Regulation of BCell Development

A number of transcription factors that regulate expression of various gene products at different stages of B-cell development have been identified. Among these are NF-6B, BSAP, Ets-1, c-Jun, Ikaros, Oct-2, Pu.1, EBF, BCF, and E2A. Like all

Comparison of naive and memory B cells

Property

Naive B cell

Memory B cell

Membrane markers Immunoglobulin Complement receptor Anatomic location Life span Recirculation Receptor affinity Adhesion molecules

IgM, IgD

Spleen

Short-lived

Lower average affinity Low ICAM-1

Bone marrow, lymph node, spleen

May be long-lived

Higher average affinity due to affinity maturation* High ICAM-1

* Affinity maturation results from somatic mutation during proliferation of centroblasts and subsequent antigen selection of centrocytes bearing high-affinity mIg.

transcription factors, these DNA-binding proteins interact with promoter or enhancer sequences, thereby either stimulating or inhibiting transcription of the associated gene. Analyses of the effects of knocking out the gene that encodes a particular transcription factor have provided clues about the role of some factors in B-cell development. For example, in knockout mice that carry a disrupted Ikaros gene, there is a general failure of lymphocyte development, and pro-B cells fail to develop in the bone marrow.

One of the most critical B-cell transcription factors, B-cell-specific activator protein (BSAP), which has been previously mentioned (see Figure 11-3), appears to function as a master B-cell regulator. It is expressed only by B-lineage cells and influences all the cell stages during B-cell maturation. Moreover, recent evidence indicates that BSAP also influences the final differentiation events leading to the formation of memory B cells and plasma cells. The latter are the only B-lineage cells that do not express BSAP. BSAP binds to promoter or enhancer sequences of various B-cell-specific genes, including the \5 and Vpre-B genes of the surrogate light chain, the J-chain gene of polymeric IgM, and the 3'a heavy-chain enhancer region, one of the two enhancers that lie 3' of the a gene in heavy-chain germ-line DNA. In addition, BSAP binds to various immunoglobulin heavy-chain switch sites and to several genes involved in B-cell activation.

The heavy-chain 3'a enhancer (E3'a) contains binding sites for several transcription factors in addition to BSAP. Binding of BSAP to E3'a appears to influence B-cell development by preventing the binding of other transcription factors. For example, when BSAP levels are high, this factor appears to block binding of NF-aP to the 3'a enhancer, thereby blocking transcription of the heavy-chain gene and promoting formation of memory B cells. When BSAP levels are low, NF-aP can bind to E3'a. As a result, transcription of the immunoglobulin heavy-chain gene is increased, leading to formation of plasma cells.

portance of the cytokines to the orchestration of appropriate immune responses. In addition to cytokines, other regulatory mechanisms may also play important immunoregulatory roles. Greater knowledge about these regulatory events, which are still not well understood, may allow the deliberate manipulation of immune responses, selectively up-regulating desirable responses and down-regulating undesirable ones.

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