1. ACQUIRED IMMUNITY RECOGNITION

2. ORGANIZATION OF IMMUNE CELLS UNDER EPITHELIAL SURFACES DC Epithelial cells PERIPHERAL LYMPHOID TISSUES PERIPHERAL TISSUES Stroma cells CELL – TO – CELL COMMUNICATION NETWORKS Granulocyte Macrophage NK cell NKT cell Macrophage activation Cellular killing Neutrofil granulocyte B Ag-specific B-cell Eosinophil granulocyte Th17 Th2 Treg CTL Th1

3. SENSINGRECOGNITION SIGNAL TRANSDUCTION RESPONSE INNATE IMMUNITY ACQUIRED IMMUNITY SENSINGRECOGNITION SIGNAL TRANSDUCTION RESPONSE CellsReceptors Signaling pathways Cell-to-cell collaboration Effector mechanisms DEFENCE SYSTEMS

4. Lamprey Fishes 450 millon years ADAPTIVE (ACQUIRED) IMMUNITY Antigen recognizing receptors B cell Helper T cell Cytotoxic T cell LYMPHOCYTES

5. WHAT IS RECOGNIZED BY INNATE AND ACQUIRED IMMUNITY? HOW DO THEY RECOGNIZE PATHOGENS? Common pattern of groups of pathogens Pathogen Associated Molecular Pattern PAMP Recognition by receptors Pattern Recognition Receptor PRR 9-13 various Toll-receptors TLR family Several millions antigen receptors Unique structural elements Antigenic determinant Recognition by highly specific antigen receptors B cell receptor BCR (sIg) T cell receptor TCR RECEPTORS Innate immunity Ancient 450 million years Acquired immunity

6. CELLS HUMORAL FACTORS Phagocytes (monocyte/macrophage, neutrophil, dendritic cell) Killer cells (NK cell,  δ T cell) B1 lymphocytes (CD5+) B lymphocytes (B2) T lymphocytes helper T cell cytotoxic T cell Enzymes (lysozyme,transferrin, lactoferrin, spermin, trypsin) Antibacterial peptides Complement system Cytokines, chemokines Antibodies Produced by B-cell derived plasma cells WHAT CELL TYPES MEDIATE ACQUIRED IMMUNITY INNATE/NATURAL IMMUNITY ACQUIRED/ADAPTIVE IMMUNITY

7. ADAPTIV IMMUNITY IS TRANSFERABLE Antibodies, antibody specificity, diversity Antibodies were discovered in the late 1800s (Emil Behting, Shibasaburo Kitasato) SERUM THERAPY antibodies specific to toxins Discovery of blood group antigens (Landsteiner) QUESTION: How can so many different pathogens and other structures be recognized by antibodies? What drives and How the production of antibodies? Ehrlich Paul Niels JerneMacferlene Burnet

8. Macfarlane Burnet (1956 - 1960) Macfarlane Burnet (1956 - 1960) CLONAL SELECTION THEORY Antibodies are natural products that appear on the cell surface as receptors and selectively react with the antigen Lymphocyte receptors are variable and carry various antigen-recognizing receptors ‘Non-self’ antigens/pathogens encounter the existing lymphocyte pool (repertoire) Antigens select their matching receptors from the available lymphocyte pool, induce clonal proliferation of specific clones and these clones differentiate to antibody secreting plasma cells The clonally distributed antigen-recognizing receptors represent about ~10 7 – 10 9 distinct antigenic specificities

9. Cc. (minimum) 10 million various (10 7 ) B lymphocyte clones with different antigen-recognizing receptors Cc. (minimum) 10 – 1000 million various (10 7 - 9 ) T lymphocyte clones with different antigen-recognizing receptors DIVERSITY OF LYMPHOCYTES Assumption 1 All lymphocytes have a different receptor Assumption 2 The receptor can be activated by many different antigens 10 12 lymphocytes in our body ( B and T lymphocytes) How many SPECIFICITIES ?

10. ACTIVATION Clonal expansion Differentiation Plasma cell Antibody (immunoglobulin Ig) secretion MEMORY B CELLS BINDING OF ANTIGEN TO THE SELECTED B-LYMPHOCYTES RESULTS IN CLONAL EXPANSION B cell B Cell Receptor (BCR) Ag

11. Clonal selection induces proliferation and increases effector cell frequency No. of cell divisions No. of cells with useful specificity Threshold of protective effector function

12. POSSIBLE FATES OF B-LIMPHOCYTE CLONES Activation Clonal expansion/proliferation Differentiation Plasma cell Antibody production Memory cell Circulation Restricted life span Homeostasis Apoptosis Transient, not final differentiation state

13. Antibody THE B-CELL RECEPTOR AND ANTIBODIES PRODUCED BY PLASMA CELLS HAVE THE SAME PROTEIN STRUCTURE = IMMUNOGLOBULIN Antigen recognizing receptor BCR Immunoglobulin (Ig) B CELL

14. a a HH LL HH LL Secreted Ig Antigen-specific soluble protein EFFECTOR MOLECULE TWO FORMS OF IMMUNOGLOBULINS Membrane-bound Ig Antigen-specificreceptor  signalling B CELL PLASMA CELL Antigen binding

15. Bacteria are not well informed how to display Ag determinants for proper binding by host-antibodies host-antibodies need to be flexible

16. FV= VH+ VL VHVHVHVH VLVLVLVL IMMUNOGLOBULIN IgG Antigen binding site

17. Days Antibody  g/ml serum Antigen A A antigén Response to antigen A Cell interactions CENTRAL Effector/execution Regulation EFFECTOR Primary response Recognition Activation AFFERENT Lag Secondary response MEMORY Antigen A TIME COURSE OF THE ADAPTIVE IMMUNE RESPONSE Antigen B Primary Response to antigen B

18. NATURAL/INNATE Rapid, prompt response (hours) No variable receptors Limited number of specificities No improvement during the response No memory Not transferable Can be exhausted, saturated CHARACTERISTICS OF INNATE AND ACQUIRED IMMUNITY ADAPTIVE/ACQUIRED Time consuming Variable antigen receptors Many very selective specificities Efficacy is improving during the response Memory Can be transferred Regulated, limited Protects self tissues COMMON EFFECTOR MECHANISMS FOR THE ELIMINATION OF PATHOGENS