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Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity

Leukemia volume 26, pages 1127–1131 (2012)Cite this article

Rheumatoid factors (RFs) are the most frequent autoantibodies in autoimmune disorders, especially rheumatoid arthritis and primary Sjögren's syndrome (SS). RFs may also develop as a monoclonal component in B-cell lymphoproliferations, including type-II mixed cryoglobulinemia (MC-II).1 MC-II develops almost exclusively in individuals infected with the hepatitis C virus (HCV) and is characterized by the presence of immune complexes composed of monoclonal IgM binding to polyclonal IgG that exhibit anti-HCV reactivity. The monoclonal IgM almost always carries kappa light chains and represents autoantibodies with RF activity.1

Chronic antigenic stimulation by HCV has been considered as a key mechanism in sustaining the proliferation of the RF-secreting B-cell clones in MC-II, as evidenced by the highly restricted immunoglobulin (IG) gene repertoire of the monoclonal IgM RF. Further, the regression of MC-II as well as HCV-associated splenic marginal-zone lymphoma (SMZL)2 following antiviral therapy might be considered as evidence that the growth and survival of monoclonal B cells in HCV-associated lymphoproliferations are dependent on continued exposure to the virus. However, it is unclear whether a direct stimulation by HCV itself is causative for any of these conditions or, alternatively, a virus-induced inflammatory condition may trigger a dysregulated (auto)immune response, eventually leading to the emergence of a monoclonal B-cell expansion.2, 3, 4

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Acknowledgements

We thank Andreas Agathangelidis, Institute of Agrobiotechnology, CERTH, Thessaloniki, Greece, for his assistance in the preparation of IG sequence logos, and Professor Christian Geissler, Rigshospitalet, Copehnagen, Denmark, for providing information about the Danish cases included in the study. This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) (Investigator Grant to PG and Special Program Molecular Clinical Oncology–5 per mille no. 9965), Milano, Italy; CARIPLO Foundation, Milano, Italy; PRIN-MIUR, Roma, Italy; Progetti Integrati Oncologia (PIO)–Ministero della Salute, Roma, Italy; IGA MZCR NS10439-3/2009; ENosAI project (code 09SYN-13-880), co-funded by the EU and the Hellenic General Secretariat for Research and Technology. EK was a recipient of fellowships from the Propondis Foundation and AG Levendis Foundation, Athens, Greece; AJ is supported by the EHA Partner Fellowship Program Jesper Jurlander, one of the co-authors of the present manuscript, unexpectedly passed away earlier this year. We dedicate this manuscript to his memory. EK performed research, analyzed data and wrote the paper. MG, AJ, FM, BT and LBP performed research and analyzed data. XB, VG and MPL co-ordinated the curation and annotation of IG gene sequence data. KT supervised the establishment of heterohybridomas. SP, DO, LF, PFdC, JJ, MP and AA provided samples and associated data. CB, RR, FD, PG and KS designed and supervised the research and wrote the paper.

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Author notes

  1. J Jurlander: Deceased.

  2. E Kostareli and M Gounari: Equal first authors.

  3. P Ghia and K Stamatopoulos: Equal senior authors.

Authors and Affiliations

  1. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece

    E Kostareli, A Anagnostopoulos & K Stamatopoulos

  2. Division of Molecular Oncology, Department of Onco-Hematology and MAGIC (Microenvironment and Genes in Cancers of the blood) Interdivisional Research Program, Laboratory of B cell Neoplasia and Unit of Lymphoid Malignancies, Istituto Scientifico San Raffaele and Università Vita-Salute San Raffaele, Milano, Italy

    M Gounari, A Janus & P Ghia

  3. School of Biology, Aristotle University of Thessaloniki, Thessaloniki, Greece

    M Gounari & A Kouvatsi

  4. Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece

    M Gounari, N Darzentas & K Stamatopoulos

  5. Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Upssala, Sweden

    F Murray & R Rosenquist

  6. IMGT, the international ImMunoGeneTics information system, Université Montpellier 2, Laboratoire d'ImmunoGénétique Moléculaire LIGM, UPR CNRS 1142, Montpellier, France

    X Brochet, V Giudicelli & M-P Lefranc

  7. Department of Hematooncology, University Hospital Brno, and Central European Institute of Technology, Masaryk University, Brno, Czech Republic

    S Pospisilova & B Tichy

  8. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    D Oscier

  9. Department of Haematology, Imperial College Academic Health Science Centre, Hammersmith Hospital, London, UK

    L Foroni

  10. CERMS, S. Giovanni Battista Hospital, Turin

    P F di Celle

  11. Italy

    P F di Celle

  12. Department of Hematology, Rigshospitalet, Copenhagen, Denmark

    L B Pedersen & J Jurlander

  13. Pathology Unit and Unit of Lymphoid Malignancies, San Raffaele Scientific Institute, Milan, Italy

    M Ponzoni

  14. Centre for Immune Regulation, Institute of Immunology, University of Oslo and Oslo University Hospital, Oslo, Norway

    K Thompson

  15. Hematology Department, Nikea General Hospital, Athens, Greece

    C Belessi

  16. Laboratory of Hematology and Université Pierre et Marie Curie, Hôpital Pitié-Salpètrière, Paris, France

    F Davi

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  1. E Kostareli
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  2. M Gounari
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  17. K Thompson
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  18. N Darzentas
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  20. C Belessi
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  22. F Davi
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  23. P Ghia
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  24. K Stamatopoulos
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Corresponding author

Correspondence to P Ghia.

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The authors declare no conflict of interest.

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Kostareli, E., Gounari, M., Janus, A. et al. Antigen receptor stereotypy across B-cell lymphoproliferations: the case of IGHV4-59/IGKV3-20 receptors with rheumatoid factor activity. Leukemia 26, 1127–1131 (2012). https://doi.org/10.1038/leu.2011.311

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