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5th SEMINAR

5th SEMINAR. THE ADAPTIVE IMMUNE RESPONSE: LYMPHOID ORGANS GENERATION OF MATURE NAIVE LYMPHOCYTES LYMPHOCYTE RECIRCULATION. RECOGNITION BY CELLS OF THE ADAPTIVE IMMUNE SYSTEM. Antigen-specific receptors: B cell receptor (BCR) and T cell receptor (TCR)

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5th SEMINAR

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  1. 5th SEMINAR THE ADAPTIVE IMMUNE RESPONSE: LYMPHOID ORGANS GENERATION OF MATURE NAIVE LYMPHOCYTES LYMPHOCYTE RECIRCULATION

  2. RECOGNITION BY CELLS OF THE ADAPTIVE IMMUNE SYSTEM Antigen-specific receptors: B cell receptor (BCR) and T cell receptor (TCR) • The basic structure (90%) of the receptors (BCR or TCR) is common • Each cell expresses a receptor that is unique in specificity (the 10% difference means different specificity) • These differences in antigen-specificity are achieved during maturation in the CENTRAL LYMPHOID ORGANS (bone marrow and thymus)

  3. PRIMARY (CENTRAL) LYMPHOID ORGANS Places of the maturation (antigen-independent development) of lymphocytes: • bone marrow: generation of lymphoid progenitors, maturation of B cells • thymus: maturation of T cells (and NK cells)

  4. GENERATION OF LYMPHOCYTES

  5. THE BONE MARROW • flat bones (sternum, ribs, scapulae, hip bone) • epiphysis of long bones Stem cells Stromal cells Osteoblasts Osteoclasts BONE Immature T cells (thymocytes) on their way to the thymus (20x106/day) Dendritic cells Progenitors Precursors Mature B cells (3x106/day) Central sinus Blood circulation

  6. Secreted factors - CYTOKINES B Cell-cell contact Stromal cell BONE MARROW STROMAL CELLS NURTURE DEVELOPING B CELLS Specific cell-cell contacts between stromal cells and developing B cells Secretion of cytokines by stromal cells Types of cytokines and cell-cell contacts needed at each stage of differentiation are different (see next figure)

  7. GENERATION OF INDIVIDUAL ANTIGEN-SPECIFIC RECEPTOR (BCR)

  8. Limphoid progenitors B B B B RAG-1/RAG-2 Pre-BCR L rearrangement H rearrangement  selectionclonal deletion STEPS OF B CELL DEVELOPMENT IN THE BONE MARROW c-kit/CD44 • rearrangement of the immunoglobulin heavy chain (somatic gene recombination – V-D-J genes) • production of heavy chains, expression of preBCR (μ chain + surrogate light chain) • allelic exclusion of heavy chain genes, IL-7-dependent proliferation of functional heavy chain expressing pre B cells • rearrangement of the immunoglobulin light chain (somatic recombination – V-J genes) • expression of functional BCRs, proliferation • negative selection: clonal deletion (by apoptosis or anergy) of self-reactive B cells • mature, selected B cells leave the bone marrow via the medullary sinuses Pro-B RAG-1/RAG-2 Pre-B immature B mature B

  9. STRUCTURE OF THE THYMUS Capsule Septum Blood circulation Epithelial cells Thymocytes Dendritic cell Macrophage Hassall’s corpuscle Mature naive T- lymphocytes

  10. STRUCTURE OF THE THYMUS

  11. INVOLUTION OF THYMUS The functional amount of the thymus tissue is decreasing by age, leading to less and less newly produced mature T cells.

  12. DEVELOPMENT OF T CELLS IN THE THYMUS • proliferation of lymphoid progenitors after their arrival to the thymus • rearrangement of the beta chain (somatic gene recombination – V-D-J genes)/or gamma and delta chains  γδ T cells/ • production of beta chains, expression of preTCR (β chain + preTα) • allelic exclusion of beta chain genes, IL-7-dependent proliferation of functional beta chain expressing pre T cells • rearrangement of the alpha chain (somatic recombination – V-J genes)/still some will become γδ T cells/ • expression of functional TCRs • positive selection: clonal ignorance for those cells which do not recognize self-MHC molecules • negative selection: clonal deletion (by AICD) of self-reactive B cells • mature, selected T cells leave the thymus via blood vessels

  13. T CELL DEVELOPMENT limphoid progenitors NK B B B B RAG-1/RAG-2 L rearrangement Pre-BCR H rearrangement  rearrangement  rearrangement Pre-T  negativeselection clonal deletion positive selection negative selection T T T mature T (B- CELL DEVELOPMENT) circulation THYMUS c-kit/CD44 Pro-T Pro-B Pre-T RAG-1/RAG-2 Pre-B T immature T immature B mature B

  14. AFTER LEAVING THE CENTRAL LIMPHOID ORGANS MATURE NAIVE LYMPHOCYTES TRAVEL TO THE SITES OF ACTIVATION: THE SECONDARY LYMPHOID ORGANS/TISSUES

  15. SECONDARY LYMPHOID ORGANS/TISSUES Sites of lymphocyteactivation and terminaldifferentiation • LYMPH NODES • SPLEEN • TONSILS (Waldeyer’s ring) • Diffuse lymphoid layers under the epithelial barriers: • SALT (skin-associated lymphoid tissue) • MALT (mucosa-associated lymphoid tissue) • BALT (bronchus-associated lymphoid tissue) • GALT (gut-associated lymphoid tissue)

  16. LYMPH NODES

  17. STRUCTURE OF LYMPH NODES

  18. THE SPLEEN • No connection to lymphatic vessels • Filtrates blood-borne antigens • Red pulp is the ‚cemetery’ of RBCs • White pulp is similar to lymph nodes

  19. WALDEYER’S RING Most pathogens are acquired through the naso-oral cavity, hence there are accumulations of mucosa-associatedlymphoid tissues (Can be referred to as NALT – nasal-associated lymphoid tissue, or organized MALT) Tonsilitis

  20. Kripta Dome area GALT Villi GC

  21. GALT • the intestines are full of symbiotic and pathogenic microbes • continuous antigen uptake from the lumen by M (microfold) cells and DCs • low dose antigen exposure enhances the fitness of the immune system • regulator mechanisms are very important

  22. THE LYMPHOCYTE RECIRCULATION • Mature naive lymphocytes leave the central lymphoid organs to travel to the sites of activation: the secondary lymphoid organs/tissues (SLO) • They enter the different SLOs randomly via the process called ‚HOMING’ • They either GET ACTIVATED after recognizing an antigen and differentiate to effector cells or they LEAVE VIA THE EFFERENT LYMPHATIC VESSELS • The lymph is collected by lymph nodes, the lymphocytes pass many of them, and in every node they may get activated • Eventually all the lymph is flowing into the THORACIC DUCT and get back to the circulation, so the lymphocytes can reach another SLO • They do their recirculation until they find an antigen or until the end of their lifespan

  23. HOMING • Similar to extravasation of neutrophil granulocytes during acute inflammation • The endothelial cells of HEVs (high endothelial venules) express mucin-like adressin type adhesion molecules • Mature naive lymphocytes express adhesion molecules (homing receptors) that can interact with the ones expressed by HEVs • T and B cells find their areasin the SLOs by chemotaxis

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