Lecture 6 √ PDF

Lecture 6 √ Tuesday 15 October 2024 13:11 1. What is removal of potentially self-reactive immature lymphocytes by? Clonal deletion 2. What allows B cell survival and differentiation? Non self Ag activates B cell Allows survival and differentiation into plasma cell that pro...

Lecture 6 √ Tuesday 15 October 2024 13:11 1. What is removal of potentially self-reactive immature lymphocytes by? Clonal deletion 2. What allows B cell survival and differentiation? Non self Ag activates B cell Allows survival and differentiation into plasma cell that produced same antibody as the BCR. 3. What induces Clonal deletion Recognition of self Ag in bone marrow. Kills self reactive B cell 4. After surviving the bone marrow selection process, where do B cells move? Into the blood and lymphatics. 5. What are the antibody functions in the humoral response? Antibody secretion by plasma cells Neutralisation: antibody prevents bacterial adherence Opsonisation: antibody promotes phagocytosis Complement activation; antibody activates complement, which enhances opsonisation and lyses some bacteria. 6. What does antibody production/ memory cell development require? B cell activation. And several signals 7. How is signal 1 provided to a B cell? Naïve B cells express membrane Ig/BCR (IgM(+IgD)) And encounters non self Ag in secondary lymphoid tissues (same as T cell) Binding of Ag to BCR provides signal 1. 8. What activates intracellular kinases in signal 1? Cross-linking BCR. 9. How can signal 1 be increased/enhanced? If antigen has activated complement cascade Lots of C3b CR2 on B cell surface (CD21) CD2/CD19/CD81 forms the BCR co-receptor complex. Augments the signal. 10. If Ag that binds BCR is coated with C, what can it also bind? What does this give/ Can also bind CR2 on B cells To give an increased signal 1. 11. True or false? B cells receive signal 2 differently depending on the type of Ag they bind. True 12. What is thymus-independent Ag (TI) signal 2 provided by? Antigen itself Or Extensive cross-linking of BCR 13. What does thymus-independent (TI) Ag lead to? Antibody production (only IgM) with no requirement for T cell involvement First demonstrated in animals lacking T cells). 14. What is the role of TI-1 Ag? Binding to BCR Binds to other receptors on all B cells providing signal 2. - E.g. lipopolysaccharide from gram -ve bacteria binds TLR4 expressed by B cells (link with innate immunity). - In high concentrations these Ag act as polyclonal activators (mitogens) for B cells (e.g. will activate many B cells irrespective of their different BCR). 15. What signals lead to B cell activation proliferation and antibody secretion? Two signals 1 from BCR 2 from TLR 16. What do thymus-independent (TD) Ag contain? Repeated epitopes Often polysaccharides (same sugar repeated lots) Important in some bacterial infections (coated0 - Will therefore cross-link many BCR molecules on same B cell surface. 17. When do antibody responses to TI-2 Ag develop? Typically don’t develop until >5 yrs in humans 18. Which TI Ag takes longer to induce B cell activation? TI-2 Ag More Ag required. 19. What is the role of activated dendritic cells? Release a cytokine, BAFF that augments production of antibody against TI-2 antigens and induces class switching. 20. What do antibodies to TD Ag require the presence of? CD4+ T cells (i.e. are absent in the absence of a thymus) 21. Are antibody responses better to TD Ag or TI Ag? TD Ag They are classic acquired responses 22. What is the process of TD Ag production? *3 T cells activated by MHC/ peptide on APC BCR binds antigen —> signal 1 Then B cell internalises Ag, processes and presents Ag to CD4+ T cells —-> receives signal 2 via CD40/CD40-L interaction – Cytokines secreted by T cell (help B cell to class switch). – Hence all classes of antibodies can be produced to TD Ag. 23. What is needed for B cells to act as an APC for TD Ag? Epitopes recognised by antibody and T cell must be physically linked: Either from different parts of the same molecule Or from different molecules of complex (e.g. viral proteins). 