Week 8 Lecture 1: B Cells - Infection and Immunity PDF

BIOL341/982 Infection and Immunity Week 8: Lecture 1 B cells Dr Debbie Watson [email protected] Building 32.309 Consultation: Em...

BIOL341/982 Infection and Immunity Week 8: Lecture 1 B cells Dr Debbie Watson [email protected] Building 32.309 Consultation: Email for appointment School of Chemistry and Molecular Bioscience 1  Learning Objectives: B cells and Antibodies Week 8 Lecture Outcomes This week’s lectures will continue looking at the adaptive arm of the immune response, focusing on B cells and antibodies Learning Outcomes  Define what a B cell is, and explain the role of B cells in immunity (including in immunological memory)  Explain the clonal selection hypothesis  Define what an antibody is (including structure), and explain their role in immunity 2 Overview Lecture 1: B cells Lecture 2: Antibodies Roles of B cells in humoral Definition of antibodies immunity Various roles of antibodies in immunity B cells activation, with emphasis Structure of antibodies and different on thymus-dependent activation antibody isotypes Clonal selection hypothesis Antibodies of different specificities Somatic hypermutation, affinity maturation and class switching 3 Learning Outcomes: Lecture 1 B cells Explain the roles of B cells in humoral immunity Describe how B cells become activated, with emphasis on thymus-dependent activation Explain the clonal selection hypothesis Describe the roles of B cells and antibodies in immunological memory 4 Revision: Cells of the Immune System 5 Cells of the Immune System Immunology – Cell Cartoons 6 Revision: Innate and adaptive immunity Innate Adaptive Response time Minutes to hours Days Specificity and Limited and fixed Highly specific; highly diverse; diversity improves during immune response Response to Identical to primary More rapid than primary repeat infection Memory None Persistent Self/nonself Non-self (breakdown in Non-self (breakdown in self/nonself discrimination homeostasis leads to discrimination leads to autoimmune autoinflammatory disorders) disorders) Main Physical/chemical barriers (e.g. B-cells, T-cells, components skin, antimicrobial peptides); DCs, macrophages; Monocytes, macrophages, Antibodies; granulocytes, DCs, NK cells, T-cell receptors innate lymphocytes; Pattern recognition receptors 7 Modified from Kindt, Goldsby, Osborne. Kuby Immunology, 6th ed. WH Freeman and Company, 2007. Tables 1-3 and 3-1. Revision: Two arms of adaptive immunity Cell-mediated (T cells) Humoral (B cells and antibodies) Often requires T cell help Immunology – Cell Cartoons 8 See Pommerville, JC. Alcomo’s Fundamentals of Microbiology, 10th ed. Garland Science, 2014. Fig. 21.14. Revision: Adaptive immune response to infection 9 Revision: Cell-mediated immunity Involves T-cells that express specific cell surface receptors (TCRs) TCRs recognise antigenic epitopes associated with major histocompatibility complex (MHC) molecules on the surface of cells Three types of T cells, each with a different function: cytotoxic, helper and regulatory 10  Revision: Humoral immunity Mediated by B-cells that produce antibodies Antibodies recognise epitopes of antigens Antibodies are secreted proteins called immunoglobulins (Ig) Ig comprise 5 classes: IgM, IgD, IgG, IgA, IgE Antibodies have various functions: neutralisation, opsonization and complement activation 11  B cells Also called B lymphocytes 5 – 15% of circulating lymphocyte pool Mature in the bone marrow (name originated from bursa) Along with T cells comprise the key cells of adaptive immunity Produce immunoglobulins (Igs) Cell-surface Igs function as the B cell receptor (BCR) Secreted Igs function as antibodies (Abs) (next lecture) Function in humoral immunity 12 Types of B cells B1 cells Appear early in foetal development (before B2 cells) Comprise 5% of all B cells Self-renewing in tissues outside the central lymphoid organs B2 cells AKA “conventional B cells” Develop in bone marrow Populate blood and lymphoid tissues Activated in secondary lymphoid tissues Main subject of these two lectures 13 B Cell Activation B cells mature in the bone marrow and leave expressing a unique B cell receptor (BCR) Naive mature B cells that do not encounter antigen will die within a few weeks via apoptosis If the BCR encounters the relevant external antigen, stimulates rapid proliferation of the B cell and antibody production 14 Once Activated, B cells Proliferate and Differentiate 15 B Cell Development 16 B cells and Antibodies Comprise the Humoral Immune Response Remember: Naive T cell activation requires co-signaling molecules MHC class II with peptide (B cell) binding to TCR and CD4 (T cells) 17 See next lecture  Example of Quiz Questions Name the tissue from where B cells originate. B cells produce what specific type of protein. Give the names for cell-surface and secreted immunoglobulins, respectively. Give the name of the immune response mediated by B cells and antibodies. Conventional B cells are activated in secondary lymphoid tissues. True or false? Activated B cells give rise to what two types of B cells. Name the three key functions of antibodies. 