Abstract
Chronic lymphocytic leukemia (CLL) is associated with impaired immunoglobulin (Ig) class-switching from IgM to IgG and IgA, a defect that leads to recurrent infections. When activated in the presence of leukemic CLL B cells, T cells rapidly up-regulate CD30 through an OX40 ligand and interleukin 4 (IL-4)-dependent mechanism. These leukemia-induced CD30+ T cells inhibit CD40 ligand (CD40L)-mediated S mu-->S gamma and S mu-->S alpha class-switch DNA recombination (CSR) by engaging CD30 ligand (CD30L), a molecule that interferes with the assembly of the CD40-tumor necrosis factor receptor-associated factor (TRAF) complex in nonmalignant IgD+ B cells. In addition, engagement of T cell CD30 by CD30L on neoplastic CLL B cells down-regulates the CD3-induced expression of CD40L. These findings indicate that, in CLL, abnormal CD30-CD30L interaction impairs IgG and IgA production by interfering with the CD40-mediated differentiation of nonmalignant B cells.
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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B-Lymphocytes / immunology*
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Base Sequence
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CD28 Antigens / metabolism
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CD30 Ligand
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CD40 Antigens / metabolism
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CD8 Antigens / metabolism
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Cell Differentiation
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DNA Primers / genetics
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Down-Regulation
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Humans
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Immunoglobulin A / biosynthesis
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Immunoglobulin Class Switching* / genetics
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Immunoglobulin G / biosynthesis
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In Vitro Techniques
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Interleukin-4 / metabolism
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Ki-1 Antigen / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics
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Leukemia, Lymphocytic, Chronic, B-Cell / immunology*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Membrane Glycoproteins / metabolism
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OX40 Ligand
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Receptors, Tumor Necrosis Factor / metabolism
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Signal Transduction
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T-Lymphocyte Subsets / immunology*
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Up-Regulation
Substances
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CD28 Antigens
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CD30 Ligand
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CD40 Antigens
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CD8 Antigens
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DNA Primers
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Immunoglobulin A
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Immunoglobulin G
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Ki-1 Antigen
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Membrane Glycoproteins
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OX40 Ligand
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Receptors, Tumor Necrosis Factor
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TNFSF4 protein, human
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TNFSF8 protein, human
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Interleukin-4