Correspondence
L&H Cells in Lymphocyte-Predominant Hodgkin's Disease
N Engl J Med 1998; 338:763-765March 12, 1998
- Article
To the Editor:
Marafioti et al. (Aug. 14 issue)1 report on monoclonal populations of lymphocytic and histiocytic (L&H) cells harboring somatically mutated genes of the antibody V H region in 11 cases of lymphocyte-predominant Hodgkin's disease. On the basis of the high load of somatic mutations and signs of ongoing mutations, the authors conclude that L&H cells are resistant to normal selection processes, perhaps because of a block in the apoptotic pathway, and that “the presence in two patients of L&H cells with disrupted capacity for coding by immunoglobulin genes supports this theory, because normally such B cells cannot survive.” Marafioti et al. thus interpret the generation of L&H cells in lymphocyte-predominant Hodgkin's disease in the same way that we earlier interpreted the generation of Reed–Sternberg cells in classic Hodgkin's disease.2
In a study parallel to that of Marafioti et al., we came to the conclusion that this scenario does not hold true for lymphocyte-predominant Hodgkin's disease, in which we found the L&H cells to be selected for antibody expression.3 However, a reevaluation of the V gene sequence in the patients in whom the coding capacity was said to be disrupted in all L&H cells (Patient 4 in the report by Marafioti et al.) revealed that this sequence was misinterpreted. It represents an out-of-frame rearrangement (about 30 percent of human B cells carry nonfunctional V H gene rearrangements in addition to a functional one4), in which the correct reading frame for translation was lost during V–D–J recombination in the B-cell precursor (sequences available on request). The two stop codons at amino acids 91 and 100 are presumably also generated during V–D–J recombination and not by somatic hypermutation. (Since 8 of 12 base pairs encoding amino acids 91 to 94 differ from the most homologous germ-line gene, it is obvious that this sequence belongs to the area generated by V–D–J joining, so that the mutation frequency of framework 3 is 0 percent, not 11.4 percent, as shown in Table 2 of the article.) It is likely that the L&H cells in this case harbor an additional in-frame V H gene rearrangement that was not amplified.
With the mistake corrected, the data reported by Marafioti et al. are perfectly compatible with our own conclusions — namely, that in contrast to the Reed–Sternberg cells in classic Hodgkin's disease,2 the L&H cells in lymphocyte-predominant Hodgkin's disease are derived not from “crippled” germinal-center B cells but from germinal-center cells in the process of selection through their antigen receptor.3 The authors add to this concept by suggesting that an established L&H tumor clone may at some point lose its dependence on antigen, perhaps because of additional transforming events.
4 ReferencesRalf Küppers, Ph.D.
Klaus Rajewsky, M.D.
University of Cologne, 50391 Cologne, GermanyAndreas Braeuninger, Ph.D.
Martin-Leo Hansmann, M.D.
University of Frankfurt, 60590 Frankfurt am Main, Germany1
Marafioti T ,Hummel M ,Anagnostopoulos I , et al. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997;337:453-458
Full Text | Web of Science | Medline2
Kanzler H ,Kuppers R ,Hansmann ML ,Rajewsky K . Hodgkin and Reed Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 1996;184:1495-1505
CrossRef | Web of Science | Medline3
Braeuninger A ,Kuppers R ,Strickler JG ,Wacker HH ,Rajewsky K ,Hansmann ML . Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 1997;94:9337-9342
CrossRef | Web of Science | Medline4
Yamada M ,Wasserman R ,Reichard BA ,Shane S ,Caton AJ ,Rovera G . Preferential utilization of specific immunoglobulin heavy chain diversity and joining segments in adult human peripheral blood B lymphocytes. J Exp Med 1991;173:395-407
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We are pleased that Küppers et al. favor our interpretation that L&H cells in lymphocyte-predominant Hodgkin's disease represent a clonal outgrowth of germinal-center blasts. However, we are surprised by their criticism that we proposed that the L&H cells originate from “crippled” germinal-center B cells, as they originally suggested for Reed–Sternberg cells in classic Hodgkin's disease.1 We did not make such a proposal; in our article we state, “in L&H cells these mutated genes usually retain the potential for translation into protein, whereas in Reed–Sternberg cells they often lose their coding capacity.”
Apart from this discrepancy, there is a disagreement about whether L&H cells can grow independently of antigen.2,3 The presence of functionally rearranged immunoglobulin genes suggests that the germinal-center–cell precursors of L&H cells were initially antigen-reactive and thus antigen-selected. In contrast, the L&H cells themselves display a very high load of somatic mutations in the VH genes, which is highly atypical of normal antigen-selected B cells. This mutation pattern can best be explained by an abnormally long stay of the L&H cells within the germinal-center environment, as evidenced by the predominant location of the L&H cells within progressively transformed germinal centers. The high load of somatic mutations in conjunction with the emigration of L&H cells into T-cell zones without any signs of apoptosis and the disruption of the immunoglobulin genes in 2 of our 11 patients underline our interpretation that L&H cells grow independently of antigen and suggest that these cells are rescued from apoptosis by mechanisms other than antigen selection.
A further point of disagreement is the interpretation of the noncoding and partially coding L&H-cell–derived VH gene sequences in Patients 4 and 7.2 In both patients, a second immunoglobulin-gene rearrangement was not detectable. Since the polymerase-chain-reaction assay we used can detect all possible rearrangements (even in the presence of many somatic mutations) and a large number of L&H cells have been investigated, it is highly unlikely that a second rearrangement has escaped detection. Therefore, it is more likely that the observed sequence modifications (frame shift or stop codons or both) have been introduced in the course of a germinal-center reaction than during immunoglobulin-gene rearrangement.
3 ReferencesMichael Hummel, Ph.D.
Harald Stein, M.D.
Theresa Marafioti, M.D.
Ioannis Anagnostopoulos, M.D.
Free University of Berlin, D-12200 Berlin, Germany1
Kanzler H ,Kuppers R ,Hansmann ML ,Rajewsky K . Hodgkin and Reed-Sternberg cells in Hodgkin's disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J Exp Med 1996;184:1495-1505
CrossRef | Web of Science | Medline2
Marafioti T ,Hummel M ,Anagnostopoulos I , et al. Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997;337:453-458
Full Text | Web of Science | Medline3
Braeuninger A ,Kuppers R ,Strickler JG ,Wacker HH ,Rajewsky K ,Hansmann ML . Hodgkin and Reed-Sternberg cells in lymphocyte predominant Hodgkin disease represent clonal populations of germinal center-derived tumor B cells. Proc Natl Acad Sci U S A 1997;94:9337-9342
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
Roland Schmitz, Jens Stanelle, Martin-Leo Hansmann, Ralf Küppers. (2009) Pathogenesis of Classical and Lymphocyte-Predominant Hodgkin Lymphoma. Annual Review of Pathology: Mechanisms of Disease 4:1, 151-174
CrossRef2
Christoph Renné, José Ignacio Martín-Subero, Martin-Leo Hansmann, Reiner Siebert. (2005) Molecular Cytogenetic Analyses of Immunoglobulin Loci in Nodular Lymphocyte Predominant Hodgkin's Lymphoma Reveal a Recurrent IGH-BCL6 Juxtaposition. The Journal of Molecular Diagnostics 7:3, 352-356
CrossRef3
Jo Spencer, Deborah K. Dunn-Walters. (1999) Somatic hypermutation and B-cell malignancies. The Journal of Pathology 187:2, 158-163
CrossRef
