Abstract
Interaction of a B cell expressing self-specific B-cell antigen receptor (BCR) with an auto-antigen results in either clonal deletion or functional inactivation. Both of these processes lead to B-cell tolerance and are essential for the prevention of auto-immune diseases. Whereas clonal deletion results in the death of developing autoreactive B cells, functional inactivation of self-reactive B lymphocytes leads to complex changes in the phenotype of peripheral B cells, described collectively as anergy. Here we demonstrate that deficiency in protein kinase Cdelta (PKC-delta) prevents B-cell tolerance, and allows maturation and terminal differentiation of self-reactive B cells in the presence of the tolerizing antigen. The importance of PKC-delta in B-cell tolerance is further underscored by the appearance of autoreactive anti-DNA and anti-nuclear antibodies in the serum of PKC-delta-deficient mice. As deficiency of PKC-delta does not affect BCR-mediated B-cell activation in vitro and in vivo, our data suggest a selective and essential role of PKC-delta in tolerogenic, but not immunogenic, B-cell responses.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibodies, Antinuclear / blood
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Antibodies, Antinuclear / immunology
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Antigens, CD / metabolism
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Autoantigens / immunology*
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B-Lymphocytes / cytology
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B-Lymphocytes / immunology*
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B7-2 Antigen
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Calcium / metabolism
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Calcium Signaling
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Cell Differentiation
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Clonal Anergy / immunology
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Enzyme-Linked Immunosorbent Assay
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Flow Cytometry
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Gene Deletion
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Immune Tolerance / immunology*
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Isoenzymes / deficiency
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Isoenzymes / genetics
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Isoenzymes / immunology
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Isoenzymes / metabolism*
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JNK Mitogen-Activated Protein Kinases
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Lymph Nodes / cytology
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Lymph Nodes / immunology
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Lymphocyte Activation
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinases / metabolism
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Protein Kinase C / deficiency
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Protein Kinase C / genetics
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Protein Kinase C / immunology
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Protein Kinase C / metabolism*
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Protein Kinase C-delta
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Signal Transduction
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Spleen / cytology
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Spleen / immunology
Substances
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Antibodies, Antinuclear
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Antigens, CD
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Autoantigens
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B7-2 Antigen
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Cd86 protein, mouse
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Isoenzymes
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Membrane Glycoproteins
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Prkcd protein, mouse
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Protein Kinase C
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Protein Kinase C-delta
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JNK Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinases
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Calcium