The immunoglobulin heavy chain locus

During normal lymphoid development, both B and T lymphocytes undergo rearrangement of their antigen receptor genes, i.e. Ig genes in B-cells and TCR genes in T-cells, and their clonal progeny bear this identical antigen receptor rearrangement. B-cell neoplasms, including NHL, ALL, myeloma and CLL, undergo irreversible somatic rearrangement of the IgH locus, providing a useful marker of clonality and the stage of differentiation in these tumors. Until recently, the lineage of Hodgkin lymphoma cells was unclear. PCR amplification of Ig genes has demonstrated that the vast majority of cases of Hodgkin disease are of B-cell lineage.

The IgH locus is located on chromosome 14q32.3. Unlike the light chain (IgL) locus, IgH contains diversity segments in addition to V, J and C segments. In humans there are around 250 heavy-chain variable region (VH) segments, of which two-thirds are probably pseudogenes, representing ancestral gene remnants (denoted by y). The VH elements fall into seven families (VH1, VH2, VH3, VH4a, VH4b, VH5 and VH6). Unlike the TCR and IgL loci, the IgH locus contains multiple heavy-chain constant region (CH) segments (Figure 6.5), some 11 in total, including two pseudogenes (C||, C5, Cy3, Cyl, Cye, Cal, Cyy, Cy2, Cy4, Ce and Ca2). Each C segment contains multiple exons corresponding to the functional domains in the heavy-chain protein (CH1, CH2, CH3, etc.). The multiple C elements correspond to the different classes of heavy chain encountered during class switching. C| generates IgM, Ca generates IgA, and so on. This mechanism ensures that, although the heavy chains are of varying class, they will all bear identical V-D-J sequences.

IgH 14q32

~100-200 VH

Fig. 6.5 Genetic map of region 14q32

The CH segments are shown towards the 3' end of the region.

~100-200 VH

Cy2 Cy4 Ce Ca2

Cy3 Cy1 Cye Ca1

Cy2 Cy4 Ce Ca2

Cy3 Cy1 Cye Ca1

If

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