ΔBAFF, an Alternate Splice Isoform That Regulates Receptor Binding and Biopresentation of the B Cell Survival Cytokine, BAFF

Gavin, Amanda L.; Aït-Azzouzene, Djemel; Ware, Carl F.; Nemazee, David

doi:10.1074/jbc.m306852200

Cited by 102 publications

(76 citation statements)

References 48 publications

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“…TWE-PRIL might represent a membrane-bound form of APRIL [11]. In addition, a splice variant of BAFF (DBAFF) inhibits regular BAFF by forming inactive heteromers [12]. This strategy could be exploited to poison endogenous BAFF with exogenously added recombinant BAFF mutants [13], and could be used to intervene in autoimmune and other conditions in which BAFF is produced in excess.…”

Section: The Interactions Of Baff and April With Their Receptors And mentioning

confidence: 99%

The role of APRIL and BAFF in lymphocyte activation

Schneider

2005

Current Opinion in Immunology

301

249

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Section: The Interactions Of Baff and April With Their Receptors And mentioning

confidence: 99%

The role of APRIL and BAFF in lymphocyte activation

Schneider

2005

Current Opinion in Immunology

301

249

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“…These BAFF-producing cells may also be myeloid in origin, or may represent some other cell type. We have found ⌬BAFF expressed in all cellular sources in which BAFF itself is expressed, including normal macrophages and myeloid cell lines of mouse and human (18), and in human peripheral blood (our unpublished results).…”

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confidence: 99%

mentioning

confidence: 99%

“…In addition, ⌬BAFF, unlike BAFF, is not efficiently cleaved from cell membranes, and so may regulate the biodistribution of BAFF (18). Furthermore, ⌬BAFF can form homotrimers, at least when overexpressed in cell lines (18), leaving open the possibility that ⌬BAFF 3 may exist naturally and play additional roles. Finally, BAFF has been shown to form heterotrimers with the related cytokine APRIL (a proliferation-inducing ligand) in human cells (19), and an APRIL isoform analogous to ⌬BAFF has been described (20), raising the possibility that additional mixed heteromers may form with unknown functions.…”

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confidence: 99%

“…We have recently identified a natural pathway for the negative regulation of BAFF, which involves the coexpression of a receptor nonbinding splice isoform ⌬BAFF, the protein product of which can comultimerize with full-length BAFF poisoning function (18). In addition, ⌬BAFF, unlike BAFF, is not efficiently cleaved from cell membranes, and so may regulate the biodistribution of BAFF (18).…”

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confidence: 99%

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ΔBAFF, a Splice Isoform of BAFF, Opposes Full-Length BAFF Activity In Vivo in Transgenic Mouse Models

Gavin

Duong²,

Skog³

et al. 2005

The Journal of Immunology

Self Cite

102

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ΔBAFF is a novel splicing isoform of the regulator B cell-activating factor (BAFF, BLyS), a TNF family protein with powerful immunoregulatory effects. Overexpression of BAFF leads to excessive B cell accumulation, activation, autoantibodies, and lupus-like disease, whereas an absence of BAFF causes peripheral B cell immunodeficiency. Based on the ability of ΔBAFF to multimerize with full-length BAFF and to limit BAFF proteolytic shedding from the cell surface, we previously proposed a role for ΔBAFF in restraining the effects of BAFF and in regulating B lymphocyte homeostasis. To test these ideas we generated mice transgenic for ΔBAFF under the control of human CD68 regulatory elements, which target expression to myeloid and dendritic cells. We also generated in parallel BAFF transgenic mice using the same expression elements. Analysis of the transgenic mice revealed that ΔBAFF and BAFF had opposing effects on B cell survival and marginal zone B cell numbers. ΔBAFF transgenic mice had reduced B cell numbers and T cell-dependent Ab responses, but normal preimmune serum Ig levels. In contrast, BAFF transgenic mice had extraordinarily elevated Ig levels and increases in subsets of B cells. Unexpectedly, both BAFF and ΔBAFF appeared to modulate the numbers of B-1 phenotype B cells.

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B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

Hong

Reiff

Yang

et al. 2009

Arthritis & Rheumatism

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Objective. To assess the expression of B lymphocyte stimulator (BLyS) in patients with pediatric systemic lupus erythematosus (SLE) or juvenile idiopathic arthritis (JIA).Methods. Blood samples collected from patients with pediatric SLE (n ‫؍‬ 56) and patients with JIA (n ‫؍‬ 54) at the beginning and end of a 6-month interval were analyzed for plasma BLyS protein levels by enzymelinked immunosorbent assay and for blood leukocyte full-length BLyS and ⌬BLyS messenger RNA (mRNA) levels by quantitative real-time polymerase chain reaction (normalized to 18S expression). Healthy siblings (n ‫؍‬ 34) of these patients served as controls.Results. In pediatric SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels were each significantly elevated, and plasma BLyS protein levels, but not blood leukocyte BLyS mRNA levels, were correlated with disease activity. In contrast, plasma BLyS protein levels were normal in JIA despite blood leukocyte BLyS mRNA levels being elevated to degrees similar to those in pediatric SLE. Among JIA patients, neither BLyS parameter was correlated with disease activity. In both pediatric SLE and JIA, the BLyS expression profiles remained stable at 6 months.Conclusion. Our findings indicate that, as previously noted in adult SLE, plasma BLyS protein and blood leukocyte BLyS mRNA levels are elevated in pediatric SLE. The correlation of plasma BLyS protein levels with disease activity points to BLyS as a candidate therapeutic target in pediatric SLE. Contrary to previous observations in adults with rheumatoid arthritis, plasma BLyS protein levels are normal in JIA despite elevated blood leukocyte BLyS mRNA levels. The absence of correlation between either of the BLyS parameters and disease activity in JIA calls for circumspection prior to assigning BLyS as a candidate therapeutic target in this disorder.

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ΔBAFF, an Alternate Splice Isoform That Regulates Receptor Binding and Biopresentation of the B Cell Survival Cytokine, BAFF

Cited by 102 publications

References 48 publications

The role of APRIL and BAFF in lymphocyte activation

The role of APRIL and BAFF in lymphocyte activation

ΔBAFF, a Splice Isoform of BAFF, Opposes Full-Length BAFF Activity In Vivo in Transgenic Mouse Models

B lymphocyte stimulator expression in pediatric systemic lupus erythematosus and juvenile idiopathic arthritis patients

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