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BAFF and Autoimmune Disease

BAFF and Autoimmune Disease. Samia Ragheb, Ph.D. Wayne State University Department of Neurology Department of Immunology & Microbiology. MG is a B-cell Mediated Disease.

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BAFF and Autoimmune Disease

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  1. BAFF and Autoimmune Disease Samia Ragheb, Ph.D. Wayne State University Department of Neurology Department of Immunology & Microbiology

  2. MG is a B-cell Mediated Disease 1. AChR-specific antibodies are present in the serum of 85% of all patients with generalized MG; these antibodies are responsible for the pathology of MG, leading to impaired neuromuscular transmission and subsequent muscle weakness 2. In vitro, lymphocyte cultures from MG patients produce AChR-specific antibodies 3. EAMG can be induced in lab animals; serum anti-AChR antibodies are present in these animals 4. EAMG can be passively transferred, via antibodies, from immune animals to naïve animals and from man to mouse

  3. Overexpression of CXCL13, CD23, and Bcl-2 in the Myasthenic Thymus CXCL13: promotes B-cell migration and homing of B-cells to lymphoid follicles CD23: promotes the survival and differentiation of germinal center B-cells through a mechanism that involves upregulation of Bcl-2 Bcl-2: pro-survival molecule that inhibits apoptosis

  4. BAFF = TNFSF13b Myeloid cells produce and secrete Baff (B-cell activating factor of the tumor necrosis factor superfamily) A membrane-bound form of Baff is also expressed on the surface of myeloid cells; these include monocytes, macrophages, and dendritic cells Baff transgenic animals exhibit hypergammaglobulinemia, lymphoproliferation, and B-cell hyperplasia; and they develop autoimmune disease In Baff deficient animals, there are defects in peripheral B-cell maturation, and there are decreased levels of circulating immunoglobulins

  5. Serum BAFF Levels

  6. Effect of Clinical Extent and Severity on BAFF Levels

  7. Effect of Presence or Absence of Serum Anti-AChR Antibody on BAFF Levels

  8. Receptors for BAFF • Baff-R deficient mice lack marginal zone and follicular B-cells • TACI deficient mice have an increased number of peripheral B-cells, they develop autoimmune disease, and they exhibit fatal lymphoproliferation The pro survival signals of Baff are mediated by the Baff-R, whereas the interaction of Baff with TACI delivers inhibitory signals

  9. Immunofluorescent Staining of Peripheral Blood Mononuclear Cells • CD3: mouse IgG1-FITC • CD20: mouse IgG2a-FITC • Baff-R: goat IgG anti human Baff-R + rabbit F(ab)’2 anti goat IgG-Cy5 • TACI: biotinylated goat IgG anti human TACI + streptavidin-Cy5

  10. Cell-Surface Expression of BAFF-R and TACI

  11. Thangarajh et al.: • MG thymus with hyperplasia: macrophages express Baff • Germinal center: B-cells express Baff-R • Plasma levels of Baff were not different • No differences in the percentages of BCMA, Baff-R, or TACI-positive B-cells • Li et al.: • Increased percentage of CD19+ Baff-R+ B-cells • Kim et al.: • Serum Baff levels are higher in MG patients

  12. Baff Monocyte Dendritic cell B-cell Myeloid Cells Produce and Secrete BAFF

  13. Immunofluorescent Staining of Peripheral Blood Monocytes • CD14: mouse IgM-FITC • Baff: mouse IgG1 anti human Baff + goat F(ab)’2 anti mouse IgG-PE

  14. BAFF Production by Adherent Monocytes

  15. BAFF Production by Adherent Monocytes

  16. BAFF Production by THP-1 Cells THP-1: human acute monocytic leukemia 1 year old male HLA: A2, A9, B5, DRw1, DRw2

  17. BAFF Production by THP-1 Cells

  18. Enrichment of Monocytes by Immunomagnetic Separation PBMC are treated with a mixture of mouse anti CD2, CD7, CD16, CD19, CD56, and CD235a followed by anti mouse IgG-coated magnetic beads

  19. BAFF Production by Monocytes

  20. Dendritic Cell Lineages Banchereau et al., 2000

  21. Differentiation of Monocytes Into Dendritic Cells

  22. Maturation of Dendritic Cells With sCD40L (CD154)

  23. Cytokine Production by Dendritic Cells sCD40L Immature DCMature DC 254.0 pg/ml IL-4 192.0 pg/ml 5.0 IL-10 5.4 0 IL-12 1.3 0 IL-17 0

  24. BAFF Production by Dendritic Cells

  25. Ueno et al., 2007

  26. Contributors Basic ScienceClinical Samia Ragheb, Ph.D. Robert Lisak, M.D. Felicitas Gonzales, B.S. Richard Lewis, M.D. Kirk Simon, B.S. Gregory Van Stavern, M.D. Yanfeng Li, M.S. Wayne State University School of Medicine Supported by the Muscular Dystrophy Association (MDA)

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