1. B – CELL ACTIVATION Where and how do all these things take place?

3. B-cell recycling in the absence of antigen (lymph node) B cells in blood Efferens lymph T cell area B cell area

4. Antigen enters node in afferent lymphatic Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y B cells leave blood & enter lymph node via high endothelial venules B cells proliferate rapidly GERMINAL CENTRE Transient structure of Intense proliferation Germinal centre releases B cells that differentiate into plasma cells Recirculating B cells are trapped by foreign antigens in lymphoid organs

5. „Dating” in the peripheral lymphoid organs

6. The structure of the germinal centre Somatic hypermutation FDC Somatic hypermutation DZ LZ LZ: light zone DZ: dark zone FDC: follicular dendritic cell

7. Antigen is bound on the surface of follicular dendritic cells (FDC) FDC  FDC-s bind immune complexes ( Ag-Ab )  Ag detectable for 12 months following immunization  A single cell binds various antigens B cells recognize Ag on the surface of FDC Fig. 9.15. On the surface of FDC-s immune complexes form the so-called iccosomes,that can be released and taken up later by the surrounding germinal center B cells

8. Ligand SIGNAL Cross - linking Ligand Conformational change SIGNAL RECEPTOR MEDIATED CELL ACTIVATION

9. ligand kinase activation phosphorylation recruitment of adaptors CROSS – LINKING OF THE RECEPTOR INITIATES A SIGNALING CASCADESIGNAL Gene transcription Activation of transcription factors

10. a a antigen binding mIg molecule HH LL V V V V   Ig-  /Ig-  heterodimer THE IgM B-CELL RECEPTOR Signal transduction Lyn Kinases Syk Btk SHP-1 Phosphatases SLP-65/BLNK PLC HS1 Vav Adaptors + substrates

11. Ig-  /CD79a Ig-  /CD79b ITAM: Immunoreceptor Tyrosine-based Activation Motif   Y Y Y Y ITAM ITAM Ig domain + CHO SIGNALING UNITS OF THE B-CELL RECEPTOR ITAM: YxxL x7 YxxI

12. Ag RECENT MODEL OF B-CELL RECEPTOR MEDIATED SIGNALING Subsequent activation of 2 kinases = ITAM 1. Cross-linking Lyn 2. Src-family kinase activation 4. SLP phosphorylation + Ca release SLP P Calcium release P P P P and ITAM phosphorylation 3. Syk recruitment and activation Syk Syk PP

13. Main steps of B-cell signal transduction

14. Activation of B-cells by receptor crosslinking

15. Antigenic determinant C3d THE CO-STIMULATORY ROLE OF CR2 (CD21) COMPLEMENT RECEPTOR IN B – LYMPHOCYTES ANTIGÉN CD21/CR2 CD19 YYYY TAPA=CD81 Enhanced B-cell activation B-CELL

16. THE NEURAMIC ACID RECEPTOR CD22 INHIBITS ACTIVATION THROUGH THE A B-CELL RECEPTOR B Cell Antigen Tissue cells Bacterium Mannose CD22 Neuraminic acid Inhibited B cell activation

17. KINETICS OF LYMPHOCYTE ACTIVATION ANTIGEN SIGNAL1. Ko-receptor Adhesion molecule Cytokines SIGNAL2. Resting lymphocyte G 0 PTK activation RNA synthesis Free Ca++ Protein synthesis Protein phosphorylation DNA synthesis Lymphoblast 0 10sec 1min 5min 1hr 6 hrs 12 hrs 24 hrs Nyugvó limfocita G 0 sejtosztódás DNA synthesis Effector cell Memory cell Transport Membrane change RNA and protein synthesis Resting lymphocyte G 0

18. EFFECTOR FUNCTIONS OF ANTIBODIES PLASMA CELL NEUTRALIZATION Small proportion of antibodies INHIBITION Binding of bacteria to epithelial cells Binding of viruses to receptor Binding of bacterial toxins to target cells OPSONIZATION Binding of antibody increases phagocytosis Fc  R Fc  R CR1 Complement C3b COMPLEMENT ACTIVATION Opsonization by C3b PHAGOCYTES ENGULFMENT, DEGRADATION

19. 30 strongly neutralising McAb 60 strongly neutralising McAb Fab regions 60 weakly neutralising McAb Fab regions Human Rhinovirus 14 - a common cold virus 30nm Models of Human Rhinovirus 14 neutralised by monoclonal antibodies

20. Electron micrographs of Antibodies and complement opsonising Epstein Barr Virus (EBV) Negatively stained EBV EBV coated with a corona of anti-EBV antibodies EBV coated with antibodies and activated complement components

21. PLASMA CELL ANTIGEN CYTOKINES B -CELL T – CELLS PROMOTE B – CELL DIFFERENTIATION ISOTYPE SWITCH AND AFFINITY MATURATION OCCURS IN COLLABORATION WITH T – CELLS ONLY HOW T – CELLS RECOGNIZE ANTIGENS?