W3 B Lymphocyte Biology (Adebiyi).pdf

B CELL BIOLOGY Raymond F Adebiyi Professor Immunology and Medical Microbiology Learning Objectives 1. 2. Describe the basic functions of B cells. Name the main stages of B cell development. Discuss the major events that characterize each stage of B cell development. At what stages do the heavy and l...

B CELL BIOLOGY Raymond F Adebiyi Professor Immunology and Medical Microbiology Learning Objectives 1. 2. Describe the basic functions of B cells. Name the main stages of B cell development. Discuss the major events that characterize each stage of B cell development. At what stages do the heavy and light chains undergo rearrangement? Discuss the roles of RAG-1, RAG-2, and TdT in B cell development. 3. Explain the why allelic exclusion is an important part of B cell rearrangement. 4. Describe central and peripheral tolerance in B cells. What do these processes achieve? 5. Compare and contrast immature B cells, mature B cells, naïve B cells, B-1 cells, B-2 cells, activated B cells, plasma cells and memory B cells. 6. Name the component parts of the B cell receptor complex and list the functions of each component. 7. Describe the process of B cell activation and differentiation. Name the cell-surface interactions and cytokines necessary to drive both B cell activation and differentiation. 8. Describe the outcomes of somatic hypermutation, affinity maturation and isotype switching. What kinds of help do B cells require to undergo these processes? Distinguish between somatic recombination and somatic hypermutation events. 9. Describe how a B cell response to a T-independent antigen differs from the response to a T-dependent antigen. 10. List the surface markers found on B cells and their functions. Recommended Readings: Lauren Sompayrac, 2019, How the Immune System Works, 6th Edition, Wiley-Blackwell, Lecture 3 and Lecture 7 Peter Parham, 2015, The Immune System, 4th Edition, Garland Science, pp 149-173 Any Questions? [email protected] Office Hours https://atge.webex.com/meet/radebiyi B Cell Activation And Proliferation Antigen binding to the B cell receptor B cell receptor signaling B cell proliferation and differentiation Germinal center formation in secondary lymphoid tissues Role of follicular T helper cells and follicular dendritic cells Somatic hypermutation Isotype switching Affinity maturation T dependent and T independent responses ROSS UNIVERSITY SCHOOLSCHOOL OF MEDICINE | 5 ROSS UNIVERSITY OF MEDICINE ROSS UNIVERSITY SCHOOLSCHOOL OF MEDICINE | 6 ROSS UNIVERSITY OF MEDICINE The BCR and coreceptor cooperate in B cell activation CD19 is the signaling chain of the complex CD21 (AKA Complement Receptor 2) recognizes C3d fragments deposited on pathogens CD81 – forms signaling complex with CD19, as well as with other surface molecules B Cell Activation By Antigen ▪ Naïve, mature B cells recognize antigen through BCR (surface IgM or IgD) ▪ Binding to antigen causes clustering, or cross-linking of BCR ▪ This results in generation of signals sent through BCR complex ▪ Signals lead to changes of gene expression Activated B Cells Undergo Differentiation Plasma cells Terminally differentiated antibody synthesizing and secreting machines IgM is no longer surface-bound, but secreted No longer can respond to antigen – Lose surface IgM (BCR) – Stop MHC class II expression – Express CD27 Activated B Cells Undergo Differentiation Memory B cells Survive for long periods Allow for more rapid and robust secondary antibody response Express CD27 Memory cells Activated B cell Differentiation Somatic Hypermutation Combinatorial joining of gene segments Junctional diversification during gene segment joining Combinatorial joining of L and H chains Somatic hypermutation Post-Activation Activated B cells undergo proliferation and clonal expansion (make lots of copies of themselves) Activated B cells have specialized method of improving antibody molecules –Somatic hypermutation –Affinity maturation –Isotype (class) switch The processes of somatic hypermutation and isotype switching are mediated by the enzyme activation-induced cytidine deaminase (AID) The synthesis of this enzyme is controlled by IL-4 and CD-40 activation signals Activation Induced Deaminase (Aid) activation induced deamination of cytosine to uracil leads to hypermutation Those B cells with improved affinity will be clonally selected and will proliferate. AFFINITY MATURATION ISOTYPE SWITCH Activated B cells need help Signal #1 Signal #2 Activated B Cells Need Help Activated B Cells Need Help Activated B Cells Need Help 3 Signals For B Cell Activation Cytokine Control Of Antibody Isotype Thymus-Independent (TI) Antigens Some bacterial antigens can stimulate naïve B cells in absence of T cell help – Examples: Polysaccharides Lipopolysaccharides – Signal #2 comes from antigen itself – Without T cell help, antibody repertoire against TI antigen is limited No class switching No affinity maturation B-1 Cells Most mature B cells in the adult circulation are ‘conventional’ B cells or B-2 cells that express the usual B cell markers B-1 cells may be found in the fetus and the neonate Preferentially respond to T-independent antigens Responsible for production of ‘natural antibodies’ - isoantibodies to ABO substance - Signal #2 is necessary for B cell activation by both Tdependent and T-independent antigens THE END ROSS UNIVERSITY SCHOOL OF MEDICINE B CELL BIOLOGY Raymond F Adebiyi Professor Immunology and Medical Microbiology