Early preplasma cells define a tolerance checkpoint for autoreactive B cells.
Ab-secreting plasma cells (PCs) are the effectors of humoral immunity. In this study, we describe regulation of autoreactive B cells specific for the ribonucleoprotein Smith (Sm) at an early pre-PC stage. These cells are defined by the expression of the PC marker CD138 and normal levels of CD19 and B220. They are present at a high frequency in normal mouse spleen and bone marrow, are Ag dependent, and are located predominantly along the T cell-B cell border and near bridging channels. Anti-Sm pre-PCs also occur at a high frequency in nonautoimmune mice and show additional phenotypic characteristics of PC differentiation. However, while some of these pre-PCs are Ab-secreting cells, those specific for Sm are not, indicating regulation. Consistent with this, anti-Sm pre-PCs have a higher turnover rate and higher frequency of cell death than those that do not bind Sm. Regulation of anti-Sm pre-PCs occurs upstream of the transcriptional repressor, B lymphocyte-induced maturation protein-1, expression. Regulation at this stage is overcome in autoimmune MRL/lpr mice and is accompanied by an altered B lymphocyte stimulator receptor profile. These data reveal a new B cell tolerance checkpoint that is overcome in autoimmunity.
Culton
Donna A
DA
Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA.
O'Conner
Brian P
BP
Conway
Kara L
KL
Diz
Ramiro
R
Rutan
Jennifer
J
Vilen
Barbara J
BJ
Clarke
Stephen H
SH
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001324:Autoantigens; D015551:Autoimmunity / Q000235:genetics; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D001483:Base Sequence; D002454:Cell Differentiation; D004247:DNA / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011509:Proteoglycans / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D053668:Syndecan-1; D053667:Syndecans; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D055517:snRNP Core Proteins
D001324:Autoantigens; C120197:BLyS receptor; D008562:Membrane Glycoproteins; C513258:Prdm1 protein, mouse; D011509:Proteoglycans; D018124:Receptors, Tumor Necrosis Factor; D012097:Repressor Proteins; D017411:Ribonucleoproteins, Small Nuclear; C508241:SDC1 protein, human; C508242:Sdc1 protein, mouse; D053668:Syndecan-1; D053667:Syndecans; D014157:Transcription Factors; D055517:snRNP Core Proteins; D004247:DNA; D000074462:Positive Regulatory Domain I-Binding Factor 1