELL

MATURE B CELL

LYMPHOID STEM CELL

H-chain genes Germ line

L-chain genes Germ line

PRO-B CELL

DhJh

Surrogate Vpre-B and X5 Germ-line K and X

PRE-B CELL

IMMATURE B CELL

NAIVE B CELL

MATURE B CELL

Surrogate Vpre-B and X5 Germ-line K and X

VlJl

RAG-1/2 TdT

Membrane Ig Heavy chain Light chain

Transcription factors

Pu.1, Ikaros, others

Surrogate light chain

BSAP(Pax-5)

Surrogate light chain

Surface markers c-Kit ■

CD45R, CD19,

HSA(CD24),

IL-7R -CD43

CD25

mIgM

mIgD

FIGURE 11-3

Sequence of events and characteristics of the stages in B-cell maturation in the bone marrow. The pre-B cell expresses a membrane immunoglobulin consisting of a heavy (H) chain and surrogate light chains, Vpre-B and \5. Changes in the RNA processing of heavy-chain transcripts following the pre-B cell stage lead to syn thesis of both membrane-bound IgM and IgD by mature B cells. RAG-1/2 = two enzymes encoded by recombination-activating genes; TdT = terminal deoxyribonucleotidyl transferase. A number of B-cell— associated transcription factors are important at various stages of B-cell development; some are indicated here.

by the co-expression of IgD and IgM on the membrane. This progression involves a change in RNA processing of the heavy-chain primary transcript to permit production of two mRNAs, one encoding the membrane form of the ^ chain and the other encoding the membrane form of the 8 chain (see Figure 5-19). Although IgD is a characteristic cell-surface marker of mature naive B cells, its function is not clear. However, since immunoglobulin 8 knockout mice have essentially normal numbers of fully functional B cells, IgD is not essential to either B-cell development or antigen responsiveness.

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