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.

  • Original Article
  • Published:

Lymphomas

Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies

Abstract

Differentiation of naïve B cells into plasma cells or memory cells occurs in the germinal centers (GCs) of lymph follicles or alternatively via a GC- and T-cell-independent pathway. It is currently assumed that B-cell lymphomas correlate to normal B-cell differentiation stages, but the precise correlation of several B-cell lymphomas to these two pathways remains controversial. In the present report, we describe the junctional adhesion molecule C (JAM-C), currently identified at the cell–cell border of endothelial cells, as a new B-cell marker with a tightly regulated expression during B-cell differentiation. Expression of JAM-C in tonsils allows distinction between two CD27+ B-cell subpopulations: JAM-C− GC B cells and JAM-C+ non-germinal B cells. The expression of JAM-C in different B-cell lymphomas reveals a disease-specific pattern and allows a clear distinction between JAM-C− lymphoproliferative syndromes (chronic lymphocytic leukemia, mantle cell lymphoma and follicular lymphoma) and JAM-C+ ones (hairy cell leukemia, marginal zone B-cell lymphoma). Therefore, we propose JAM-C as a new identification tool in B-cell lymphoma diagnosis.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Kuppers R, Klein U, Hansmann ML, Rajewsky K . Cellular origin of human B-cell lymphomas. N Engl J Med 1999; 341: 1520–1529.

    Article  CAS  PubMed  Google Scholar 

  2. Chiorazzi N, Rai KR, Ferrarini M . Chronic lymphocytic leukemia. N Engl J Med 2005; 352: 804–815.

    Article  CAS  PubMed  Google Scholar 

  3. Stevenson FK, Sahota SS, Ottensmeier CH, Zhu D, Forconi F, Hamblin TJ . The occurrence and significance of V gene mutations in B cell-derived human malignancy. Adv Cancer Res 2001; 83: 81–116.

    Article  CAS  PubMed  Google Scholar 

  4. Liu YJ, Arpin C . Germinal center development. Immunol Rev 1997; 156: 111–126.

    Article  CAS  PubMed  Google Scholar 

  5. Dunn-Walters DK, Isaacson PG, Spencer J . Analysis of mutations in immunoglobulin heavy chain variable region genes of microdissected marginal zone (MGZ) B cells suggests that the MGZ of human spleen is a reservoir of memory B cells. J Exp Med 1995; 182: 559–566.

    Article  CAS  PubMed  Google Scholar 

  6. Tierens A, Delabie J, Michiels L, Vandenberghe P, De Wolf-Peeters C . Marginal-zone B cells in the human lymph node and spleen show somatic hypermutations and display clonal expansion. Blood 1999; 93: 226–234.

    CAS  PubMed  Google Scholar 

  7. Cattoretti G, Buttner M, Shaknovich R, Kremmer E, Alobeid B, Niedobitek G . Nuclear and cytoplasmic AID in extrafollicular and germinal center B cells. Blood 2006; 107: 3967–3975.

    Article  CAS  PubMed  Google Scholar 

  8. Willenbrock K, Jungnickel B, Hansmann ML, Kuppers R . Human splenic marginal zone B cells lack expression of activation-induced cytidine deaminase. Eur J Immunol 2005; 35: 3002–3007.

    Article  CAS  PubMed  Google Scholar 

  9. Walsh SH, Rosenquist R . Immunoglobulin gene analysis of mature B-cell malignancies: reconsideration of cellular origin and potential antigen involvement in pathogenesis. Med Oncol 2005; 22: 327–341.

    Article  CAS  PubMed  Google Scholar 

  10. Agematsu K, Hokibara S, Nagumo H, Komiyama A . CD27: a memory B-cell marker. Immunol Today 2000; 21: 204–206.

    Article  CAS  PubMed  Google Scholar 

  11. Klein U, Rajewsky K, Kuppers R . 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 1998; 188: 1679–1689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Weller S, Braun MC, Tan BK, Rosenwald C, Cordier C, Conley ME et al. Human blood IgM ‘memory’ B cells are circulating splenic marginal zone B cells harboring a prediversified immunoglobulin repertoire. Blood 2004; 104: 3647–3654.

    Article  CAS  PubMed  Google Scholar 

  13. Aurrand-Lions M, Duncan L, Ballestrem C, Imhof BA . JAM-2, a novel immunoglobulin superfamily molecule, expressed by endothelial and lymphatic cells. J Biol Chem 2001; 276: 2733–2741.

    Article  CAS  PubMed  Google Scholar 

  14. Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 679–691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Arrate MP, Rodriguez JM, Tran TM, Brock TA, Cunningham SA . Cloning of human junctional adhesion molecule 3 (JAM3) and its identification as the JAM2 counter-receptor. J Biol Chem 2001; 276: 45826–45832.

    Article  CAS  PubMed  Google Scholar 

  16. Lamagna C, Hodivala-Dilke KM, Imhof BA, Aurrand-Lions M . Antibody against junctional adhesion molecule-C inhibits angiogenesis and tumor growth. Cancer Res 2005; 65: 5703–5710.

    Article  CAS  PubMed  Google Scholar 

  17. Aurrand-Lions M, Lamagna C, Dangerfield JP, Wang S, Herrera P, Nourshargh S et al. Junctional adhesion molecule-C regulates the early influx of leukocytes into tissues during inflammation. J Immunol 2005; 174: 6406–6415.

