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

Abstract

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.

Aging murine B cells have decreased class switch induced by anti-CD40 or BAFF

“…BAFF-or BAFF-R-deficient mice have similar phenotypes, characterized by hypogammaglobulinemia and a severe loss of follicular B cells (Gavin et al, 2005) and mount poor, especially the secondary, TD antibody responses. This may be due to the reduced survival of splenic B cells in these mice.…”

New ELISA for B Cell–Activating Factor

“…The most tenable explanation is that none of the assays provides sensitive and specific means of measurements, as suggested by the observation that disease activity correlates with the number of transcripts for BAFF in blood cells from SLE patients, but not with the protein concentration (15 ). It is also possible that the lack of increase in BAFF concentrations in the serum of some SLE patients, notwithstanding the activity of their disease, reflects the diminished release of the cytokine by an increased proportion of ⌬3BAFF (36 ).…”

Replacing mouse BAFF with human BAFF does not improve B-cell maturation in hematopoietic humanized mice

“…Moreover, Figure 4A) within CD20 1 (-PB) cells (x-axis) relative to the percentage of supraphysiological levels of serum BAFF as achieved in BAFFTg mice, lead to higher numbers of mature B cells, [43][44][45] indicating that B-cell numbers are regulated by BAFF levels. Whether this is also true in humans is difficult to verify because the consumption of BAFF by B cells leads to an inverse correlation between BAFF levels and B-cell numbers.…”