Skip to main content
Springer Nature Link
Log in

Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

BAFF-receptor (BAFF-R) is required for the successful maturation and survival of B-cells. We developed an anti-human BAFF-R monoclonal antibody (mAb), 8A7. The reactivity of 8A7 in normal and neoplastic tissue was examined by performing immunohistochemistry on paraffin-embedded sections. 8A7 reacted with lymphocytes in the mantle and marginal zones, but not with lymphocytes in the interfollicular area. Lymphocytes in the germinal centers were found to be negative or occasionally weakly positive for 8A7. BAFF-R expression was found only in B-cell lymphoma (44/80, positive cases/examined cases): B-lymphoblastic lymphoma 0/3, B-chronic lymphocytic leukemia/small lymphocytic lymphoma 4/4, mantle cell lymphoma 9/11, follicular lymphoma 10/14, diffuse large B-cell lymphoma (DLBCL) 11/25, marginal zone B-cell lymphoma 8/10, lymphoplasmacytic lymphoma 2/2, plasma cell myeloma 0/2, and Burkitt lymphoma 0/9, but not in T/NK cell lymphomas (0/19) or Hodgkin lymphoma (0/10). BAFF-R was expressed in most low-grade B-cell neoplasms and a small number of DLBCL, suggesting that BAFF-R may play an important role in the proliferation of neoplastic lymphoid cells. Thus, the mAb is very useful for further understanding of both healthy B-cell biology and its pathogenic neoplasms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Avery DT, Kalled SL, Ellyard JI et al (2003) BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin invest 112:286–297

    Article  CAS  PubMed  Google Scholar 

  2. Briones J, Timmerman JM, Hilbert DM, Levy R (2002) BLyS and BlyS receptor expression in non-Hodgkin’s lymphoma. Exp Hematol 30:135–141

    Google Scholar 

  3. Gross JA, Johnston J, Mudri S, Enselman R, Dillon SR, Madden K, Xu W, Parrish-Novak J, Foster D, Lofton-Day C, Moore M, Littau A, Grossman A, Haugen H, Foley K, Blumberg H, Harrison K, Kindsvogel W, Clegg CH (2000) TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 404:995–999

    Article  PubMed  Google Scholar 

  4. Gross JA, Dillon SR, Mudri S, Johnston J, Littau A, Roque R, Rixon M, Schou O, Foley KP, Haugen H, McMillen S, Waggie K, Schreckhise RW, Shoemaker K, Vu T, Moore M, Grossman A, Clegg CH (2001) TACI-Ig neutralizes molecules critical for B cell development and autoimmune disease. Impaired B cell maturation in mice lacking BLyS. Immunity 15:289–302

    Article  CAS  PubMed  Google Scholar 

  5. Hase H, Kanno Y, Kojima H, Morimoto C, Okumura K, Kobata T (2002) CD27 and CD40 inhibit p53-independent mitochondrial pathways in apoptosis of B cells induced by B cell receptor ligation. J Biol Chem 277:46950–46958

    Google Scholar 

  6. Hase H, Kanno Y, Kojima M, Hasegawa K, Sakurai D, Kojima H, Tsuchiya N, Tokunaga K, Masawa N, Azuma M, Okumura K, Kobata T (2004) BAFF/BLyS can potentiate B-cell selection with the B-cell co-receptor complex. Blood 103:2257–2265

    Article  CAS  PubMed  Google Scholar 

  7. He B, Chadburn A, Jou E, Schattner EJ, Knowles DM, Cerutti A (2004) Lymphoma B cells evade apoptosis through the TNF family members BAFF/BLyS and APRIL. J Immunol 172:3268–3279

    CAS  PubMed  Google Scholar 

  8. Karasuyama H, Kudo A, Melcher F (1990) The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain. J Exp Med 172:969–972

    Article  CAS  PubMed  Google Scholar 

  9. Khare SD, Sarosi I, Xia XZ, McCabe S, Miner K, Solovyev I, Hawkins N, Kelley M, Chang D, Van G, Ross L, Delaney J, Wang L, Lacey D, Boyle WJ, Hsu H (2000) Severe B cell hyperplasia and autoimmune disease in TALL-1 transgenic mice. Proc Natl Acad Sci USA 97:3370–3375

    Article  CAS  PubMed  Google Scholar 

  10. Klein U, Rajewsky K, Kuppers R (1998) Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med 188:1679–1689

    Article  CAS  PubMed  Google Scholar 

  11. Klein U, Goossens T, Fischer M, Kanzler H, Braeuninger A, Rajewsky K, Kuppers R (1998) Somatic hypermutation in normal and transformed human B cells. Immunol Rev 162:261–280

