Cell Antigen Receptor Genes

Antigen receptors are the primary effector molecules of the adaptive immune system and consist of multisubunit glycoprotein molecules present on all B and T lympho cytes.3 In B cells, the AgRs are membrane-bound immunoglobulins (Ig). B-cell AgR genes include the heavy-chain gene (IGH) at 14q32, the kappa light-chain gene (IGLK) at 2p11, and the lambda light-chain gene (IGLL) at 22q11. In a germline, or nonrearranged state,AgR genes are composed of separate coding segments distributed in a region of DNA estimated to be several hundred kilobases (kb) in length. During B-cell development, one IGH allele undergoes rearrangement, during which double-stranded breaks in DNA occur with subsequent deletion of large intervening DNA segments. This is followed by DNA repair at the site of recombination to bring the separated AgR gene segments together, to form a functional IGH gene. Each AgR gene in germline configuration consists of variable (V), joining (J), constant (C), and in the case of the IGH gene, diversity (D) regions. There are approximately 45 V, 23 D, and 6 J regions. AgR rearrangement occurs in a specific order: one IGH D segment is fused to one J segment first, and this DJ segment is then fused with a V segment to form a functional VDJ exon that encodes the variable antigen recognition site of the IGH protein. Following IGH rearrangement, the final product is a gene containing one V region (plus all upstream V regions not involved in the rearrangement), one J region (plus all the downstream J regions not involved in the rearrangement), one D region, and one C region, arranged in the following order on the chromosome: V-D-J-C (Figure 32-1).

The large variety of different recombinations that can occur within these genes creates the diversity and specificity of the receptors necessary for recognition of a vast number of antigens. However, recom-binational diversity alone does not account for the full range of diversity of the Ig repertoire. Nucleotide loss and random nucleotide addition between the D-J and V-D junctions by the enzyme terminal deoxynucleotidyl transferase (TdT) provides additional diversity, as does the variability of combinations among the V, D, and J segments of the IGH, IGLK, and IGLL genes in the formation of the antigen recognition site.

A hierarchy for Ig AgR gene rearrangements exists.4 Ig gene rearrangement is an error-prone process, and many

Table 32-1. World Health Organization Classification of B-Cell

Lymphomas

Abbreviation

Lymphoma Subtype

Used in Text

Precursor B-cell lymphoblastic

Pre-B ALL

leukemia/lymphoma

Mature B-Cell Lymphomas

Chronic lymphocytic leukemia/small

CLL/SLL

lymphocytic lymphoma

Lymphoplasmacytic lymphoma

LPL

Splenic marginal zone lymphoma

SMZL

Extranodal marginal zone B-cell lymphoma

MALToma

of MALT

Nodal marginal zone B-cell lymphoma

Nodal MZL

Follicular lymphoma

FL

Mantle cell lymphoma

MCL

Diffuse large B-cell lymphoma

DLBCL

Mediastinal large B-cell lymphoma

MBCL

Intravascular large B-cell lymphoma

ILBCL

Primary effusion lymphoma

PEL

Burkitt lymphoma

BL

Plasmacytoma/plasma cell myeloma

PCT/MM

attempted rearrangements result in nonfunctional AgR genes, mostly due to a disruption of the open reading frame for translation of the encoded transcript by the N-region nucleotides. If the first attempt at IGH rearrangement fails, the cell can try to rearrange the second IGH allele to produce a functional gene. A single B cell may therefore have two IGH rearrangements, one nonfunctional and one functional. The IGLK alleles rearrange in a similar fashion, but only after the successful rearrangement of one of the IGH alleles. The IGLL genes rearrange in most cases only if the IGLK genes have been deleted on both alleles, following their unsuccessful rearrangement. Normal B cells that fail to produce a functional IGH or light chain rearrangement are usually eliminated through apoptosis.

Even after successful rearrangement, the Ig genes in mature B cells often undergo additional changes, including IGH isotype switching, V-segment substitution due to a second round of rearrangement in the germinal center, and somatic hypermutation. When somatic hypermutation of the IGH V region (IgVH) occurs in germinal center-derived B cells in response to antigen exposure, affinity maturation of an already rearranged IGH gene occurs through point mutations, small insertions, or deletions, or some combination of these. The term "postgerminal center" is used to refer to B cells that have been exposed to antigen in the germinal center and undergone additional somatic mutations of IgVH.

Structurally and genetically unique AgR rearrangements occur in every B cell and have been exploited for years as markers of cell lineage and clonality. B cells with these unique gene rearrangements may undergo limited clonal expansion as a part of a normal immune response, but uncontrolled clonal expansion occurs in BCLs (and other B-cell malignancies). In this setting, the unique AgR rearrangement can serve as a diagnostic marker of B-cell clonality and a marker for detection of minimal residual disease following therapy. Clonal rearrangements of IGH and IGLK can be detected in essentially all malignancies of mature B cells,but many precursor B-cell malignancies will have only IGH rearrangements, since malignant transformation occurs before rearrangement of the IGLK gene.

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