Events in the rearrangement of immunoglobulin genes.
| Rearrangement of the Immunoglobulin heavy chain (IgH) gene |
| • The first step occurs in the “early pre-B-cells” and involves the recombination of the D-(Diversity) and J-(Joining) segments of the heavy chain genes (IgH). During this process, one of 27 possible D-segments and one of 6 possible J-segments are randomly chosen and fused closely together, resulting in exclusion of the DNA segments which previously separated them (see Figure 2). In addition, nucleotides of variable length and composition are randomly inserted between the rearranged D- and J-segments (N′-region). |
| • The second step occurs in the “late pre-B-cells” and involves the rearrangement of the V-(Variable) segment, resulting in the complete rearrangement of the IgH gene (Figure 2). It involves the insertion of one of a possible 59 V-segments with the above-formed D-J-segment and the exclusion of the DNA segments which previously separated them (see Figure 2). In addition, as above, nucleotides of variable length and composition are randomly inserted between the rearranged D-J- segments and the V-segment (N-region). In this way, a different DNA segment (V-N-D-N′-J) for each B-cell is created, which serves as a “finger-print” for it and all of its' daughter cells. |
| Rearrangement of the Immunoglobulin light chain (IgL) gene |
| •The rearrangement of the two IgL-genes (κ and λ) also takes place in the pre-B-cell, and occurs in a similar manner to the rearrangement of IgH. In contrast to the IgH, the IgL-genes do not possess any D-segments. As a consequence the rearrangement of the IgL involves only one step, whereby nucleotides of variable length and composition (N-sequence) are inserted between the V- and J-segments. In this way, a second DNA segment (V-N-J) is created, which differs between each B-cell. When the Ig-gene rearrangements are completed the immature B cells have evolved. |
| Non-functional Ig-rearrangements |
| • Through the above-mentioned randomised insertion of nucleotides during the IgH and IgL rearrangements, “Stop-codons” or “Frame-shifts,” which inhibit Ig-protein functioning, occur relatively frequently. In such cases, a second independent rearrangement of either the IgH or IgL occurs. Should this additional rearrangement result in a non-coding DNA sequence and, therefore, to a non-functional Ig receptor molecule, the B-cell is eliminated via apoptosis. |
| Rearrangement of the Ig genes in normal and lymphomatous B-cells |
| • As described above, every cell which arises from progenitor B-cells possesses two Ig gene rearrangement products, VH-N-DH-N′-JH and VL-N-JL, which are individual to that cell. This means that the individual B cells differ from each other through differently rearranged IgH genes. This diversity is termed “polyclonality.” |
| •The tumor cells of B-cell lymphomas, in contrast, possess identical VH-N-DH-N′-JH and VL-N-JL sequences, indicating that they have arisen from the same transformed B-cell and, thereby, have formed a clone. This is termed “monoclonality”. |
| Rearrangement of the Immunoglobulin heavy chain (IgH) gene |
| • The first step occurs in the “early pre-B-cells” and involves the recombination of the D-(Diversity) and J-(Joining) segments of the heavy chain genes (IgH). During this process, one of 27 possible D-segments and one of 6 possible J-segments are randomly chosen and fused closely together, resulting in exclusion of the DNA segments which previously separated them (see Figure 2). In addition, nucleotides of variable length and composition are randomly inserted between the rearranged D- and J-segments (N′-region). |
| • The second step occurs in the “late pre-B-cells” and involves the rearrangement of the V-(Variable) segment, resulting in the complete rearrangement of the IgH gene (Figure 2). It involves the insertion of one of a possible 59 V-segments with the above-formed D-J-segment and the exclusion of the DNA segments which previously separated them (see Figure 2). In addition, as above, nucleotides of variable length and composition are randomly inserted between the rearranged D-J- segments and the V-segment (N-region). In this way, a different DNA segment (V-N-D-N′-J) for each B-cell is created, which serves as a “finger-print” for it and all of its' daughter cells. |
| Rearrangement of the Immunoglobulin light chain (IgL) gene |
| •The rearrangement of the two IgL-genes (κ and λ) also takes place in the pre-B-cell, and occurs in a similar manner to the rearrangement of IgH. In contrast to the IgH, the IgL-genes do not possess any D-segments. As a consequence the rearrangement of the IgL involves only one step, whereby nucleotides of variable length and composition (N-sequence) are inserted between the V- and J-segments. In this way, a second DNA segment (V-N-J) is created, which differs between each B-cell. When the Ig-gene rearrangements are completed the immature B cells have evolved. |
| Non-functional Ig-rearrangements |
| • Through the above-mentioned randomised insertion of nucleotides during the IgH and IgL rearrangements, “Stop-codons” or “Frame-shifts,” which inhibit Ig-protein functioning, occur relatively frequently. In such cases, a second independent rearrangement of either the IgH or IgL occurs. Should this additional rearrangement result in a non-coding DNA sequence and, therefore, to a non-functional Ig receptor molecule, the B-cell is eliminated via apoptosis. |
| Rearrangement of the Ig genes in normal and lymphomatous B-cells |
| • As described above, every cell which arises from progenitor B-cells possesses two Ig gene rearrangement products, VH-N-DH-N′-JH and VL-N-JL, which are individual to that cell. This means that the individual B cells differ from each other through differently rearranged IgH genes. This diversity is termed “polyclonality.” |
| •The tumor cells of B-cell lymphomas, in contrast, possess identical VH-N-DH-N′-JH and VL-N-JL sequences, indicating that they have arisen from the same transformed B-cell and, thereby, have formed a clone. This is termed “monoclonality”. |