Induction of B cell apoptosis by co-cross-linking CD23 and sIg involves aberrant regulation of c-myc and is inhibited by bcl-2.
A novel system to study the effects of co-cross-linking CD23/FceRII and sIg on murine B lymphocytes utilizes a highly multivalent form of anti-Ig prepared by covalently linking anti-Ig antibodies to a DNP-dextran backbone. CD23-sIg co-cross-linking is accomplished by the addition of DNP-specific monoclonal IgE. Previous studies demonstrated that co-cross-linking CD23 and sIg significantly inhibited mouse B cell proliferation, especially at high doses of the multivalent anti-Ig. Interestingly, examination of early activation signals reveals no difference in B cells subjected to co-cross-linking conditions as compared to B cells activated with anti-Ig alone. Total cellular protein tyrosine phosphorylation levels are unchanged by co-cross-linking. Analysis of B cell mRNA reveals that co-cross-linking the receptors does not alter the expression levels of ornithine decarboxylase 8 h after stimulation as compared to the controls. In contrast, levels of the proto-oncogene c-myc were significantly elevated 1 h after inducing B cell activation under co-cross-linking conditions. However, it remains unclear whether this aberrant c-myc regulation plays any role in inducing apoptosis. In addition, on day 3 after stimulation, the co-cross-linking of CD23 and sIg resulted in the formation of apoptotic B cells, determined by both photomicroscopy of the B cell cultures and FACS analysis of B cell nuclei. B cells obtained from bcl-2 transgenic mice proliferated as well as controls, and failed to undergo apoptosis when CD23 and sIg were co-cross-linked on their surface. These studies indicate that co-cross-linking of CD23 with B cell sIg inhibits B cell proliferation by a mechanism that is distinct from that seen by co-cross-linking of the Fc gamma RII and sIg. In addition, these results suggest a means by which antigen-specific IgE can down-regulate additional B cell activation and IgE synthesis.
Campbell
K A
KA
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond 23298, USA.
Studer
E J
EJ
Kilmon
M A
MA
Lees
A
A
Finkelman
F
F
Conrad
D H
DH
D000818:Animals; D017209:Apoptosis / Q000276:immunology / Q000502:physiology*; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D018122:B7-1 Antigen / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation; D019254:Genes, bcl-2 / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D006023:Glycoproteins / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010940:Plant Proteins / Q000276:immunology / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D017455:Receptors, IgE / Q000276:immunology / Q000378:metabolism*; D019076:Transgenes
D018122:B7-1 Antigen; D006023:Glycoproteins; D010940:Plant Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D017455:Receptors, IgE; C064156:self-incompatibility locus specific glycoprotein, Brassica