Rearrangement of immunoglobulin heavy chain variableregion genes

The heavy chain gene is located at 14q32.3 and the germline organization of the part of the gene that encodes for the variable region of IgH is shown at the top of Figure 20.6. The variableregion component of the immunoglobulin heavy chain gene is divided into three types of gene segment. V segments, D segments and J segments. A large number of individual V gene segments are encoded within the genome. The V gene segments are longer than J or D segments and encode much of the framework of the variable-region domain, together with the first and second hypervariable regions (known as the complementarity-determining regions - CDR1 and CDR2). The CDR1 and CDR2 regions encode two out of the three parts of the variable region that determine the antigenic specificity of the heavy-chain V region.

There are fewer D and J gene segments. The third hypervariable region (CDR3) is encoded at the site of joining of one of the to DJ rearrangement is able to encode a variable region then there is no V to DJ rearrangement on the other chromosome; if it has been unsuccessful (e.g. the rearrangement is out of frame) the cell goes on to attempt to rearrange a V segment to the DJ on the other chromosome. The D to J and V to DJ alignment is made possible by the presence of recombinase signalling sequences that flank (i) the upstream end of each J segment and the downstream end of each D segment and (ii) the upstream end of each D segment and the downstream of each V segment. Additional diversity at the junctions between the rearranged V, D and J segments results in part from imprecise splicing and partially through the insertion of additional non-encoded (N) basepairs at the D to J and V to DJ junctions through the action of terminal deoxynucleotidyl transferase (tdt).

functional D segments with any one of the functional J segments and includes the downstream end of one of the V segments. Heavy-chain rearrangement involves two looping-out manoeuvres (Figure 20.6). In the first of these, one of the J segments becomes spliced to one of the D segments and the intervening sequences are deleted. Next, one of the two rearranged D-J pairs becomes linked to one of the V segments and again the intervening sequences are deleted. The association of segments appears to occur at random and the theoretical number of different variable region genes that might be generated in this way is the product of the number of functional V, D and J segments, i.e. ~8262. In practice, D to J and V to D-J joining is not exact and additional random nucleotides may be added at the point where the gene segments join. This results in very much greater diversity, which is seen only in CDR3 and which includes both the D to J and V to D-J junctions.

The diversity of CDR1 and CDR2 is therefore much less than that of CDR3. Junctional diversity in CDR3 is sufficiently

Pro-B cell

Stem cell

Early pre-B cell

Late pre-B cell

Newly produced virgin B cell

Surface IgM

Pro-B cell

Early pre-B cell

Late pre-B cell

Surface IgM

Stem cell

Proliferating lymphoblast,

RAG genes expressed,

D to J and then V to

DJ rearrangements occur

Proliferating lymphoblast, expression of RAG genes, cytoplasmic (c)|, surface |VpreBX5

Non-dividing, light chain genes rearrange, expression of RAG genes, cytoplasmic |

Non-dividing small lymphocyte, expressing surface IgM (with heavy and gh chains)

Proliferating lymphoblast,

RAG genes expressed,

D to J and then V to

DJ rearrangements occur

Proliferating lymphoblast, expression of RAG genes, cytoplasmic (c)|, surface |VpreBX5

Non-dividing, light chain genes rearrange, expression of RAG genes, cytoplasmic |

Non-dividing small lymphocyte, expressing surface IgM (with heavy and gh chains)

Figure 20.7 Outline of the main stages of B lymphopoiesis. The central process in B-cell formation is the rearrangement of Ig variable-region genes. For rearrangement of V-region genes to occur in either T or B cells, recombinase-activating genes (RAG) 1 and 2 have to be expressed. Absence of these genes totally blocks further differentiation towards B or T cells. After a successful heavy-chain VDJ has been made, a B cell must express the heavy chain with the surrogate light chain composed of V-pre-B and X5 if further differentiation is to occur. Cells that fail to make either a productive heavy- or light-chain rearrangement destroy themselves by apoptosis.

great to allow the conclusion that B cells with the same CDR3 sequence are almost certainly derived from the same clone and this fact is used widely to identify the origin and relationship of malignant B cells. Further details about the process of rearrangement are given in the legend to Figure 20.6.

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