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\|/III.2 N.2 \|/N.l m .l 1 2 3 y 4 v|/5 \j/6 7

VÀ locus J - C l locus

prevented and in the absence of the k locus ’ The preferential use of k and the

apparently ordered rearrangement of k then X loci probably results simply from the k gene

being more readily and therefore more frequently rearranged In man there is only a 2:1 preferential usage of k light chain in serum and peripheral blood B cells

1.3.3 Control of immunoglobulin gene rearrangement and

transcription

Only immature B and T cells are able to rearrange immunoglobulin genes, and these cells express RAG-1 and RAG-2. RAG-1 and RAG-2 are both required for recombination and may be part o f the unidentified recombinase enzyme or may activate the recombination process indirectly They are required for cleavage of DNA at signal sequences,

pointing to a role early in the recombination process A nuclear envelope protein Rchl, which binds to RAG-1, is also required for efficient recombination

Immunoglobulin gene rearrangement only occurs while cells are not proliferating. This may be achieved by phosphorylation of RAG-2 by a cyclin-dependent kinase, which controls RAG-2 stability ’24.127,128

The accessibility model proposes that initiation of immunoglobulin gene rearrangement is dependent on the accessibility of the gene to the recombinase. This is suggested by the observation that portions of the genes are transcribed and become sensitive to nuclease digestion just prior to rearrangement. Germline transcription may function to open up the DNA giving access to the recombinase 22.129,130 heavy chain and light chain intronic

recombination as well as controlling transcription of rearranged immunoglobulin loci 134

The level and tissue specificity of immunoglobulin transcription are controlled by the interaction o f positive and negative transcription factors binding to sequence motifs in the 5' promoters, intronic enhancers and 3' enhancers of the immunoglobulin loci

Some factors are ubiquitously expressed, others are tissue-specific and it is the

combination of factors that determine gene expression. All immunoglobulin promoters have 2 motifs that are sufficient for lymphoid-restricted promoter activity, the TATA box and the octamer motif. The octamer motif is bound by the largely B lineage-specific factor Oct-2 and the ubiquitous Oct-1 and Oct-3. Oct-2 is expressed by pro-B cells, pre-B cells, B cells and plasma cells The heavy chain intronic enhancer Ep spans 700 bp between the VDJ and the constant domain coding regions. It contains many identified sequence motifs, some of which it shares with the heavy chain promoter such as the octamer motif. The 3' heavy chain enhancer also contains the octamer motif. The Ep motif pE5 mediates negative regulation of the locus in non-lymphoid cells. Factors expressed in non-lymphoid cells bind pE5 to suppress transcription of the locus. The pE5 motif is probably also a positive element in B cells. Some motifs are only active at particular stages of B cell development, for example n only confers enhancement in pre-B cells.

The K gene contains an intronic enhancer Ek that shares many motifs with Ep It is only active in mature B cells and plasma cells, and this stage-restricted activity is mainly determined by the 10 bp motif kB which binds the factor NF-kB A silencer element in

Ek suppresses activation of the locus by N F -kB in T cells, N F -kB is constitutively

expressed in mature B cell stages and is inducible in pre-B cells. It exists in an inactive form in the cytoplasm, when bound to its inhibitor I-kB . Phosphorylation of I-kB releases

N F -kB allowing its translocation to the nucleus. N F -kB induces many genes involved in

B cell responses such as the IL-2, IL-2 receptor a chain (CD25), IL-6 and MHC class II genes. The murine X locus contains 2 intronic enhancers and the human locus contains one "9.

1.4 T

(tLC)

The surrogate light chain (vj/LC) is a protein with homology to the k and X

immunoglobulin light chains that is expressed in B cell precursors, whereas conventional light chains are found in mature B cells. The ij/LC is expressed by pro-B cells, pre-BI and pre-Bn cells but is not found in mature B cells, plasma cells or in other cell lineages In pre-Bn cells the Vj/LC associates with p, heavy chain forming a complex that resembles IgM and is expressed on the cell surface (shown in figure 1.4). The ij/LC forms a complex with a surrogate heavy chain on the surface of pro-B and pre-BI cells in mice and possibly also in man. Each v|/LC is formed by the non-covalent association of two polypeptides, encoded by the VpreB and X14.1 (À5 in the mouse) genes These genes do not undergo rearrangement. The VpreB and X5 proteins were formerly called iota (i) and omega (©) respectively.