18 Learning Outcomes: Lecture 1 B cells Explain the roles of B cells in humoral immunity Describe how B cells become activated, with emphasis on thymus-dependent activation Explain the clonal selection hypothesis Describe the roles of B cells and antibodies in immunological memory 19  The B Cell Receptor (BCR) Cell-surface immunoglobulins function as the B cell receptor (BCR) Comprises 4 polypeptide chains linked by disulphide bonds (2 light and 2 heavy chains) Associated with 2 other chains, Igα and Igβ (disulphide-linked) and involved in cell signalling 20 Thymus-Dependent and Thymus Independent B Cell Activation B cell activation Thymus-dependent Thymus-independent proceeds by two routes depending on the nature of the antigen: Thymus-independent Thymus-dependent antigens (e.g. antigens (e.g. most bacterial endotoxin, proteins) LPS) - requires direct - do not require direct contact with TH contact with TH cells cells; more but recognition of a common PAMPs by PRR on B cells activation route Both routes require cross-linking of BCRs (B cells not activated if one BCR alone binds Ag) 21 B Cell Activation Requires Cross-linking of BCRs Both routes require cross- linking of BCRs B cells not activated if one BCR alone binds antigen 22  Thymus-independent B Cell Activation Activate B cells without T cell Thymus-independent help Generally B1 subset Antigens are generally microbial cell wall components or polysaccharides Induce weaker, less specific antibody responses Short-lived plasma cells producing IgM No class switching (see next lecture) 23  Thymus-dependent B Cell Activation Thymus-dependent Activate B cells requires direct contact with helper T cells Antigens are most proteins Induce antigen specific antibody responses Long lived plasma B cells and memory B cells More common activation route 24  Activation of B cells requires co-stimulation Similar to activation of naive T cells, activation of B cells involves multiple co-stimulatory molecules Signal 1: Antigenic peptide presented by B cell MHC class II molecules to TH cell Signal 2: B cell CD40 interacts with TH cell CD40L Signal 3: Induces the release of cytokines (IL-4), that stimulate B cell cytokine receptors (IL-4R) B and TH cells need to recognize the same antigen for activation (but not necessarily the same epitopes) https://www.youtube.com/watch?v=Y_CYUTC9PcI 25  Thymus-dependent B Cell Activation When stimulated by cytokines (e.g. IL-4) and co- stimulatory molecules (e.g. CD40), B cells proliferate and differentiate to yield: Plasma cells which secrete soluble antibody Memory B cells which persist in the body to quickly respond to subsequent exposures to the same antigen 26 Thymus-dependent B Cell Activation Following Viral or Bacterial Infection Virus Bacteria 1. Antigen binds BCR 2. Antigen is internalised via receptor-mediated endocytosis 27 Thymus-dependent B Cell Activation Following Viral or Bacterial Infection Virus Bacteria 3. Antigen is processed (degraded) and loaded onto MHC class II 4. Antigenic peptide is presented in the context of MHC class II to TH cells 5. B cell becomes activated and produces antigen-specific antibody 28 Revision: Lymphoid Tissues Primary lymphoid tissues - sites where lymphocytes form and mature: Bone marrow Thymus Secondary lymphoid tissues - sites where lymphocytes encounter and respond to foreign antigen: Lymph nodes (“glands”) Spleen Mucosa-associated lymphoid tissues (MALT) (gastrointestinal tract, nasopharynx, thyroid, breast, lung, salivary glands, eye, and skin) 29 B Cell Activation Lymph Node Naive B cells travel via the blood stream to secondary lymphoid tissues such as lymph nodes or spleen B cells meet and are activated by T cells Some B cells proliferate to form plasmablasts (short-lived plasma cells), giving rise to an initial wave of antibody production Other B cells and some plasmablasts proliferate Germinal Centre to form germinal centres, where they may undergo somatic hypermutation (affinity maturation) and class switching and differentiate into plasma and memory cells (see next lecture) The majority of plasma cells migrate back to bone marrow to continue antibody production 30 B Cell Activation Can occur in spleen or germinal centres in lymph nodes https://www.youtube.com/watch?v=fMOxSBwA_rI 31 Example of Quiz Questions: True or False The B cell receptor (BCR) includes membrane bound immunoglobulin. B cell activation always requires T cell help. BCR activation induces multiple intracellular signalling events. B cells are activated if an antigen (Ag) binds to a single BCR. Following antigen binding to the BCR, antigens are internalized and processed and presented via MHC class II Activation of thymus-dependent B cells does not require co-stimulation 32 Learning Outcomes: Lecture 1 B cells Explain the roles of B cells in humoral immunity Describe how B cells become activated, with emphasis on thymus-dependent activation Explain the clonal selection hypothesis Describe the roles of B cells and antibodies in immunological memory 33  Clonal Selection Hypothesis Sir Frank Macfarlane Burnet 1899 - 1985 “A man who threw off ideas like sparks which caused a blaze that leapt across to the minds of others.” Clonal selection theory is a scientific theory in immunology that explains the functions of cells (lymphocytes) of the immune system in response to specific antigens invading the body. The concept was introduced by the Australian doctor Frank Macfarlane Burnet in 1957, in an attempt to explain the formation of a diversity of antibodies during initiation of the