    CAS  PubMed  Google Scholar 

  12. Mackay F, Woodcock SA, Lawton P et al. (1999) Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med 190:1697–1710

    Article  CAS  PubMed  Google Scholar 

  13. Mackay F, Schneider P, Rennert P, Browning JL (2003) BAFF and APRIL: a tutorial on B cell survival. Annu Rev Immunol 21:231–264

    Google Scholar 

  14. Madry C, Laabi Y, Callebaut I et al. (1988) The characterization of murine BCMA gene defines it as a new member of the tumor necrosis factor superfamily. Int Immunol 10:1063–1702

    Google Scholar 

  15. Maes B, De Wolf-Peeters C (2002) Marginal zone cell lymphoma—an update on recent advances. Histopathology 40:117–126

    Article  CAS  PubMed  Google Scholar 

  16. Marafioti T, Hummel M, Foss HD, Laumen H, Korbjuhn P, Anagnostopoulos I, Lammert H, Demel G, Theil J, Wirth T, Stein H (2000) Hodgkin and Reed-Sternberg cells represent an expansion of a single clone originating from a germinal center B-cell with functional immunoglobulin gene rearrangements but defective immunoglobulin transcription. Blood 95:1443–1450

    CAS  PubMed  Google Scholar 

  17. Martinez-Valdez H, Guret C, de Bouteiller O, Fugier I, Banchereau J, Liu YJ (1996) Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, P53, and Bax but not the survival gene bcl-2. J Exp Med 183:971–977

    Article  CAS  PubMed  Google Scholar 

  18. Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P, Soppet D, Charters M, Gentz R, Parmelee D, Li Y, Galperina O, Giri J, Roschke V, Nardelli B, Carrell J, Sosnovtseva S, Greenfield W, Ruben SM, Olsen HS, Fikes J, Hilbert DM (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263

    Article  CAS  PubMed  Google Scholar 

  19. Nakamura N, Abe M (2003) Histogenesis of CD5-positive and CD5-negative B-cell neoplasms on the aspect of somatic mutation of immunoglobulin heavy chain gene variable region. Fukushima J Med Sci 49:55–67

    CAS  PubMed  Google Scholar 

  20. Nathwani BN, Harris NL, Weisenburger D, Isaacson PG, Piris MA, Berger F, Muller-Hermalink HK, Swerdlow SH (2001) Follicular lymphoma. In: Jaffe ES, Harris NL, Stein H, Vardiman JW (eds) Tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, France pp 162–167

    Google Scholar 

  21. Ng LG, Sutherland AP, Newton R, Qian F, Cachero TG, Scott ML, Thompson JS, Wheway J, Chtanova T, Groom J, Sutton IJ, Xin C, Tangye SG, Kalled SL, Mackay F, Mackay CR (2004) B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 173:807–817

    CAS  PubMed  Google Scholar 

  22. Novak AJ, Bram RJ, Kay NE, Jelinek DF (2002) Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood 100:2973–2979

    Article  CAS  PubMed  Google Scholar 

  23. Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF (2004) Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 103:689–694

    Article  CAS  PubMed  Google Scholar 

  24. O’Connor BP, Raman VS, Erickson LD, Cook WJ, Weaver LK, Ahonen C, Lin L-L, Mantchev GT, Bram RJ, Noelle RJ (2004) BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med 199:91–97

    Article  CAS  PubMed  Google Scholar 

  25. Pascual V, Liu YJ, Magalski A, de Bouteiller O, Banchereau J, Capra JD (1994) Analysis of somatic mutation in five B cell subsets of human tonsil. J Exp Med 180:329–339

    Article  CAS  PubMed  Google Scholar 

  26. Rassidakis GZ, Medeiros LJ, Vassilakopoulos TP, Viviani S, Bonfante V, Nadali G, Herling M, Angelopoulou MK, Giardini R, Chilosi M, Kittas C, McDonnell TJ, Bonadonna G, Gianni AM, Pizzolo G, Pangalis GA, Cabanillas F, Sarris AH (2002) BCL-2 expression in Hodgkin and Reed-Sternberg cells of classical Hodgkin disease predicts a poorer prognosis in patients treated with ABVD or equivalent regimens. Blood 100:3935–3941

    Article  CAS  PubMed  Google Scholar 

  27. Schiemann B, Gommerman JL, Vora K, Cachero TG, Shulga-Morskaya S, Dobles M, Frew E, Scott ML (2001) An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293:2111–2114

    Article  CAS  PubMed  Google Scholar 

  28. Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N, Ambrose C, Lawton P, Bixler S, Acha-Orbea H, Valmori D, Romero P, Werner-Favre C, Zubler RH, Browning JL, Tschopp J (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747–1756