24. What is a way of improving the efficiency of a vaccine against pathogens that have T1 antigens? Converting TI Ag to a TD Ag 25. What is the process of antigen processing and presentation of a virus? B cell binds virus through viral coat proteins Virus particle is internalised and degraded Peptides from internal proteins of the virus are presented to the T cell, which activates the B cell. Activated B cell produces antibody against viral coat protein. 26. What is the process of antigen processing and presentation of a bacterium? B cell binds bacterial polysaccharide epitope linked to tetanus toxoid protein Antigen is internalised and processed Peptides from protein component are presented to the T cell Activated B cell produces antibody against polysaccharide antigen on the surface of the bacterium. 27. Give an example of a conjugate vaccine Haemophilic influenza type b. Protective response requires antibodies to capsular polysaccharide (which is a TI Ag). Coupling this to a protein such as tetanus toxoid converts to a TD Ag. - This allows young children to be immunised and protected. (TI antibodies not produced until 5 yrs). - Other examples: MenC, pneumococcal conjugate vaccine. 28. What does a B cell present if the Ag is TD? Peptide from Ag to CD4+ Th cells at the boundary of the T/B areas within the lymph nodes forming B/T cell conjugates. – If a B cell comes into contact with its specific Ag it can then be activated. 29. Where do mature B cells encounter antigens? 30. What is signal 1 that induces B cell activation? 31. Define a TI Ag B cell response? 32. How does the delivery of signal 2 in a TD response differ from that delivered by a TI Ag? 33. Could a polysaccharide act as a TD Ag? They act as a T-dependent antigen but only under certain conditions. Must be conjugated to a protein, which provides the necessary signals to activate CD4+ T helper cells. Polysaccharides alone are typically T-independent antigens (TI Ags) which stimulate a weaker immune response without T cell involvement. 34. What happens to B cells having survived the bone marrow selection processes? Move into the blood and lymphatics 35. Describe B/CD4+ T cell interactions B cell binds Ag via BCR and presents peptide (on MHC class II) from Ag to activated CD4+ Th cell. – T cell then expresses CD40 ligand (CD40L) – secretes cytokines B cell receives signal 2 from T cell via CD40/CD40L binding and via cytokine from T cells binding receptors -> B cell proliferation. CD40 signal also induced deaminase (AID) which is required for class switching and somatic hypermutation. 36. Where do B/CD4+ T cell interactions occur? Secondary lymphoid organs such as the lymph nodes and spleen B cells capture and present antigens to CD4+ T helper cells in T-B border regions of lymphoid tissues. 37. Where does subsequent B cell signalling (via CD40/CD40L and cytokines) occur? Germinal centres of lymphoid follicles (Leads to B cell activation, proliferation, class switching and somatic hypermutation). 38. Describe the activation of B cells with TD Ag Conjugates of B lymphoblastic and T cells move to primary follicles (B cell areas) Form germinal centres (GC) within a B cell follicle in secondary lymphoid tissues. B cells divide rapidly to become central lasts and undergo: – somatic hypermutation of Ig genes – isotope switching Differentiate into non-dividing centrocytes (smaller). 39. B/CD4+ T cell interactions lead to ___________ GC formation 40. What happens to B/CD4+ T cell interactions (GC formation) once in a GC B cell? Either differentiate into plasma cells – secrete various isotopes – high affinity antibody, somatically mutated Form long-loved memory cells – recirculate Die within lymphoid tissue – if BCR no longer binds antigen (as a result of unsuccessful V region created or somatic mutation). 41. What is somatic hypermutation? Introduces point mutation into V regions of Ig Approx. One mutation/ V region/ cell division. – ~10^6 x normal DNA mutation rate Enzymes primarily involved include: – activation induced deaminase (AID) and DNA repair genes. 