Topic 2 Adaptive immune system part B.pdf

Foundations in Pharmacology PHRM2005 Dr. Ricky R Lareu Adaptive Immune System part B 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed.: Chapter 11 3 Clonal Expansion of Lymphocytes Ther...

Foundations in Pharmacology PHRM2005 Dr. Ricky R Lareu Adaptive Immune System part B 2 Information See Lecture Outline document for Key Concepts, Learning Outcome and Lecture Summary Reading and reference material: Mim’s Medical Microbiology 5th Ed.: Chapter 11 3 Clonal Expansion of Lymphocytes There are many millions of possible antigens The body therefore has a small population of lymphocytes that can recognise each type Upon activation, lymphocytes proliferate and produce many clones → Clonal Expansion, B cells, T helper & T cytotoxic cells Each clone has the original recognition sequence Effector cells – deal with pathogen Memory cells – rapid response in future Already primed to proliferate 4 Clonal Expansion of B cells B cells reside in lymph nodes, spleen and mucosa-associated lymphatic tissue (MALT) Activated when an antigen is presented to them or detect antigen with PRRs – response is more intense if antigen is on an antigen presenting cell (APC e.g. macrophage, dendritic cell) and involve a Th cell B cells undergoes clonal expansion and transform into plasma cells and secrete antibodies to one antigen type (~2000 molecules/sec for 4-5 days) (~173 million/day) Some become memory cells for that antigen – allows rapid response to subsequent infection with same antigen Antibodies secreted into body fluids, circulate and bind to extracellular pathogens that multiply in body fluids but rarely enter body cells 5 Clonal Expansion of B cells cont. 6 Immunological Memory Immunological Memory is achieved by: the presence of long-lasting antibodies very long-lived lymphocytes that arise during clonal selection of antigen-stimulated B cells and T cells (memory cells) Provides the basis for acquired immunity i.e. immunization Figure 11.8 Primary and secondary infection; MMM, p100 7 Immunological Memory cont. Primary response A slow rise in the antibody titre after an initial contact with an antigen, followed by a gradual decline with the recovery from an infection. Memory cells are formed and may remain for decades Secondary response Rapid proliferation of memory cells upon encountering the same antigen, results in a far greater antibody titre than during the primary → effective protection against same pathogen Response is faster, more intense resulting in early removal of pathogen, symptoms may not even develop 8 Secondary Response – Ab Class Switching Class switching, IgM → IgG (still to the same antigen) produces more specific antibodies and greater coverage e.g. IgA secreted into mucus 9 Activation and Clonal Expansion of T Cells A T cell is activated when it receives two signals First signal – Antigen recognition by a T-cell receptor (TCR) with CD4 or CD8 proteins T-cell receptors (TCRs): recognize and bind to specific foreign antigen fragments that are presented in antigen– MHC: Th, MHC-II; Tc, MHC-I CD4 or CD8 proteins: surface proteins on T cells, interact with the MHC antigens and help maintain the TCR–MHC coupling. Second signal – Co-stimulation by soluble factors (cytokines) or plasma membrane molecules For a particular antigen, need first activation of Th cell, which then confirms and activates Tc cell, which do the killing 10 Activation and Clonal Expansion of T Cells cont. 11 Activation and Clonal Expansion of T Cells cont. T Helper cells (CD4+) Th cells are necessary for activation of Tc cells → Clonal expansion Both must be activated by antigens from pathogen, but not necessarily to same antigen Remember that a pathogen will contain many antigens T Cytotoxic cells (CD8+) 12 Activated Cytotoxic T (Tc) Killing Mechanisms cont. Cytotoxic T (Tc) cells – Act as soldiers in cell mediated response Migration – Tc cells leave secondary lymphoid organs & tissues, migrate to site of infection, tumour formation, or transplanted tissues Tc cells recognize and attach to target cells. Attack – Cytotoxic T cells kill infected target/pathogen by: A. Tc activate intracellular killing mechanisms in other cells by the release of cytokines e.g. IFN activate macrophages to kill intracellular microbes 13 Activated Cytotoxic T (Tc) Killing Mechanisms cont. B. Direct cytotoxic activity killing infected cell and parasites Perforin – creates channels in the plasma membrane of a target cell, allows extracellular fluid flows into the target cell and cause cytolysis. Granulysin – Enters through the channels and destroys the microbes by creating holes in their plasma membranes C. Tc destroys vital tissue in the process of killing pathogen D. Tc can lyse infected cell, releasing live parasite into extracellular fluids Releasing Granzymes – protein-digesting enzymes that trigger apoptosis in infected cell E. Released parasites can be taken up by more effective immune cell and acted upon by extracellular responses e.g. antibodies, complement 14 Activated Cytotoxic T (Tc) Killing Mechanisms 15 Activated Cytotoxic T (Tc) Killing Mechanisms cont. 16 B Cell Activation – T-independent Antigens Activation of B cells to produce antibodies without Th cells These responses give rise to weaker activity: only low affinity IgM and no memory B cells detect LPS, bacterial DNA, capsule polysaccharides Type 1 T-independent antigens (polyclonal