    Article  CAS  PubMed  Google Scholar 

  29. Schneider P, Takatsuka H, Wilson A, Mackay F, Tardivel A, Lens S, Cachero TG, Finke D, Beermann F, Tschopp J (2001) Maturation of marginal zone and follicular B cells requires B cell activating factor of the tumor necrosis factor family and is independent of B cell maturation antigen. J Exp Med 194:1691–1697

    Article  CAS  PubMed  Google Scholar 

  30. Seshasayee D, Valdez P, Yan M, Dixit VM, Tumas D, Grewal IS (2003) Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as as inhibitory BLys receptor. Immunity 18:279–288

    Article  CAS  PubMed  Google Scholar 

  31. Smith SH, Cancro MP (2003) Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors. J Immunol 170:5820–5823

    CAS  PubMed  Google Scholar 

  32. Thompson JS, Bixler SA, Qian F et al. (2001) BAFF-R, a newly identified TNF receptor that specifically interacts with BAFF. Science 293:2108–2111

    Article  CAS  PubMed  Google Scholar 

  33. von Bulow GU, Bram RJ (1997) NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor superfamily. Science 278:138–141

    Article  PubMed  Google Scholar 

  34. von Bulow GU, van Deursen JM, Bram RJ (2001) Regulation of the T-independent humoral response by TACI. Immunity 14:573–582

    Article  PubMed  Google Scholar 

  35. Vora KA, Wang LC, Rao SP, Liu ZY, Majeau GR, Cutler AH, Hochman PS, Scott ML, Kalled SL (2003) Germinal centers formed in the absence of B cell-activating factor belonging to the TNF family exhibit impaired maturation and function. J Immunol 171:547–551

    CAS  PubMed  Google Scholar 

  36. Yamaguchi M, Seto M, Okamoto M, Ichinohasama R, Nakamura N, Yoshino T, Suzumiya J, Murase T, Miura I, Akasaka T, Tamaru J, Suzuki R, Kagami Y, Hirano M, Morishima Y, Ueda R, Shiku H, Nakamura S (2002) De novo CD5+ diffuse large B-cell lymphoma: a clinicopathologic study of 109 patients. Blood 99:815–821

    Article  CAS  PubMed  Google Scholar 

  37. Yan M, Wang H, Chan B et al. (2001) Activation and accumulation of B-cells in TACI-deficient mice. Nat Immunol 2:638–645

    Google Scholar 

  38. Yatabe Y, Oka K, Asai J, Mori N (1996) Poor correlation between clonal immunoglobulin gene rearrangement and immunoglobulin gene transcription in Hodgkin’s disease. Am J Pathol 149:1351–1361

    CAS  PubMed  Google Scholar 

  39. Yoshino T, Kondo E, Cao L, Takahashi K, Hayashi K, Nomura S, Akagi T (1994) Inverse expression of bcl-2 protein and Fas antigen in lymphoblasts in peripheral lymph nodes and activated peripheral blood T and B lymphocytes. Blood 83:1856–1861

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Dr. Hajime Karasuyama for the pBCMGSneo expression vector, Dr. Hidefumi Kojima for helpful discussion, and Ms. Yumiko Kanno for participating in technical assistance. We also thank the Laboratory Animal Research Center and the Laboratory of Analytical Instruments, Institute for Medical Science, Dokkyo University School of Medicine, for the use of their facilities.

A grant-in-aid for Scientic Research (c) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (KAKENHI 16590410 to T.K.) and The Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools of Japan (to T.K.)

Author information

Authors and Affiliations

  1. Department of Pathology, Fukushima Medical University, Hikarigaoka-1, Fukushima-shi, 960-1295, Japan

    Naoya Nakamura, Sachiko Yoshida & Masafumi Abe

  2. Department of Immunology, Dokkyo University School of Medicine, Tochigi, Japan

    Hidenori Hase, Daisuke Sakurai & Tetsuji Kobata

  3. First Department of Internal Medicine, Niigata University Medical Hospital , Niigata University, Niigata, Japan

    Nobuhiro Tsukada, Jun Takizawa & Sadao Aoki

  4. Department of Pathology, Dokkyo University School of Medicine, Tochigi, Japan

    Masaru Kojima

  5. Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan

    Shigeo Nakamura

Authors
  1. Naoya Nakamura
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hidenori Hase
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Daisuke Sakurai
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Sachiko Yoshida
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Masafumi Abe
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Nobuhiro Tsukada
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Jun Takizawa
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Sadao Aoki
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Masaru Kojima
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Shigeo Nakamura
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Tetsuji Kobata
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Naoya Nakamura.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakamura, N., Hase, H., Sakurai, D. et al. Expression of BAFF-R (BR3) in normal and neoplastic lymphoid tissues characterized with a newly developed monoclonal antibody. Virchows Arch 447, 53–60 (2005). https://doi.org/10.1007/s00428-005-1275-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-005-1275-6

Keywords