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Apoptosis of Burkitt's lymphoma cells induced by specific interaction of
surface IgM with a self-antigen: implications for lymphomagenesis in
acquired immunodeficiency syndrome
S Roncella, G Cutrona, A Favre, M Ulivi, F Fais, A Signorini, CE Grossi, N Chiorazzi and M Ferrarini
Servizi di Immunologia Clinica e Patologia Clinica, Istituto Nazionale per
la Ricerca sul Cancro-IST, Genova, Italy.
In a previous study, we described a cell line (BRG-P) derived from a woman
with Burkitt's lymphoma (BL) and acquired immunodeficiency syndrome that
shared the same characteristic cytogenetic abnormalities as the patient's
malignant cells. This cell line contained subclones that displayed an
isotype switch from IgM to IgA1 and an accumulation of point mutations in
the Vh region genes. Because these two features suggested an antigen-driven
process, we began a search for the antigen responsible for the stimulation
of the malignant B cells. Specifically, we hypothesized that because the
patient's tumor had presented as a lymphomatous infiltration of the breast,
the malignant B cells were recruited to this site because of the reactivity
of their surface lg with breast tissue. A hybridoma (BRG-H) was obtained by
fusing BRG-M cells (an IgM producing subclone of the BRG-P cell) with an
appropriate cellular partner. The monoclonal antibody (BRG MoAb) produced
by this hybridoma reacted strongly with two of five breast cancer cell
lines and stained normal and malignant ductal epithelial cells on breast
tissue sections. The antigen recognized by the BRG MoAb consisted of a
single, minimally glycosylated polypeptide chain of 45 kD (p45). The BRG
MoAb failed to react with a panel of human cell lines from different
tissues, except for one cell line from a uterine cervical carcinoma. No
reactivity was detected for a panel of exogenous antigens from various
pathogens, including human immunodeficiency virus and self- antigens
frequently recognized by polyspecific antibodies. Experiments were
performed to investigate the functional consequences of the interaction of
surface IgM with its specific ligand. Coculture of BRG-M cells with p45+,
but not with p45-, breast cells caused apoptosis of BRG-M cells. The
specificity of the interaction was shown by the observation that apoptosis
was prevented by pretreatment of BRG-M cells with a monovalent F(ab')
fragment of rabbit IgG antibody to human mu chains. Moreover, only BRG-M
cells, but not other BL cells, underwent apoptosis after exposure to p45+
breast cells. The interaction between the CD40 molecule expressed by BRG-M
cells and its specific ligand (CD40L) prevented p45-induced cell apoptosis.
Because this interaction mimics that occurring in vivo between T and B
cells during immune responses, our data suggest that various events
contributed to the emergence of the BL, in this particular patient,
including antigenic stimulation possibly assisted by T-cell help.
Volume 88,
Issue 2,
pp. 599-608,
07/15/1996
Copyright © 1996 by The American Society of Hematology
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