Systemic Lupus Erythematosus
Systemic Lupus Erythematosus
B lymphocyte stimulator (BLyS) protein is among the novel tumor necrosis factor (TNF) ligands and receptor superfamily members recently described. BLyS protein can promote B cell survival, expansion, and differentiation both in vitro and in vivo. Constitutive overexpression of BLyS protein can result in systemic lupus erythematosus (SLE)-like disease in mice, and circulating levels of BLyS protein are elevated in a subset of human SLE patients. Treatment of SLE mice with a BLyS protein antagonist ameliorates disease progression and enhances survival. By inference, BLyS protein may also play an important contributory role in pathogenesis and/or propagation of human SLE and becomes a legitimate candidate target for antagonist biologic agents.
BLyS protein is a 285-amino acid member of the TNF ligand superfamily. Other names for this protein include BAFF (B-cell-activating factor belonging to the TNF family), TALL-1 (TNF-and ApoL-related leukocyte-expressed ligand 1), THANK (a TNF homologue that activates apoptosis, NF-
B, and JNK), TNFSF20 (TNF superfamily member 20; subsequently renamed TNFSF13B), and zTNF4. Expression of BLyS protein is highly restricted to myeloid lineage cells, including monocytes, macrophages, and dendritic cells.
The cellular targets of BLyS protein are also highly restricted. There are three known receptors for BLyS protein: BCMA (B cell maturation antigen); TACI (transmembrane activator and calcium-modulator and cyclophilin ligand-interactor); and BAFFR (BAFF receptor; also called BR3 [BLyS receptor 3]). mRNA expression of each of these receptors is restricted to B cells and tissues that contain B cells, although activated T cells may express some TACI mRNA. In concordance with the mRNA results, BLyS protein binds strongly to B cells, weakly to T cells, and not at all to NK cells or to monocytes.
BLyS protein is expressed as a type-II transmembrane protein that is cleaved by a furin protease from the cell surface, resulting in release of a soluble 17-kDa protein. Under physiologic conditions, soluble BLyS protein circulates in trimeric form. Because of its unique three-dimensional conformation, soluble BLyS protein contains a "flap" region. One group determined that this flap region conferred on soluble rBLyS protein the ability, under appropriate in vitro conditions, to self-assemble into virus-like clusters of 60 monomers. Two other groups, however, failed to appreciate any self-assembly into virus-like clusters. Whether virus-like clusters of BLyS protein are actually formed in vivo under physiologic or pathologic conditions remains to be determined.
In any case, BLyS protein is an effective costimulator of B cell expansion and function. Soluble recombinant (r) BLyS protein costimulates in vitro B cell proliferation and immunoglobulin (Ig) production, and in vivo administration of rBLyS protein to mice induces B lymphocytosis and polyclonal hypergammaglobulinemia. These effects of BLyS protein on in vitro and in vivo B cell function are, at least in part, consequent to its inhibition of B cell apoptosis.
In contrast to its potent effects on B cells, soluble rBLyS protein has no discernible costimulatory effect on T cells. However, very high concentrations of immobilized rBLyS can augment proliferation of anti-CD3-activated T cells via a pathway that does not result in enhanced T cell survival. This in vitro observation is consistent with low levels of BLyS protein receptor (TACI) being expressed by activated T cells. Whether the localized high concentrations of BLyS protein necessary to costimulate T cells can actually be achieved in vivo remains uncertain.
B lymphocyte stimulator (BLyS) protein is among the novel tumor necrosis factor (TNF) ligands and receptor superfamily members recently described. BLyS protein can promote B cell survival, expansion, and differentiation both in vitro and in vivo. Constitutive overexpression of BLyS protein can result in systemic lupus erythematosus (SLE)-like disease in mice, and circulating levels of BLyS protein are elevated in a subset of human SLE patients. Treatment of SLE mice with a BLyS protein antagonist ameliorates disease progression and enhances survival. By inference, BLyS protein may also play an important contributory role in pathogenesis and/or propagation of human SLE and becomes a legitimate candidate target for antagonist biologic agents.
BLyS protein is a 285-amino acid member of the TNF ligand superfamily. Other names for this protein include BAFF (B-cell-activating factor belonging to the TNF family), TALL-1 (TNF-and ApoL-related leukocyte-expressed ligand 1), THANK (a TNF homologue that activates apoptosis, NF-
B, and JNK), TNFSF20 (TNF superfamily member 20; subsequently renamed TNFSF13B), and zTNF4. Expression of BLyS protein is highly restricted to myeloid lineage cells, including monocytes, macrophages, and dendritic cells.
The cellular targets of BLyS protein are also highly restricted. There are three known receptors for BLyS protein: BCMA (B cell maturation antigen); TACI (transmembrane activator and calcium-modulator and cyclophilin ligand-interactor); and BAFFR (BAFF receptor; also called BR3 [BLyS receptor 3]). mRNA expression of each of these receptors is restricted to B cells and tissues that contain B cells, although activated T cells may express some TACI mRNA. In concordance with the mRNA results, BLyS protein binds strongly to B cells, weakly to T cells, and not at all to NK cells or to monocytes.
BLyS protein is expressed as a type-II transmembrane protein that is cleaved by a furin protease from the cell surface, resulting in release of a soluble 17-kDa protein. Under physiologic conditions, soluble BLyS protein circulates in trimeric form. Because of its unique three-dimensional conformation, soluble BLyS protein contains a "flap" region. One group determined that this flap region conferred on soluble rBLyS protein the ability, under appropriate in vitro conditions, to self-assemble into virus-like clusters of 60 monomers. Two other groups, however, failed to appreciate any self-assembly into virus-like clusters. Whether virus-like clusters of BLyS protein are actually formed in vivo under physiologic or pathologic conditions remains to be determined.
In any case, BLyS protein is an effective costimulator of B cell expansion and function. Soluble recombinant (r) BLyS protein costimulates in vitro B cell proliferation and immunoglobulin (Ig) production, and in vivo administration of rBLyS protein to mice induces B lymphocytosis and polyclonal hypergammaglobulinemia. These effects of BLyS protein on in vitro and in vivo B cell function are, at least in part, consequent to its inhibition of B cell apoptosis.
In contrast to its potent effects on B cells, soluble rBLyS protein has no discernible costimulatory effect on T cells. However, very high concentrations of immobilized rBLyS can augment proliferation of anti-CD3-activated T cells via a pathway that does not result in enhanced T cell survival. This in vitro observation is consistent with low levels of BLyS protein receptor (TACI) being expressed by activated T cells. Whether the localized high concentrations of BLyS protein necessary to costimulate T cells can actually be achieved in vivo remains uncertain.
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