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Persistent polyclonal B-cell lymphocytosis: extensively proliferated CD27+IgM+IgD+ memory B cells with a distinctive immunophenotype

Leukemia volume 28, pages 1560–1564 (2014)Cite this article

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Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare disorder, which mostly affects middle-aged women and is associated with smoking.1 It is characterized by the persistent expansion of CD27+IgM+IgD+ B cells, the presence of circulating binucleated lymphocytes and increased IgM serum levels.1, 2, 3 Furthermore, PPBL is associated with HLA-DRB1*07 carriership and a supernumerary isochromosome +i(3q) in a small proportion of lymphocytes.3 Although the disorder is usually benign,4 ∼10% of patients present with mild splenomegaly and a few patients subsequently develop a mature B-cell malignancy, such as diffuse large B-cell lymphoma (DLBCL) or splenic marginal zone lymphoma (MZL).4 Despite an increasing number of described cases, the nature of the persistent lymphocytosis and its relation to mature B-cell malignancies remain poorly understood. Therefore, we subjected PPBL patients and healthy controls to immunoglobulin (Ig) repertoire and replication history analyses, and gene expression profiling (detailed Materials and Methods online).

Five patients (4 women, 1 man) were included with a moderate lymphocytosis of CD27+IgM+IgD+ B cells that was persistent for >1 year (Supplementary Table 1, Supplementary Figure 1a). These cells showed a normal Igκ/Igλ ratio, but abnormally low CD38 and CD21 expression levels (Supplementary Figure 1b). IGH-CDR3 immunospectratyping revealed polyclonal IGH rearrangements with a normal length distribution and in-frame selection (Supplementary Figure 1c). This was confirmed by detailed sequence analyses of 375 in-frame IGH gene rearrangements from sorted CD27+IgM+IgD+ cells. Similar to healthy controls, each clone yielded a unique sequence, and diverse IGHV, IGHD and IGHJ genes were used without signs for preferential pairing (Supplementary Figure 2). The IGHV1-2*04 allele that is associated with splenic MZL was used in only four rearrangements from three patients.5 Considering that 4/5 patients carried an IGHV1-2*04 allele in their germline DNA, it did not seem preferentially rearranged in PPBL cells. Finally, the IGH-CDR3 size distribution in IGH gene rearrangements of PPBL was similar to control natural effector and IgM-only memory B cells (Supplementary Figure 2f). Thus, PPBL cells showed a diverse Ig gene repertoire with normal IGH-CDR3 size selection and without obvious selection for IGHV gene use.

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Acknowledgements

We thank I Pico and AA Tarique for technical support, S de Bruin-Versteeg for assistance with preparing the figures, Drs AW Langerak, VHJ van der Velden and M van der Burg for fruitful discussions and critical reading of the manuscript and the EuroFlow Consortium for kindly providing the EuroFlow tools and the data on mature B-cell malignancies. This work was supported by a grant from the Erasmus University Rotterdam (EUR-Fellowship to MCvZ).

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Author notes

  1. Current address: Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands.

  2. Current address: Bioinformatics Group, Wageningen University and Research centre, Wageningen, The Netherlands.

Authors and Affiliations

  1. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    M A Berkowska, C Grosserichter-Wagener, J J M van Dongen & M C van Zelm

  2. Department of Clinical Chemistry and Laboratory Hematology, Gelre ziekenhuizen, Apeldoorn, The Netherlands

    H J Adriaansen

  3. The Delft Bioinformatics Lab, Faculty of Electrical Engineering, Mathematics and Computer Science, Delft University of Technology, Delft, The Netherlands

    D de Ridder

  4. Department of Clinical Chemistry, Franciscus Hospital, Roosendaal, The Netherlands

    K P Mirani-Oostdijk

  5. Department of Internal Medicine, Admiraal De Ruyter Ziekenhuis, Goes, The Netherlands

    H J Agteresch

  6. Second Department of Medicine, University Hospital of Schleswig-Holstein, Campus Kiel, Kiel, Germany

    S Böttcher

  7. Department of Medicine, Service of Cytometry, Cancer Research Center (IBMCC-CSIC/USAL, IBSAL) University of Salamanca, Salamanca, Spain

    A Orfao

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  1. M A Berkowska
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Correspondence to M C van Zelm.

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Author Contributions

MAB, JJMvD and MCvZ designed the experiments. CG-W, HJA and DdR provided conceptual advice. MAB and CG-W performed and analyzed most of the experiments. DdR and MCvZ contributed to data analyses. HJA, KPM-O, HJA, SB, AO provided material necessary for performing experiments and data analysis. MAB and MCvZ wrote the manuscript. CG-W, HJA, DdR, KPM-O, HJA, SB, AO and JJMvD commented on the manuscript.

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Berkowska, M., Grosserichter-Wagener, C., Adriaansen, H. et al. Persistent polyclonal B-cell lymphocytosis: extensively proliferated CD27+IgM+IgD+ memory B cells with a distinctive immunophenotype. Leukemia 28, 1560–1564 (2014). https://doi.org/10.1038/leu.2014.77

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