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Blood, 1 October 2003, Vol. 102, No. 7, pp. 2698-2699
CORRESPONDENCE
To the editor:
Expression of Fc receptors type II (FcRII) in chronic lymphocytic leukemia B cells
We have read with interest the paper from Damle et al1 analyzing the surface membrane phenotype of B lymphocytes in chronic lymphocytic leukemia (B-CLL). The authors stated that the leukemic cells from all B-CLL patients evaluated (irrespective of immunoglobulin heavy chain (IgVH) gene mutational status) bear the phenotype of antigen-experienced B cells based, among other features, on the very low expression of Fc receptors type IIb (FcRIIb, CD32), which is the main isoform of FcRII in B lymphocytes.2 We would like to comment on this issue on the basis of our own results, which differ from those of Damle et al.
We analyzed membrane expression of FcRII by flow cytometry in leukemic cells from 52 B-CLL patients who were classified by Rai stage system as indolent (0-I), intermediate (II), or aggressive (III-IV) disease. We have used 3 different monoclonal antibodies (mAbs): clones AT10 and 2E1, which recognize all isoforms of FcRII; and clone IV.3, which recognizes FcRIIa when used as Fab fragment but is capable of reacting with FcRIIb when used as a whole molecule.3 IV.3 Fab was tested because, to our knowledge, it is the only mAb capable of discriminating between FcRII isoforms by fluorescence-activated cell sorter analysis; in fact, mAb II8D2 used by Damle et al has been shown to react with both isoforms.4 By using IV.3 Fab, we found that FcRIIa is expressed only marginally in B-CLL cells from some patients (data not shown). On the other hand, more than 95% of leukemic cells, in all samples analyzed, were stained with mAbs AT10, 2E1, or IV.3 (whole molecule), which can be attributed to the presence of FcRIIb. Moreover, we found that B-CLL cells displayed comparable or even higher levels of FcRII expression than B lymphocytes from healthy volunteers (Figure 1). No significant differences in FcRII expression were observed between CD5+ and CD5- B lymphocytes from control donors (not shown). Discrepancy between Damle et al's findings and ours could not be attributed to antigen loss due to cryopreservation, as we obtained comparable results with fresh and thawed B-CLL cells.
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Figure 1.. Expression of FcRII in B cells from B-CLL patients and healthy donors. (A) CD19+ lymphocytes from peripheral blood were stained with anti-FcRII (clone AT.10, purified mouse IgG1; generous gift from Dr M. Daeron, Institut Curie, Paris, France) and anti-mouse IgG fluorescein isothiocyanate (FITC), F(ab')2 fragments (Coulter-Immunotech, Marseille, France). Results are expressed as the mean fluorescence intensity (MFI) of FcRII expression in CD19+ cells for each sample analyzed. MFI of control isotype ranged between 8 and 10 in all cases. (B) Representative histograms of FcRII expression (white histograms) assessed by direct immunofluorescence analysis with anti-FcRII (clone IV.3-FITC [whole molecule], Medarex, Annandale, NJ, or clone 2E1-PE, Coulter-Immunotech). Gray histograms indicate control isotype.
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In conclusion, our findings show that B-CLL cells from patients in early or advanced stage disease express comparable or even higher levels of FcRII than normal peripheral B lymphocytes, suggesting that FcRII expression is not a useful parameter to define antigen experience of B-CLL cells. However, given that FcRII is far from being just a cell marker, we believe that the receptors' role in B-CLL deserves further analysis. The main isoform expressed by B cells, FcRIIb, functions as an inhibitory receptor.2,5 Its coaggregation with B-cell receptors (BCRs) dampens B-cell activation by recruitment of a limited number of Src homology 2 domain (SH2)-containing phosphatases, predominantly SHIP (SH2-containing inositol phosphatase), which causes a dramatic and immediate hydrolysis of PIP3 (phosphatidylinositol 3,4,5-trisphosphate).5 FcRIIb and SHIP are able to inhibit not only BCR-mediated signals but also signals induced by other cell surface receptors that require PIP3 generation.6 On the other hand, FcRIIb can also signal independently of BCR colligation to directly mediate an apoptotic response.7 Whether or not this receptor is functional in B-CLL cells remains to be solved.
Romina Gamberale,
Jorge R. Geffner,
Julieta Sanjurjo,
Paula X. Fernandez-Calotti,
Guillermo Arrosagaray,
Julio Sanchez Avalos, and
Mirta Giordano
Correspondence: Mirta Giordano, Inmunología Oncológica, Academia Nacional de Medicina, Pacheco de Melo 3081, Buenos Aires, 1425 Argentina; e-mail: mirtagiordano{at}imaginaria.com.ar
References
- Damle RN, Ghiotto F, Valetto A, et al. B-cell chronic lymphocytic leukemia cells express a surface membrane phenotype of activated, antigen-experienced B lymphocytes. Blood. 2002;99: 4087-4093.[Abstract/Free Full Text]
- Ravetch JV, Bolland S. IgG Fc receptors. Annu Rev Immunol. 2001;19: 275-290.[CrossRef][Medline]
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- Maresco DL, Osborne JM, Cooney D, Coggeshall KM, Anderson CL. The SH2-containing 5'-inositol phosphatase (SHIP) is tyrosine phosphorylated after Fc receptor clustering in monocytes. J Immunol. 1999;162: 6458-6465.[Abstract/Free Full Text]
- Budde P, Weinrich V, Sondermann P, et al. Specificity of CD32 mAb for FcRIIa, FcRIIb1, and FcRIIb2 expressed in transfected mouse B cells and BHK-21 cells. In: Schlossman SF, Boumsell L, Gilks W, Harlan JM, Kishimoto T, eds. Leucocyte Typing V: White Cell Differentiation Antigens. New York, NY: Oxford University Press; 1995: 828.
- Coggeshall KM. Positive and negative signaling in B lymphocytes. Curr Top Microbiol Immunol. 2000;245: 213-260.[Medline]
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- Brauweiler AM, Cambier JC. FcgammaRIIB activation leads to inhibition of signalling by independently ligated receptors. Biochem Soc Trans. 2003;31(pt 1): 281-285.[Medline]
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- Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV. SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. Immunity. 1999;10: 753-760.[CrossRef][Medline]
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