immune response. The theory has become a widely accepted model for how the immune system responds to Source of Image: "Clonal Selection Theory of Immunity" by The Rockefeller University infection and how certain types of B and T lymphocytes are selected for a destruction of specific antigens Sir Frank Macfarlane Burnet won a Nobel Prize in 1960 for https://youtu.be/HUSDvSknIgI?si=KVpBIjZItXR04qmH predicting acquired immune tolerance and he developed the theory of clonal selection. He was the first Australian of the year 34  Clonal Selection Hypothesis Each individual contains a large number (~1011) of clonally derived lymphocytes (memory cells) each being capable of recognizing and responding to a distinct antigenic determinant or epitope The binding of antigen selects a specific pre-existing clone and activates it The cell surface receptor for antigen (BCR or TCR) is membrane-bound Each clone has a BCR (or TCR) of a unique specificity 35 Clonal Selection Hypothesis One B cell binds antigen (via BCR) from a pool of B cells with different specificities BCR binding to the antigen epitope “selects” that cell to form a clone of activated B cells Activated B cells (after T cell interactions) differentiate into plasma and memory B cells Plasma cells secret antibodies that recognise the antigen that originally bound and cross-linked the BCR 36 Clonal Selection Hypothesis for B cells (Video) Clonal Selection and Activation of B Cells Tiny Teach - YouTube 37 Learning Outcomes: Lecture 1 B cells Explain the roles of B cells in humoral immunity Describe how B cells become activated, with emphasis on thymus-dependent activation Explain the clonal selection hypothesis Describe the roles of B cells and antibodies in immunological memory 38 Activation of B cells leads to B cell proliferation and differentiation into memory and plasma cells 39  Immunological Memory: B cells Secondary antibody responses (responses to repeated exposure to the same antigen) are faster and more specific than primary antibody responses 40 Immunological Memory: B cells Immunological memory (via B cells) can last an organism’s entire life, depending on the nature of the original antigen 41 From Amanna and Slifka. Immunological Reviews, 236: 125–138, 2010 Example: Immunological Memory: B cells 42 Simplified Overview of Adaptive Immune Response 43 Source of Image: Decrease in Antibodies Against SARS-CoV-2 Over Time and Current Role of Serological Testing - Ontario COVID-19 Science Advisory Table (covid19-sciencetable.ca) Hallmarks of Adaptive Immunity Principles and therapeutic applications of adaptive immunity (cell.com) 44 What happens if you have a B cell disorder? B-cell disorders B cell disorders B-cell autoimmune diseases defects of B-cell development/immunoglobulin B cells in hypersensitivities production (immunodeficiencies) B-cell immunodeficiencies B-cell malignancies excessive/uncontrolled proliferation (lymphomas, leukemias) Primary B-cell immunodeficiencies diseases resulting from impaired antibody production due to either molecular defects intrinsic to B- cells or a failure of interaction between B-cells and T-cells 45 Example: B Cell Deficiency Patients typically have recurrent infections E.g. Selective Immunoglobulin Deficiency – IgM deficiency (recurrent respiratory infections) Presentation and complications vary where defect has occurred in B-cell development degree of functional impairment 46  Example of B and T cell Deficiency: Severe Combined Immune Deficiency (SCID) SCID is often called “bubble boy disease,” made “Boy in the bubble” known by the 1976 movie “The Boy in the Plastic No immune system – risk of Bubble.” Essentially, children with SCID lack the ability to produce an immune system. infections SCID – due to genetic defects X-linked SCID David Vetter, a young boy ADA -SCID from Texas, lived out in the real world - in a plastic bubble. Nicknamed "Bubble Boy," David was born in 1971 with severe combined immunodeficiency (SCID), and was forced to live in a specially constructed sterile plastic 47 bubble from birth until Medical Journal of Australia, 2005 he died at age 12.  Example of Quiz Questions Name the main types of B cells resulting from B cell activation. Naive B cells encounter antigen in what tissues? B cells undergo somatic hypermutation, class switching and differentiation in what lymphoid structures? The majority of B cells travel to the Peyer’s patches and tonsils to continue antibody production. True or false? Secondary antibody responses occur faster than primary antibody responses to the same antigen. True or false? The clonal selection hypothesis states that a single B cell (or T cell) expresses BCRs (or TCRs) of multiple specificities. True or false? 48 Summary B cells are bone marrow-derived lymphocytes expressing the B cell receptor (BCR) The humoral immune response is the production of antibodies by B cells to cause the removal and destruction of extracellular microorganisms Most B cell responses need two events to occur for B cells to become active: Bound antigen cross-linking BCRs Stimulation via T helper cells that respond to the same antigen Activated B cells produce plasma cells and memory B cells The clonal selection hypothesis states that each B cell (or T cell) recognises and responds to a distinct antigenic epitope 49 Star Wars and learning immunology 50