The Journal of Experimental Medicine
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Published 16 August 2004. doi:10.1084/jem.20040544
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 4, 519-525
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Brief Definitive Report

 Multiple Distinct Sets of Stereotyped Antigen Receptors Indicate a Role for Antigen in Promoting Chronic Lymphocytic Leukemia

Bradley T. Messmer1, Emilia Albesiano1, Dimitar G. Efremov4, Fabio Ghiotto2,3,4, Steven L. Allen1,2, Jonathan Kolitz1,2, Robin Foa8, Rajendra N. Damle1,2, Franco Fais5, Davorka Messmer1, Kanti R. Rai1,9,10, Manlio Ferrarini6,7, and Nicholas Chiorazzi1,2

1 North Shore–LIJ Research Institute and 2 Department of Medicine, North Shore University Hospital and 3 Department of Medicine, NYU School of Medicine, Manhasset, NY 11030
4 ICGEB Outstation-Monterotondo, CNR Campus "Adriano Buzzati-Traverso," 00016 Rome, Italy
5 Dipartimento di Medicina Sperimentale, Sezione di Anatomia Umana, 6 Division of Medical Oncology C, Istituto Nazionale per la Ricerca sul Cancrom, and 7 Dipartmento di Oncologia Clinica e Sperimentale, Universitá di Genova, 16132 Genova, Italy
8 Ematologie Dipartmento di Biotecnologie Cellulari ed Ematologia, University "La Sapienza," 00161 Rome, Italy
9 Department of Medicine, Long Island Jewish Medical Center and 10 Department of Medicine, Albert Einstein School of Medicine, New Hyde Park, NY 11040

Address correspondence to Nicholas Chiorazzi, North Shore–LIJ Research Institute, 350 Community Dr., Manhasset, NY 11030. Phone: (516) 562-1001; Fax: (516) 562-1022; email: nchizzi{at}nshs.edu

Previous studies suggest that the diversity of the expressed variable (V) region repertoire of the immunoglobulin (Ig)H chain of B-CLL cells is restricted. Although limited examples of marked constraint in the primary structure of the H and L chain V regions exist, the possibility that this level of restriction is a general principle in this disease has not been accepted. This report describes five sets of patients, mostly with unmutated or minimally mutated IgV genes, with strikingly similar B cell antigen receptors (BCRs) arising from the use of common H and L chain V region gene segments that share CDR3 structural features such as length, amino acid composition, and unique amino acid residues at recombination junctions. Thus, a much more striking degree of structural restriction of the entire BCR and a much higher frequency of receptor sharing exists among patients than appreciated previously. The data imply that either a significant fraction of B-CLL cells was selected by a limited set of antigenic epitopes at some point in their development and/or that they derive from a distinct B cell subpopulation with limited Ig V region diversity. These shared, stereotyped Ig molecules may be valuable probes for antigen identification and important targets for cross-reactive idiotypic therapy.

Key Words: Ig variable region genes • human • B lymphocytes • antibodies • autoantibodies

B.T. Messmer and E. Albesiano contributed equally to this paper.


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