    Article  CAS  PubMed  Google Scholar 

  18. Phan RT, Dalla-Favera R . The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature 2004; 432: 635–639.

    Article  CAS  PubMed  Google Scholar 

  19. Lamagna C, Meda P, Mandicourt G, Brown J, Gilbert RJ, Jones EY et al. Dual interaction of JAM-C with JAM-B and alpha(M)beta2 integrin: function in junctional complexes and leukocyte adhesion. Mol Biol Cell 2005; 16: 4992–5003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wall RT, Harker LA, Quadracci LJ, Striker GE . Factors influencing endothelial cell proliferation in vitro. J Cell Physiol 1978; 96: 203–213.

    Article  CAS  PubMed  Google Scholar 

  21. Johnson-Leger CA, Aurrand-Lions M, Beltraminelli N, Fasel N, Imhof BA . Junctional adhesion molecule-2 (JAM-2) promotes lymphocyte transendothelial migration. Blood 2002; 100: 2479–2486.

    Article  CAS  PubMed  Google Scholar 

  22. Legler DF, Wiedle G, Ross FP, Imhof BA . Superactivation of integrin alphavbeta3 by low antagonist concentrations. J Cell Sci 2001; 114: 1545–1553.

    CAS  PubMed  Google Scholar 

  23. Matthes T, Werner-Favre C, Zubler RH . Cytokine expression and regulation of human plasma cells: disappearance of interleukin-10 and persistence of transforming growth factor-beta 1. Eur J Immunol 1995; 25: 508–512.

    Article  CAS  PubMed  Google Scholar 

  24. Koppler B, Cohen C, Schlondorff D, Mack M . Differential mechanisms of microparticle transfer to B cells and monocytes: anti-inflammatory propertiesof microparticles. Eur J Immunol 2006; 36: 648–660.

    Article  PubMed  Google Scholar 

  25. Martinez-Valdez H, Guret C, de Bouteiller O, Fugier I, Banchereau J, Liu YJ . 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 1996; 183: 971–977.

    Article  CAS  PubMed  Google Scholar 

  26. Kremmidiotis G, Zola H . Changes in CD44 expression during B cell differentiation in the human tonsil. Cell Immunol 1995; 161: 147–157.

    Article  CAS  PubMed  Google Scholar 

  27. Hummel M, Tamaru J, Kalvelage B, Stein H . Mantle cell (previously centrocytic) lymphomas express VH genes with no or very little somatic mutations like the physiologic cells of the follicle mantle. Blood 1994; 84: 403–407.

    CAS  PubMed  Google Scholar 

  28. Chiorazzi N, Ferrarini M . B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor. Annu Rev Immunol 2003; 21: 841–894.

    Article  CAS  PubMed  Google Scholar 

  29. Klein U, Dalla-Favera R . New insights into the phenotype and cell derivation of B cell chronic lymphocytic leukemia. Curr Top Microbiol Immunol 2005; 294: 31–49.

    CAS  PubMed  Google Scholar 

  30. Palmeri D, van Zante A, Huang CC, Hemmerich S, Rosen SD . Vascular endothelial junction-associated molecule, a novel member of the immunoglobulin superfamily, is localized to intercellular boundaries of endothelial cells. J Biol Chem 2000; 275: 19139–19145.

    Article  CAS  PubMed  Google Scholar 

  31. Gliki G, Ebnet K, Aurrand-Lions M, Imhof BA, Adams RH . Spermatid differentiation requires the assembly of a cell polarity complex downstream of junctional adhesion molecule-C. Nature 2004; 431: 320–324.

    Article  CAS  PubMed  Google Scholar 

  32. Klein U, Tu Y, Stolovitzky GA, Mattioli M, Cattoretti G, Husson H et al. Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 2001; 194: 1625–1638.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rosenwald A, Alizadeh AA, Widhopf G, Simon R, Davis RE, Yu X et al. Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 2001; 194: 1639–1647.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tiacci E, Liso A, Piris M, Falini B . Evolving concepts in the pathogenesis of hairy-cell leukaemia. Nat Rev Cancer 2006; 6: 437–448.

    Article  CAS  PubMed  Google Scholar 

  35. Tierens A, Delabie J, Malecka A, Wang J, Gruszka-Westwood A, Catovsky D et al. Splenic marginal zone lymphoma with villous lymphocytes shows on-going immunoglobulin gene mutations. Am J Pathol 2003; 162: 681–689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Matutes E, Owusu-Ankomah K, Morilla R, Garcia Marco J, Houlihan A, Que T et al. The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL. Leukemia 1994; 8: 1640–1645.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are thankful to D Wohlwend (FACS facility, CMU, Geneva), M Donquier (Genomics platform, CMU, Geneva) and P Ropraz for their technical assistance; B Huard for supplying reagents; and P Bradfield for critical reading of this paper. This study was financially supported to TM by Swiss Cancer League No. OCS-01343-02-2003 and OCS-01781-08-2005; Foundation Dr Henri Dubois-Ferrière et Dinu Lipatti; and to BI by Swiss National Science Foundation No 3100.108099; Swiss Cancer league No. OCS-01335-02-2003.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to T Matthes.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ody, C., Jungblut-Ruault, S., Cossali, D. et al. Junctional adhesion molecule C (JAM-C) distinguishes CD27+ germinal center B lymphocytes from non-germinal center cells and constitutes a new diagnostic tool for B-cell malignancies. Leukemia 21, 1285–1293 (2007). https://doi.org/10.1038/sj.leu.2404689

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2404689

Keywords

Search

Quick links