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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2215-2216. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mason, D. Y. Search for Related Content PubMed Articles by Mason, D. Y. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Comment on Moldenhauer et al, page 2470 Clues to lymphoma's cellular origin David Y. Mason UNIVERSITY OF OXFORD Moldenhauer and colleagues show that a key enzyme in germinal center cells is also found in a population of interfollicular B cells. Are these cells relevant to Hodgkin disease? B-cell maturation looks straightforward in textbooks, but it can still be surprisingly difficult to fit some of the cell types recognized by the hematopathologist into the neat schemes drawn by immunologists. An example is found in a paper by Marafioti et al1 from 2003 that drew attention to a novel population of B cells, often carrying dendritic surface processes, that are scattered through T-cell–rich interfollicular areas in peripheral lymphoid tissue (see figure). These B cells are probably closely related to "asteroid" B cells in the medulla of the thymus, but neither cell type appears in any immunologic text. In this issue of Blood, Moldenhauer and colleagues report that a proportion of these interfollicular B cells, and also their thymic counterparts, contain activation-induced cytidine deaminase (AID), a key enzyme for immunoglobulin (Ig) heavy-chain class switch recombination and somatic hypermutation in germinal centers. This could indicate that they have only recently exited from the germinal center, although it is also possible that they represent B cells that undergo Ig recombination without entering the germinal center. In the earlier paper, Marafioti et al proposed that interfollicular dendritic B cells and asteroid B cells might represent the elusive cell of origin of classical Hodgkin disease (arising respectively in lymph nodes and thymus). Features in common include their dendritic surface morphology, their location (early nodal Hodgkin disease shows a predilection for interfollicular areas), and their mutated Ig gene status. It is also notable that the interfollicular area is the region where Epstein-Barr virus (present in 50% of classical Hodgkin but rarely in other lymphomas) proliferates during mononucleosis and where it persists subsequently. View larger version (105K): [in this window] [in a new window]   Double immunofluorescence labeling of lymphoid tissue to show interfollicular B cells. Top panel: The low-power view (left) shows B cells (labeled in red for CD20) and CD8+ T cells (green). Scattered B cells are present in the interfollicular area adjacent to a B cell follicle (Foll). The high-power view (right) shows dendritic processes extending from several of these interfollicular B cells (arrow) and a single example of an interfollicular B cell (asterisk) in intimate contact with a CD8 cell. Bottom panel: Double immunofluorescence labeling for CD20 (green) and the dendritic cell marker CD208/DC-LAMP (red) shows that these 2 cell populations are clearly distinct. In the high-power view (right), typical interfollicular dendritic B cells are seen (eg, in the inset and as indicated by an arrow). Adapted from Marfioti et al1 (used with permission).   This hypothesis concerning the cellular origin of Hodgkin disease subsequently received support from studies showing that mediastinal B-cell lymphoma (a tumor arising from thymic asteroid B cells) is closer in terms of gene expression profile to classical Hodgkin disease than to diffuse large B-cell lymphoma.2,3 It was suggested therefore that asteroid B cells in the thymus may give rise, through different secondary genetic alterations, either to Hodgkin disease or to mediastinal B-cell lymphoma.2 If interfollicular dendritic B cells are indeed the peripheral equivalent of thymic asteroid cells, these gene expression studies would strengthen the idea that they are the cell of origin of classical Hodgkin disease arising in lymph nodes. It may be added that AID expression has been reported in mediastinal B-cell lymphoma4:itis apparently usually absent from Reed-Sternberg cells,5 but this may reflect the down-regulation of many B-cell genes that is well documented in Hodgkin disease. In the light of the findings outlined here it would be of interest to isolate asteroid B cells from the thymus in sufficient numbers for gene expression and/or proteomic profiling, looking for similarities to nodal interfollicular B cells and to Reed-Sternberg cells. It might also be worth exploring the possibility that occasional cases of nodal diffuse large B-cell lymphomas arise from these cells (ie, are the peripheral equivalent of mediastinal B-cell lymphoma). References Marafioti T, Jones M, Facchetti F, et al. Phenotype and genotype of interfollicular large B cells, a subpopulation of lymphocytes often with dendritic morphology. Blood. 2003;102: 2868-2876.[Abstract/Free Full Text] Savage KJ, Monti S, Kutok JL, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102: 3871-3879.[Abstract/Free Full Text] Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198: 851-862.[Abstract/Free Full Text] Bodor C, Bognar A, Reiniger L, et al. Aberrant somatic hypermutation and expression of activation-induced cytidine deaminase mRNA in mediastinal large B-cell lymphoma. Br J Haematol. 2005;129: 373-376.[CrossRef][Medline] [Order article via Infotrieve] Greiner A, Tobollik S, Buettner M, et al. Differential expression of activation-induced cytidine deaminase (AID) in nodular lymphocyte-predominant and classical Hodgkin lymphoma. J Pathol. 2005;205: 541-547.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: AID expression identifies interfollicular large B cells as putative precursors of mature B-cell malignancies Gerhard Moldenhauer, Sergey W. Popov, Beate Wotschke, Silke Brüderlein, Petra Riedl, Nicolas Fissolo, Reinhold Schirmbeck, Olga Ritz, Peter Möller, and Frank Leithäuser Blood 2006 107: 2470-2473. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Mason, D. Y. Search for Related Content PubMed Articles by Mason, D. Y. 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