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Molecular Medicine

, Volume 14, Issue 11–12, pp 665–674 | Cite as

Chronic Lymphocytic Leukemia Cells Recognize Conserved Epitopes Associated with Apoptosis and Oxidation

  • Rosa Catera
  • Gregg J. Silverman
  • Katerina Hatzi
  • Till Seiler
  • Sebastien Didier
  • Lu Zhang
  • Maxime Hervé
  • Eric Meffre
  • David G. Oscier
  • Helen Vlassara
  • R. Hal Scofield
  • Yifang Chen
  • Steven L. Allen
  • Jonathan Kolitz
  • Kanti R. Rai
  • Charles C. Chu
  • Nicholas Chiorazzi
Research Article

Abstract

Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5+ B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.

Notes

Acknowledgments

We appreciate the statistical help of Peter A Clement, Bull Information Systems, Chelmsford, Massachusetts, United States of America. Studies were funded in part by CA87956 (National Cancer Institute) and RR018535 (National Center for Research Resources). The Karches Foundation, Peter Jay Sharp Foundation, Prince Foundation, Marks Foundation, Jean Walton Fund for Lymphoma and Myeloma Research, and Joseph Eletto Leukemia Research Fund also provided support.

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Copyright information

© Feinstein Institute for Medical Research 2008

Authors and Affiliations

  • Rosa Catera
    • 1
  • Gregg J. Silverman
    • 2
  • Katerina Hatzi
    • 1
  • Till Seiler
    • 1
  • Sebastien Didier
    • 1
  • Lu Zhang
    • 1
  • Maxime Hervé
    • 3
  • Eric Meffre
    • 3
  • David G. Oscier
    • 4
  • Helen Vlassara
    • 5
  • R. Hal Scofield
    • 6
  • Yifang Chen
    • 2
  • Steven L. Allen
    • 1
    • 7
  • Jonathan Kolitz
    • 1
  • Kanti R. Rai
    • 1
    • 8
  • Charles C. Chu
    • 1
    • 9
  • Nicholas Chiorazzi
    • 1
    • 7
  1. 1.Feinstein Institute for Medical ResearchNorth Shore-LIJ Health SystemManhassetUSA
  2. 2.Rheumatic Diseases Core Center and Laboratory of B-Cell ImmunobiologyUniversity of CaliforniaSan DiegoUSA
  3. 3.Laboratory of Biochemistry and Molecular ImmunologyHospital for Special SurgeryNew YorkUSA
  4. 4.Molecular Biology and CytogeneticsRoyal Bournemouth HospitalBournemouthUK
  5. 5.Division of Diabetes and Aging Research, Brookdale Department of GeriatricsMount Sinai School of MedicineNew YorkUSA
  6. 6.Oklahoma Medical Research FoundationOklahoma CityUSA
  7. 7.Departments of MedicineNorth Shore University Hospital and Albert Einstein College of MedicineManhassetUSA
  8. 8.Departments of MedicineLong Island Jewish Medical Center and Albert Einstein College of MedicineNew Hyde ParkUSA
  9. 9.Departments of MedicineNorth Shore University Hospital and NYU School of MedicineManhassetUSA

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