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Chronic Lymphocytic Leukemia Cells Bind and Present the Erythrocyte Protein Band 3: Possible Role as Initiators of Autoimmune Hemolytic Anemia¹

Jeremías Galletti^*, Cristian Cañones^*, Pablo Morande^*, Mercedes Borge^*, Pablo Oppezzo, Jorge Geffner^*, Raimundo Bezares, Romina Gamberale^* and Mirta Giordano^2,*

^* Department of Immunology, Institute for Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina; Protein Production Unit, Institut Pasteur, Montevideo, Uruguay; and Hospital Dr. T. Alvarez, Buenos Aires, Argentina

The mechanisms underlying the frequent association between chronic lymphocytic leukemia (CLL) and autoimmune hemolytic anemia are currently unclear. The erythrocyte protein band 3 (B3) is one of the most frequently targeted Ags in autoimmune hemolytic anemia. In this study, we show that CLL cells specifically recognize B3 through a still unidentified receptor. B3 interaction with CLL cells involves the recognition of its N-terminal domain and leads to its internalization. Interestingly, when binding of erythrocyte-derived vesicles as found physiologically in blood was assessed, we observed that CLL cells could only interact with inside-out vesicles, being this interaction strongly dependent on the recognition of the N-terminal portion of B3. We then examined T cell responses to B3 using circulating CLL cells as APCs. Resting B3-pulsed CLL cells were unable to induce T cell proliferation. However, when deficient costimulation was overcome by CD40 engagement, B3-pulsed CLL cells were capable of activating CD4⁺ T cells in a HLA-DR-dependent fashion. Therefore, our work shows that CLL cells can specifically bind, capture, and present B3 to T cells when in an activated state, an ability that could allow the neoplastic clone to trigger the autoaggressive process against erythrocytes.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from CONICET, Agencia Nacional de Promoción, Científica y Tecnológica (FONCyT) and Fundación Alberto J. Roemmers.

J. Galletti performed research, analyzed data, and wrote the paper; C. Cañones performed research and analyzed data; P. Morande performed research; M. Borge performed research; P. Oppezzo contributed vital analytical tools, J. Geffner reviewed the manuscript; R. Bezares provided patients and reviewed the manuscript; R. Gamberale analyzed data and reviewed the manuscript; and M. Giordano designed the research and wrote the paper.

² Address correspondence and reprint requests to Dr. Mirta Giordano, Department of Immunology, Institute for Hematologic Research, National Academy of Medicine, Buenos Aires, Argentina. E-mail address: mgiordano{at}hematologia.anm.edu.ar

³ Abbreviations used in this paper: CLL, chronic lymphocytic leukemia; AHA, autoimmune hemolytic anemia; B3, band 3; RSOV, right-side out vesicle; IOV, inside-out vesicle; sIg, surface Ig; MFI, mean fluorescence intensity.