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The Extracellular Membrane-Proximal Domain of Human Membrane IgE Controls Apoptotic Signaling of the B Cell Receptor in the Mature B Cell Line A20

International Centre for Genetic Engineering and Biotechnology, Trieste, Italy

Ag engagement of BCR in mature B cells can deliver specific signals, which decide cell survival or cell death. Circulating membrane IgE⁺ (mIgE⁺) cells are found in extremely low numbers. We hypothesized that engagement of an BCR in a mature isotype-switched B cell could induce apoptosis. We studied the role of the extracellular membrane-proximal domain (EMPD) of human mIgE upon BCR engagement with anti-Id Abs. Using mutants lacking the EMPD, we show that this domain is involved in controlling Ca²⁺ mobilization in immunoreceptors of both and isotypes, as well as apoptosis in signaling originated only from the BCR. We mapped to the CH4 ectodomain the region responsible for apoptosis in EMPD-deleted receptors. Ca²⁺ mobilization was not related to apoptotic signaling. This apoptotic pathway was caspase independent, involved ERK1/2 phosphorylation and was partially rescued by CD40 costimulation. We therefore conclude that the EMPD of human mIgE is a key control element of apoptotic signaling delivered through engagement of BCR within the context of a mature B cell.

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¹ Address correspondence and reprint requests to Dr. Oscar R. Burrone, International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34012 Trieste, Italy. E-mail address: burrone{at}icgeb.org

² Abbreviations used in this paper: mIg, membrane Ig; m, transmembrane potential; CytoD, cytoplasmic domain; _L, -long isoform; EMPD, extracellular membrane-proximal domain; _Sh, -short isoform; mSIP, membrane small immunoprotein; PARP, poly(ADP-ribose) polymerase; PI, propidium iodide; SIP, small immune protein; TMD, transmembrane domain; wt, wild type; z-VAD-fmk, N-benxyloxycarbonyl-Val-Ala-Asp(Ome)-fluoromethylketone.

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