activators) B cells carry PRRs that enable them to activate without specific antigen but produce only their specific antibody Type 2 T-independent antigens Specialised macrophages present repeating antigen determinants on their membrane Cross-link specific Ig receptor Figure 11.10 MMM, p101 17 B Cell Activation – T Cell Dependent Most B cells will be activated by Th cells, producing a strong reaction with memory cells, produce IgG The Th cell will be activated by APC through recognition of MHC-II-Ag complex B cell will bind to pathogen with specific Ig receptor on cell surface, phagocytose pathogen, process antigens and present it with MHC-II Th cell will recognise MHC-II-Ag complex on B cell surface and activate B cell into clonal expansion The B cell will differentiate into many plasma cells producing antibodies to the antigen it recognised Memory cells will also be distributes in lymphoid tissue 18 B Cell Activation – T Cell Dependent cont. 19 Structure of Lymphoid System Provide generation (hematopoiesis), maturation, niches for residence and interaction with other immune cells and foreign/deleterious agents Primary lymphoid organs: Bone marrow and thymus Generation and maturation of immune cells Secondary lymphoid organs: spleen, lymph nodes, Peyer’s patches, MALT ▪ distributed throughout body, provide niches ▪ interaction between immune cells and their proliferation and products e.g. antibodies ▪ identification of microbes, inactivation, killing and removal The lymph system – network of vessels draining excess body fluid from organs back to heart, immune surveillance and highways for immune cells 20 Lymphocyte Responses in Lymphoid Organs 21 Lymphocyte Circulation Thymus An encapsulated, multi-lobed organ Located in chest cavity behind sternum Large at birth and diminishes with age Composed of cortex and medulla – containing various cells and structures for the maturation and selection of T cells Thymocytes from bone marrow enter thymus and leave as mature T cells (or immunocompetent) Only about 1% selected through positive and negative selection Those that are auto-reactive are deleted Mature CD4+ T-cells (Helper T) and CD8+ (Cytotoxic T) T-cells released into circulation 23 Lymph Nodes kidney-shaped structures, ~200, various sizes located at junction of lymph vessels Immune surveillance centres Site of immune cell interaction, activation and response amplification eg antigen presenting (dendritic cell), B and T cell Lymph from tissues enters through afferent vessels and exits through efferent vessel, filtering microbe and cancer cells from lymph Cortex – proliferating B cells & memory B cell with dendritic cells Paracortex – T cell area Medulla – Macrophages and plasma cell (secreting antibodies) 24 Spleen Spleen – largest lymphoid organ, located in upper left quadrant of abdomen ▪ Divided into red and white pulp ▪ Red pulp filters foreign material from blood and removes old or damaged RBCs, by macrophages; storage of platelets ▪ White pulp contains lymphocytes (B and T cells) clustered along splenic arteries White pulp Red pulp 25 Mucosal-associated Lymphoid Tissue (MALT) Mucous membranes lining digestive, respiratory and urogenital systems – combined surface area of ~400 m2 (~area of basketball court) Are the major sites of entry of most pathogens Defended by group of organised lymphoid tissue known as Mucosal-associated Lymphoid Tissue (MALT) Structurally, range from loose, barely organised clusters of lymphoid cells in the mucosa to organised structures such as the tonsils in the throat to Peyer’s patches in the gastrointestinal tract (GI) MALTs are un-encapsulated structures containing lymphocytes They contain lymphocytes, macrophages and dendritic cells which sample antigens in the mucosal 26 Mucosal-associated Lymphoid Tissue (MALT) cont. After activation in mucosa, immune cells migrate to mesenteric lymph nodes and amplify response Activated T cells and B cells enter blood circulation and disperse throughout mucosal surfaces of GI tract 27 Tolerance Immune cells develop non-reactivity or tolerance to the body’s own or self molecules Otherwise reactivity to self would result in autoimmune reactions, causing tissue and organ damage Mechanisms: Self-reactive T cells are deleted in the thymus Self-reactive B cells are deleted in the bone marrow Self-reactive Tc and B cells remain anergic (no second signal) Th cell suppressed by regulatory T cells (Tregs) ▪ Develop in the thymus ▪ Do not suppress initial self-reaction but control activity of Th cells ▪ Evidence: when this population is removed → autoimmune disease in mice Summary Once lymphocytes recognise their specific antigen, they undergo activation and clonal expansion. This requires recognition of antigen and confirmation by Th cells. Once activated, a population of B and T cells will become effector cells and another, smaller population will become memory cells. The secondary response to a pathogen is stronger and faster and is driven by immune memory cells. When activated, B cells become plasma cells to produce antibodies, Tc cells kill infected cells, and Th activate the immune response. B cell can undergo T-independent activation through their PRRs but no memory cells are produced. Lymphocytes populate secondary lymphoid organs which have niches that enable immune surveillance, activation and proliferation and effector activity e.g. killing, antibody production.