Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia - PubMed (original) (raw)

. 2004 Apr;113(7):1008-16.

doi: 10.1172/JCI19399.

Franco Fais, Angelo Valetto, Emilia Albesiano, Shiori Hashimoto, Mariella Dono, Hideyuki Ikematsu, Steven L Allen, Jonathan Kolitz, Kanti R Rai, Marco Nardini, Anna Tramontano, Manlio Ferrarini, Nicholas Chiorazzi

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Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia

Fabio Ghiotto et al. J Clin Invest. 2004 Apr.

Abstract

Studies of B cell antigen receptors (BCRs) expressed by leukemic lymphocytes from patients with B cell chronic lymphocytic leukemia (B-CLL) suggest that B lymphocytes with some level of BCR structural restriction become transformed. While analyzing rearranged V(H)DJ(H) and V(L)J(L) genes of 25 non-IgM-producing B-CLL cases, we found five IgG(+) cases that display strikingly similar BCRs (use of the same H- and L-chain V gene segments with unique, shared heavy chain third complementarity-determining region [HCDR3] and light chain third complementarity-determining region [LCDR3] motifs). These H- and L-chain characteristics were not identified in other B-CLL cases or in normal B lymphocytes whose sequences are available in the public databases. Three-dimensional modeling studies suggest that these BCRs could bind the same antigenic epitope. The structural features of the B-CLL BCRs resemble those of mAb's reactive with carbohydrate determinants of bacterial capsules or viral coats and with certain autoantigens. These findings suggest that the B lymphocytes that gave rise to these IgG(+) B-CLL cells were selected for this unique BCR structure. This selection could have occurred because the precursors of the B-CLL cells were chosen for their antigen-binding capabilities by antigen(s) of restricted nature and structure, or because the precursors derived from a B cell subpopulation with limited BCR heterogeneity, or both.

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Figures

Figure 1

Figure 1

Amino acid sequences of HCDR3 and LCDR3 of IgG+ B-CLL cases. Amino acid sequences are shown flanked by the 3′ end of FR3 and the 5′ end of FR4. A consensus sequence is shown for each. Color code: identical amino acids are in brown, chemically similar amino acids in blue, unrelated amino acids in black, and differences within areas of identity or similarity in red. (A) HCDR3. The consensus sequence consists of two hydrophilic amino acids (blue), seven amino acids that represent a portion of the germline D6–13 gene segment (brown), a glycine or serine (both with small side chains; brown), one to two variable amino acids, and five amino acids from the 5′ portion of the germline JH5b segment. (B) LCDR3. The LCDR3 sequences of all cases are identical, except for a difference in the last amino acid in CLL no. 039, due to the use of the Jκ2 segment. In each case, an arginine occurs at the Vκ-Jκ junction (underlined and in italics).

Figure 2

Figure 2

Different mechanisms generate an arginine at the VL-JL junctions. The codons for arginine are listed. Color code: identical nucleotides of the arginine codon are in brown, nucleotides deleted are in black, nucleotides probably resulting from nontemplated nucleotide addition are in dark blue, and differences within areas of identity or similarity in red. (A and B) An appropriate codon results from coding end trimming and recombination of the two germline Vκ and Jκ1 segments. (C) The arginine codon develops via a more complex combinatorial process, requiring the trimming of one nucleotide from the 3′ end of VL, the deletion of seven nucleotides from the 5′ end of Jκ2, and the nontemplated insertion of two G nucleotides.

Figure 3

Figure 3

C-alpha trace of the structural models produced by WAM. (A) Overlay of main chains of the five CLL three-dimensional structures. For CLL no. 209, the consensus L-chain amino acid sequence was added for WAM analysis. B-CLL L chains are shown in blue color (hypervariable loops L1, L2, and L3 in light blue), and H chains are shown in green color (hypervariable loops H1, and H2 in light green). The different H3 loop structures are color-coded, as noted by the lime green, red, black, purple, and dark green lines in the H3 area. Figure was prepared with MOLSCRIPT (91), and Raster3D (92). (B and C) Electrostatic and molecular surface representation of the structure of CLL no. 039 as a model representative of the B-CLL cases of nonbulged conformation (nos. 039 and 114; B) and of the CLL no. 057 as a model of the cases of bulged conformation (nos. 057, 202, and 209; C). Negative surface potentials are indicated in red, positive surface potentials in blue, and neutral potentials in white. The arginine L96 side chain is shown in yellow CPK representation. The structures are shown from a top view (left panels) and from a side view, corresponding to an approximately 70° rotation relative to the top view (right panels). Figures were prepared with GRASP (93). Arg L96; arginine L96 side chain.

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References

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