42. What are follicular dendritic cells (FDC)? Present in GC Not bone-marrow derived dendritic APC as we know. Cells in primary follicle that capture intact Ag for centrocytes to bind via BCR. Capture Ag via FcR and CR as immune complexes 43. Describe B cell affinity maturation Centrocytes that have undergone somatic hypermutation express mutated BCR on surface. Centrocytes compete with eachother for Ag on FDC and for signals from Tfh cell. If mutated BCR binds Ag on FDC better than in-mutated BCR, will present more efficiently and receive CD40 signal from Tfh cell. – failure = apoptosis or recycle to dark zone. Those centrocytes that have generated higher affinity BCR survive to differentiate into plasma cells. 44. Describe follicular T helper cells (Tfh) Recently defined CD4+Th subset found predominantly in the b cell follicles of the lymph node. Specialised to provide help to B cells Secrete either Th or Th2 type cytokines. Can be identified with specific markers that differ from other sub-sets of CD4 Th cells. 45. Describe the process and products of somatic hypermutation of B cells Activated B cell -> somatic hypermutation of immunoglobulin V regions in rapidly proliferating germinal centre B cells -> Mutated BCR with lower affinity for Ag -> – germinal centre B cell with mutated low-affinity surface immunoglobulin -> – B cell receptor is not cross linked and B cell cannot present antigen to T cell -> B cell dies by apoptosis. Mutated BCR with high affinity for Ag -> – germinal centre B cell with mutated high affinity surface immunoglobulin – T cell helper and B cell receptor cross-linking sustain B- cell proliferation and maturation -> memory B cell or plasma cell. 46. What is the role of CD40 (expressed by B cell)? CD40 signal via CD40-L expressed on Tfh – protects centrocytes from apoptosis Induces isotype switching (CD40L deficiency - hyper-IgM syndrome). – different cytokines induce different isotypes to be produced. 47. Describe the process of isotype (class) switching BCR on B cells is initially IgM –co-expressed with IgD by differential mRNA splicing Activation induced deaminase (AID) Induces DNA breakage new constant region of antibody joined without affecting existing VDJ region. 48. How is isotype switching controlled? Different Ag induce different isotypes – polysaccharides: IgM (TI) – proteins: IgG1 and IgG3 or IgG4 (TD) Ag at mucosal surfaces induce IgA Some Ag. Elicit IgE Cytokines - IL-4 important for IgE switch. 49. Why are MHC class II molecules essential for a B cell response to a TD Ag? MHCII present processed antigen to CD4+ T cells Provides signal for B cell activation and antibody production. 50. What is CD40 and which cell type is it usually expressed by? CD40 is a co-stimulatory molecule Expressed by B cells Required for activation and class switching Interacts with CD40L on T cells. 51. What are the roles of IgA and Igß once B cells leave the bone marrow? Components of the BCR complex Help in antigen internalization and signal transduction 52. What is a conjugated vaccine? Links a polysaccharide antigen to a protein carrier to enhance the immune response. 53. What is a centroblast and where is it found? A rapidly dividing B cell Found in the dark zone of the germinal centre 54. What is a centrocyte and where is it found? A B cell found in the light zone of the germinal centre, involved in selecting high-affinity variants. 55. Why is AID important? (activation-induced cytidine deaminase) Essential for somatic hypermutation and class switching in B cells. 56. What are follicular T helper cells (Tfh) and where are they usually found? Subset of CD4+ T cells found in B cell follicles, aiding B cell activation and germinal centre formation. 57. How do follicular dendritic cells (FDC) differ to DC2 and DC3? Are stromal cells that present antigens to B cells, like DC2 and DC3, which are antigen-presenting cells that activate T cells. 58. Which BCR isotypes can be co-expressed by a single B cell? A single B cell can co-express IgM and IgD. 59. How do the signals needed for B cell activation differ from those needed to activate T cells B cells require antigen binding to BCR (signal 1) and co- stimulation from T cells (signal 2), while T cells require antigen binding to TCR (signal 1) and co-stimulation from other T cell signals (signal 2) *3