2. REAPPRAISAL OF BAFF IN AUTOIMMUNE CONDITIONS Pierre Youinou European University of Brittany, Brest, France
3. T NF-like WEAK inducer of apoptosis ( TWEAK ) A Pr oliferation I nducing L igand ( APRIL ) B -cell A ctivation F actor of the TNF F amily ( BAFF ) TUMOR NECROSIS FACTOR FAMILY
4.
5. SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
6. THE CELL SOURCES OF BAFF Monocytes Macrophages Astrocytes Synoviocytes Dendritic cells Activated T lymphocyte Epithelial cells Neutrophils
7. BR3 TACI BCMA HSPG BAFF SPECIFIC AND NON-SPECIFIC RECEPTORS APRIL BAFF BAFF APRIL APRIL Simone Forest 2010
8. A VARIETY OF MOLECULES Furin BAFF APRIL TWEAK-PRIL TWEAK Daridon, Youinou et al, Autoimmun Rev 2007
9. OVEREXPRESSION OF BAFF IN AUTOIMMUNE DISEASES Number of sera tested Proportion with increased level 94 192 126 52 57 2 Systemic lupus erythematosus patients Autoimmune disease controls Normal controls
10. BAFF IS NOT Stohl et al, Arthritis Rheum 2003 Day of observation Day of observation Persistently elevated serum BAFF Intermittently elevated serum BAFF CONSTANT
11.
12. Menbrane-bound Cell-free BAFF APRIL Glycosylated or not - + PNGaseF 28 21 Anti-BAFF Complexes Virus-like clusters Rochas, Youinou et al, Arthritis Rheum, 2009 Roschke et al, J Immunol, 2004 Le Pottier, Youinou et al, submitted Liu et al, Cell, 2002 BAFF ? Receptor for BAFF Alternative splices 28 17 TFMS - + Rabbit - + Goat BAFF IS NOT RECOGNIZED
16. BT1 BT2 High affinity BCR Low affinity BCR Lymphoid follicle germinal center Marginal zone Pre-B MARGINAL ZONE B CELLS AT RISK OF BEING ACTIVATED Apoptosis BAFF
17. MICE TRANSFECTED WITH cDNA FOR HUMAN BAFF Groom, Mackay et al, J Clin Invest 2002 1/1280
18. Walters et al, J Immunol, 2009 BAFF-INDUCED REGULATORY T CELLS WT BAFF-Tg CD4 + Foxp3 +
19. SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
20. DISCOVERY OF A NEW mRNA FOR BAFF 3’ RACE-PCR ? Exon 5 Exon 3 748 862 Δ 4 BAFF 1 2 4 3 5 6 BAFF Δ BAFF φ BAFF
21. Δ 4 (D->124) LOCATION OF THE NEW PROTEIN GFP Δ 4 RAMOS BAFF pIRES Δ 4 WT 21 kDa 17 kDa Mouse anti-BAFF Rabbit anti-BAFF BAFF Δ 4 BAFF