deltaBAFF, a splice isoform of BAFF, opposes full-length BAFF activity in vivo in transgenic mouse models.
DeltaBAFF 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 DeltaBAFF to multimerize with full-length BAFF and to limit BAFF proteolytic shedding from the cell surface, we previously proposed a role for DeltaBAFF in restraining the effects of BAFF and in regulating B lymphocyte homeostasis. To test these ideas we generated mice transgenic for DeltaBAFF 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 DeltaBAFF and BAFF had opposing effects on B cell survival and marginal zone B cell numbers. DeltaBAFF 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 DeltaBAFF appeared to modulate the numbers of B-1 phenotype B cells.
Gavin
Amanda L
AL
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Duong
Bao
B
Skog
Patrick
P
Aït-Azzouzene
Djemel
D
Greaves
David R
DR
Scott
Martin L
ML
Nemazee
David
D
D017398:Alternative Splicing; D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D015214:Antigens, Differentiation, Myelomonocytic / Q000235:genetics; D053264:B-Cell Activating Factor; D016175:B-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D053264:B-Cell Activating Factor; D018076:DNA, Complementary; D007136:Immunoglobulins; D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse