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PMID: 9348309 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells.

The Journal of experimental medicine ·Vol. 186 ·No. 9 ·1997-11-03 ·Pages 1513-22

Lang J, Arnold B, Hammerling G, Harris AW, Korsmeyer S, Russell D, Strasser A, Nemazee D

Abstract

The mechanisms that establish immune tolerance in immature and mature B cells appear to be distinct. Membrane-bound autoantigen is thought to induce developmental arrest and receptor editing in immature B cells, whereas mature B cells have shortened lifespans when exposed to the same stimulus. In this study, we used Emu-bcl-2-22 transgenic (Tg) mice to test the prediction that enforced expression of the Bcl-2 apoptotic inhibitor in B cells would rescue mature, but not immature, B cells from tolerance induction. To monitor tolerance to the natural membrane autoantigen H-2Kb, we bred 3-83mudelta (anti-Kk,b) Ig Tg mice to H-2(b) mice or to mice expressing transgene-driven Kb in the periphery. In 3-83mudelta/bcl-2 Tg mice, deletion of autoreactive B cells induced by peripheral Kb antigen expression in the liver (MT-Kb Tg) or epithelia (KerIV-Kb Tg), was partly or completely inhibited, respectively. Furthermore, Bcl-2 protected peritoneal B-2 B cells from deletion mediated by acute antigen exposure, but this protection could be overcome by higher antigen dose. In contrast to its ability to block peripheral self-tolerance, Bcl-2 overexpression failed to inhibit central tolerance induced by bone marrow antigen expression, but instead, enhanced the receptor editing process. These studies indicate that apoptosis plays distinct roles in central and peripheral B cell tolerance.

MeSH Terms
Animals Antibodies, Anti-Idiotypic/analysis B-Lymphocyte Subsets/classification,immunology,metabolism Cell Differentiation/immunology Cell Survival/immunology Clonal Deletion Dose-Response Relationship, Immunologic Epithelial Cells/immunology Gene Rearrangement, B-Lymphocyte, Light Chain H-2 Antigens/administration & dosage Hybridomas/transplantation Immunoglobulin M/analysis Immunoglobulin kappa-Chains/genetics Immunoglobulin lambda-Chains/genetics Injections, Intraperitoneal Leukocyte Common Antigens/analysis Liver/cytology,immunology Lymphocyte Count Lymphoid Tissue/cytology Mice Mice, Inbred A Mice, Inbred C3H Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Proto-Oncogene Proteins c-bcl-2/biosynthesis,physiology
Chemicals
Antibodies, Anti-Idiotypic H-2 Antigens H-2Kb protein, mouse Immunoglobulin M Immunoglobulin kappa-Chains Immunoglobulin lambda-Chains Proto-Oncogene Proteins c-bcl-2 Leukocyte Common Antigens
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Lang J
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, Colorado 80206, USA.
Arnold B
Hammerling G
Harris A W
Korsmeyer S
Russell D
Strasser A
Nemazee D
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Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.186.9.1513
Published
1997-11-03
Pages
1513-22
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2199120
Subset
IM
Grants
NIGMS NIH HHS · R01 GM 44809 · United States
NIAID NIH HHS · R01 AI 33608 · United States
NIAID NIH HHS · K04 AI 01161 · United States
NIAID NIH HHS · R01 AI033608 · United States
NIGMS NIH HHS · R01 GM044809 · United States
External Links
PubMed source DOI: 10.1084/jem.186.9.1513 PMC Full Text View journal details
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