Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient

Leukemia volume 27, pages 738–740 (2013)Cite this article

Subjects

Rheumatoid factors (RFs) are auto-antibodies, mostly of the IgM isotype, that specifically bind to the Fc portion of IgG. RFs are transiently produced in healthy individuals in response to infections and after immunization with mismatched red blood cells (RBCs). RFs are chronically produced in patients suffering from rheumatoid arthritis, Sjögren’s syndrome and in hepatitis C virus (HCV)-induced type-II mixed cryoglobulinemia (MC-II) (reviewed in Newkirk1). Analyses of RFs in MC-II and in donors immunized with mismatched RBCs revealed four groups of stereotyped immunoglobulin (Ig) VH-DH-JH rearrangements, each with distinct heavy-chain complementary-determining region 3 (HCDR3) amino acid sequences: two with IGHV1-69/JH4 rearrangements, designated V1-69-RF and RF-WOL, and two with IGHV3-7/JH3 and IGHV4-59/JH2 rearrangements, designated V3-7-RF and V4-59-RF, respectively.2, 3, 4

Remarkably, similar stereotyped RF-rearrangements are frequently expressed in malignant B-cell lymphomas.2, 5, 6 Previously, we have shown that recombinantly produced V1-69-RF, V3-7-RF and RF-WOL, derived from gastric and salivary gland marginal zone B-cell lymphomas (MZBCL), bind with high-affinity to IgG in vitro.2, 7 V1-69-RF, V3-7-RF, RF-WOL and V4-59-RF rearrangements are also frequently expressed in HCV-associated lymphomas, splenic marginal zone lymphomas and in individual cases of ocular MZBCLs and diffuse–large B-cell lymphomas.5, 6, 8, 9, 10 Recently, Kostareli et al.10 reported 12 cases of B-cell chronic lymphocytic leukemia (CLL) expressing V4-59-RF and Fazi et al.11 reported two cases of V3-7-RF in monoclonal B-cell lymphocytosis.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Newkirk MM . Rheumatoid factors: host resistance or autoimmunity? Clin Immunol 2002; 104: 1–13.

    Article  CAS  Google Scholar 

  2. Bende RJ, Aarts WM, Riedl RG, de JD, Pals ST, van Noesel CJ . Among B cell non-Hodgkin’s lymphomas, MALT lymphomas express a unique antibody repertoire with frequent rheumatoid factor reactivity. J Exp Med 2005; 201: 1229–1241.

    Article  CAS  Google Scholar 

  3. Borretzen M, Randen I, Natvig JB, Thompson KM . Structural restriction in the heavy chain CDR3 of human rheumatoid factors. J Immunol 1995; 155: 3630–3637.

    CAS  PubMed  Google Scholar 

  4. De Re V, De Vita S, Gasparotto D, Marzotto A, Carbone A, Ferraccioli G et al. Salivary gland B cell lymphoproliferative disorders in Sjögren’s syndrome present a restricted use of antigen receptor gene segments similar to those used by hepatitis C virus-associated non-Hodgkins’s lymphomas. Eur J Immunol 2002; 32: 903–910.

    Article  CAS  Google Scholar 

  5. De Re V, De Vita S, Marzotto A, Rupolo M, Gloghini A, Pivetta B et al. Sequence analysis of the immunoglobulin antigen receptor of hepatitis C virus-associated non-Hodgkin lymphomas suggests that the malignant cells are derived from the rheumatoid factor−producing cells that occur mainly in type II cryoglobulinemia. Blood 2000; 96: 3578–3584.

    CAS  PubMed  Google Scholar 

  6. Ottensmeier CH, Thompsett AR, Zhu D, Wilkins BS, Sweetenham JW, Stevenson FK . Analysis of VH Genes in follicular and diffuse lymphoma shows ongoing somatic mutation and multiple isotype transcripts in early disease with changes during disease progression. Blood 1998; 91: 4292–4299.

    CAS  PubMed  Google Scholar 

  7. Hoogeboom R, Bende RJ, van Noesel CJ . MALT lymphoma-derived rheumatoid factors are nonpolyreactive high-affinity antibodies. Blood 2010; 116: 1818–1819.

    Article  CAS  Google Scholar 

  8. Dagklis A, Ponzoni M, Govi S, Cangi MG, Pasini E, Charlotte F et al. Immunoglobulin gene repertoire in ocular adnexal lymphomas: hints on the nature of the antigenic stimulation. Leukemia 2011; 26: 814–821.

    Article  Google Scholar 

  9. Ivanovski M, Silvestri F, Pozzato G, Anand S, Mazzaro C, Burrone OR et al. Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus−associated immunocytomas. Blood 1998; 91: 2433–2442.

    CAS  PubMed  Google Scholar 

  10. Kostareli E, Gounari M, Janus A, Murray F, Brochet X, Giudicelli V et al. Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity. Leukemia 2011; 26: 1127–1131.

    Article  Google Scholar 

  11. Fazi C, Dagklis A, Cottini F, Scarfo L, Bertilaccio M, Finazzi R et al. Monoclonal B cell lymphocytosis in hepatitis C virus infected individuals. Cytometry 2010; 78B: S61–S68.

    Article  CAS  Google Scholar 

  12. Bende RJ, van Maldegem F, van Noesel CJM . Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas. Haematologica 2009; 94: 1109–1123.

    Article  CAS  Google Scholar 

  13. Forconi F, Potter KN, Wheatley I, Darzentas N, Sozzi E, Stamatopoulos K et al. The normal IGHV1-69-derived B-cell repertoire contains stereotypic patterns characteristic of unmutated CLL. Blood 2010; 115: 71–77.

    Article  CAS  Google Scholar 

  14. Potter KN, Orchard J, Critchley E, Mockridge CI, Jose A, Stevenson FK . Features of the overexpressed V1-69 genes in the unmutated subset of chronic lymphocytic leukemia are distinct from those in the healthy elderly repertoire. Blood 2003; 101: 3082–3084.

    Article  CAS  Google Scholar 

  15. Widhopf GF, Kipps TJ . Normal B cells express 51p1-encoded Ig heavy chains that are distinct from those expressed by chronic lymphocytic leukemia B cells. J Immunol 2001; 166: 95–102.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by the Dutch cancer society, grant UVA 2006-3644.

Author information

Authors and Affiliations

  1. Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

    R Hoogeboom, T A Wormhoudt, J E J Guikema, R J Bende & C J M van Noesel

  2. Department of Hematology, HagaZiekenhuis, The Hague, The Netherlands

    M R Schipperus

  3. Department of Immunology, Erasmus MC, Erasmus University, Rotterdam, The Netherlands

    A W Langerak

  4. Peter Gorer Department of Immunobiology, King’s College London School of Medicine, London, UK

    D K Dunn-Walters

Authors
  1. R Hoogeboom
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T A Wormhoudt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M R Schipperus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A W Langerak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. D K Dunn-Walters
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J E J Guikema
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R J Bende
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C J M van Noesel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C J M van Noesel.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hoogeboom, R., Wormhoudt, T., Schipperus, M. et al. A novel chronic lymphocytic leukemia subset expressing mutated IGHV3-7-encoded rheumatoid factor B-cell receptors that are functionally proficient. Leukemia 27, 738–740 (2013). https://doi.org/10.1038/leu.2012.238

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.238

This article is cited by

Search

Advanced search

Quick links