BAFF, Linfocitos B y Autoinmunidad <ul><li>Pierre Youinou, MD, Dr.Sc. </li></ul><ul><li>Jefe, Servicio del Laboratorio de ...
REAPPRAISAL OF BAFF IN AUTOIMMUNE CONDITIONS Pierre Youinou European University of Brittany, Brest, France
T NF-like   WEAK   inducer of apoptosis   ( TWEAK ) A   Pr oliferation   I nducing   L igand ( APRIL ) B -cell   A ctivati...
 
SETTING  THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
THE CELL SOURCES OF BAFF Monocytes Macrophages Astrocytes Synoviocytes Dendritic cells Activated T lymphocyte Epithelial c...
BR3 TACI BCMA HSPG BAFF SPECIFIC AND NON-SPECIFIC RECEPTORS APRIL BAFF BAFF APRIL APRIL Simone Forest 2010
A VARIETY OF MOLECULES Furin BAFF APRIL TWEAK-PRIL TWEAK Daridon, Youinou et al, Autoimmun Rev 2007
OVEREXPRESSION OF BAFF IN AUTOIMMUNE DISEASES Number of sera tested Proportion with increased level 94 192 126 52 57 2 Sys...
BAFF IS NOT Stohl et al, Arthritis Rheum 2003 Day of observation Day of observation Persistently elevated serum BAFF Inter...
BAFF IS NOT <ul><li>Inserted   into B-cell receptors ( Carter et al, Arthritis Rheum 2005 ) </li></ul><ul><li>Included   w...
Menbrane-bound Cell-free BAFF APRIL Glycosylated or not - + PNGaseF 28 21 Anti-BAFF Complexes Virus-like clusters Rochas, ...
IN-HOUSE ELISA FOR BAFF Le Pottier, Youinou et al, Clin Chem 2009 28 21 S#1 S#2 Rabbit Ab S#1 S#2 Mouse Ab 28 21 Absorbanc...
SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
BAFF-MEDIATED B-CELL HOMEOSTASIS PROLIFERATION BAFF Tg TNF-/- BAFF Tg DIFFERENTIATION CD40-dependent CD40 +IL-4 BAFF CD40-...
BT1 BT2 High affinity BCR Low affinity BCR Lymphoid follicle germinal center Marginal zone Pre-B MARGINAL ZONE B CELLS AT ...
MICE TRANSFECTED WITH cDNA FOR HUMAN BAFF Groom, Mackay et al, J Clin Invest 2002 1/1280
Walters et al, J Immunol, 2009 BAFF-INDUCED REGULATORY T CELLS WT BAFF-Tg CD4 +  Foxp3 +
SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
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
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 BA...
Cold probe (20x) Mouse  anti-BAFF Nuclear extract - - - - + - - + - - - + - + - + Rabbit  Anti-BAFF - - + + Supershift Shi...
TRUNCATED BAFF  TRANSPORTS TRANSCRIPTION FACTOR(S) FOR  FULL-LENGTH BAFF INTO THE NUCLEUS Le Pottier, Tob ón, Mackay,  You...
mRNA for  Δ 4 BAFF Δ 4 BAFF protein product Full-length BAFF Transcription factor
SUMMARY <ul><li>The BAFF family members display an ever-growing complexity. </li></ul><ul><li>Excess BAFF causes the aberr...
 
Upcoming SlideShare
Loading in...5
×

BAFF, Linfocitos B y Autoinmunidad

813

Published on

0 Comments
0 Likes
Statistics
Notes
  • Be the first to comment

  • Be the first to like this

No Downloads
Views
Total Views
813
On Slideshare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
0
Comments
0
Likes
0
Embeds 0
No embeds

No notes for slide
  • BAFF_Colombie mars 2011
  • BAFF_Colombie mars 2011
  • BAFF_Colombie mars 2011
  • BAFF_Colombie mars 2011
  • BAFF, Linfocitos B y Autoinmunidad

