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SOMATIC HYPERMUTATION

SOMATIC HYPERMUTATION. VL. J2 gene product. V35 gene product. CDR1. CDR2. CDR3. C omplementary D etermining R egion = hypervariable region. STRUCTURE OF THE VARIABLE REGION. H y pervariable (HVR) or complimentarity determining regions (CDR). HVR3. 150. Variability Index. 100. HVR2.

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SOMATIC HYPERMUTATION

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  1. SOMATIC HYPERMUTATION

  2. VL J2 gene product V35 gene product CDR1 CDR2 CDR3 Complementary Determining Region = hypervariable region

  3. STRUCTURE OF THE VARIABLE REGION Hypervariable (HVR) or complimentarity determining regions (CDR) HVR3 150 Variability Index 100 HVR2 HVR1 50 FR2 FR1 FR4 FR3 0 25 75 100 50 Amino acid residue • Framework regions (FR)

  4. Szomatikus hipermutáció FR1 CDR1 FR2 CDR2 FR3 CDR3 FR4 Variabilitás 100 80 60 40 20 20 40 60 80 100 120 Aminsavszám A különböző specificitású ellenanyagokban található pont mutációk összehasonlítása Wu - Kabat analízissel Mik a következményei az immunválasz során végbemenő mutációknak egy adott epitóp ellen irányuló ellenanyagban? Hogyan befolyásolja az ellenanyag specificitását és affinitását?

  5. Light chain LIGHT CHAIN Disulphide bridges FR1 FR2 FR3 FR4 CDR1 CDR2 CDR3 Heavy chain VLCL FR1 FR2 FR3 FR4 CDR1 CDR2 CDR3

  6. SOMATIC HYPERMUTATION Day 0. Ag Plasma cell clones 1 2 3 4 5 6 7 8 Day 7 PRIMARY immune response AFFINITYMATURATION 9 1011 12 13 14 15 16 Day 14 Day 14. Ag 17 1819 20 21 22 23 24 Day 21 SECONDARY Immune response Hypervariable regions

  7. Day 6 Day 12 Day 8 Day 18 Clone 1 Clone 2 Clone 3 Clone 4 Clone 5 Clone 6 Clone 7 Clone 8 Clone 9 Clone 10 Deleterious mutation CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 CDR1 CDR2 CDR3 Beneficial mutation Neutral mutation Somatic hypermutation leads to affinity maturation Lower affinity - Not clonally selected Higher affinity - Clonally selected Identical affinity - No influence on clonal selection Hypermutation occurs under the influence of activated T cells Mutations are focussed on ‘hot spots’ (i.e. the CDRs) and are due to double stranded breaks repaired by an error prone DNA repair enzyme.

  8. CDR1 and CDR2 regions are encoded by the V-gene The CDR3 of L-chain is encoded by V and J The CDR3 of H-cain is encoded by V, D and J genes

  9. Hypervariable loops and framework: Summary • The framework supports the hypervariable loops • The framework forms a compact b barrel/sandwich with a hydrophobic core • The hypervariable loops join, and are more flexible than, the b strands • The sequences of the hypervariable loops are highly variable amongst antibodies of different specificities • The variable sequences of the hypervariable loops influences the shape, hydrophobicity and charge at the tip of the antibody • Variable amino acid sequence in the hypervariable loops accounts for the diversity of antigens that can be recognised by a repertoire of antibodies

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

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

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

  13. Germinal Center Reaction

  14. T CELL DEPENDENT B CELL ACTIVATION IN LYMPHOID ORGANS IgM IgG IgA IgE

  15. „Dating” in the peripheral lymphoid organs

  16. Antigen-stimulated B cellsbecometrappedintheT-cellzone

  17. The primary foci and secondaryfollicleformation

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

  19. 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 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 B cells recognize Ag on the surface of FDC

  20. Ig domain + CHO a b ITAM ITAM Y Y Y Y SIGNALING UNITS OF THE B-CELL RECEPTOR Ig-a/CD79a Ig-b/CD79b ITAM: YxxLx7YxxI ITAM: Immunoreceptor Tyrosine-based Activation Motif

  21. Main steps of B-cell signal transduction

  22. CONSEQUENCES OF B-CELL RECEPTOR CROSS LINKING Ag binding, cross-linking of surface Ig Lymphocyte activation Phenotypic/ Functional change

  23. KINETICS OF LYMPHOCYTE ACTIVATION Nyugvó limfocita G0 Resting lymphocyte G0 Ko-receptor Adhesion molecule Cytokines SIGNAL2. Effector cellMemory cell Transport Membrane change RNA and protein synthesis sejtosztódás DNA synthesis Lymphoblast PTK activation RNA synthesis Free Ca++ Protein synthesis Protein phosphorylation DNA synthesis Resting lymphocyte G0 0 10sec 1min 5min 1hr 6 hrs 12 hrs 24 hrs ANTIGEN SIGNAL1.

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

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

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

  27. FEATURES OF THE BINDING SITE SIZE SHAPE HYDROPHOBIC HYDROPHYLIC POSITIVELY CHARGED NEGATIVELY CHARGED ANTIGEN BINDING IS MEDIATED BY NON-COVALENT INTERACTIONS One binding site is able to interact with more than one antigen The strength of interaction (affinity/avidity) varies in a broad range

  28. Growth factors MHC – peptid - TCR Adhesion molecules ANTIBODIES Affinity

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