    1. 1. BAFF, Linfocitos B y Autoinmunidad <ul><li>Pierre Youinou, MD, Dr.Sc. </li></ul><ul><li>Jefe, Servicio del Laboratorio de Inmunología, Centro Hospitalario y Universitario de Brest, Miembro de la oficina del Consejo Científico y Pedagógico de la Escuela Doctoral “Ciencias la Salud, Información, Comunicaciones, Matemáticas y Materia”, Universidad de Bretaña Occidental, Escuela Nacional Superior de Telecomunicaciones y Universidad de Bretaña Meridional; Miembro del Consejo Científico de la Fundación Martine Midy, Brest, Francia </li></ul>
    2. 2. REAPPRAISAL OF BAFF IN AUTOIMMUNE CONDITIONS Pierre Youinou European University of Brittany, Brest, France
    3. 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
    5. 6. THE CELL SOURCES OF BAFF Monocytes Macrophages Astrocytes Synoviocytes Dendritic cells Activated T lymphocyte Epithelial cells Neutrophils
    6. 7. BR3 TACI BCMA HSPG BAFF SPECIFIC AND NON-SPECIFIC RECEPTORS APRIL BAFF BAFF APRIL APRIL Simone Forest 2010
    7. 8. A VARIETY OF MOLECULES Furin BAFF APRIL TWEAK-PRIL TWEAK Daridon, Youinou et al, Autoimmun Rev 2007
    8. 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
    9. 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
    10. 11. BAFF IS NOT <ul><li>Inserted into B-cell receptors ( Carter et al, Arthritis Rheum 2005 ) </li></ul><ul><li>Included within immune-complexes ( Collins et al, Arthritis Res Ther 2006 ) </li></ul><ul><li>Excreted in the urine of patients with nephrotic syndrome ( Cheemer et al, Arthritis Rheum 2001 ) </li></ul>ACCESSIBLE
    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
    12. 13. IN-HOUSE ELISA FOR BAFF Le Pottier, Youinou et al, Clin Chem 2009 28 21 S#1 S#2 Rabbit Ab S#1 S#2 Mouse Ab 28 21 Absorbance (492nm) 0 1 2 3 BAFF (  g/L) 0.1 1 10 100 Goat / Rabbit-biot Goat / Goat-biot Rabbit / Rabbit-biot Rabbit / Goat-biot
    13. 14. SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
    14. 15. BAFF-MEDIATED B-CELL HOMEOSTASIS PROLIFERATION BAFF Tg TNF-/- BAFF Tg DIFFERENTIATION CD40-dependent CD40 +IL-4 BAFF CD40-independent BAFF no BAFF yes SSC SURVIVAL ACTIVATION
    15. 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
    16. 17. MICE TRANSFECTED WITH cDNA FOR HUMAN BAFF Groom, Mackay et al, J Clin Invest 2002 1/1280
    17. 18. Walters et al, J Immunol, 2009 BAFF-INDUCED REGULATORY T CELLS WT BAFF-Tg CD4 + Foxp3 +
    18. 19. SETTING THE SCENE FOR BAFF KNOWN ACTIVITIES OF BAFF REGULATION OF BAFF PRODUCTION
    19. 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
    20. 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
    21. 22. Cold probe (20x) Mouse anti-BAFF Nuclear extract - - - - + - - + - - - + - + - + Rabbit Anti-BAFF - - + + Supershift Shift Δ 4BAFF IS A TRANSCRIPTION FACTOR
    22. 23. TRUNCATED BAFF TRANSPORTS TRANSCRIPTION FACTOR(S) FOR FULL-LENGTH BAFF INTO THE NUCLEUS Le Pottier, Tob ón, Mackay, Youinou and Pers , submitted Rabbit Mouse -1600 ATG CD40 NF- κ B subunits Negative control Positive control  actin Mouse Plas Δ 4 wt Mouse/ β -actin 0.85 0.90 1.24 0.86 Rabbit Rabbit/ β -actin 0.83 0.90 1.57 0.70 1 1
    23. 24. mRNA for Δ 4 BAFF Δ 4 BAFF protein product Full-length BAFF Transcription factor
    24. 25. SUMMARY <ul><li>The BAFF family members display an ever-growing complexity. </li></ul><ul><li>Excess BAFF causes the aberrant survival of autoreactive B cells. </li></ul><ul><li>New insights into the regulation of BAFF synthesis are currently being provided. This approach should open new therapeutic avenues. </li></ul>

    ×