IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES

1. IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES

2. IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES • B lymphocytes recognize extracellular pathogens and toxins transported to secondary lymphoid tissues • Recognition stimulates proliferation and differentiation into • Plasma cells and memory B cells • B lymphocytes generally require help from activated T lymphocytes for differentiation into plasma cells • Plasma cells produce antibodies

3. ACTIVATION OF B LYMPHOCYTES • Begins with antigen binding by receptors resulting in crosslinking of receptors • Clustering and aggregation of receptors activates • Tyrosine kinases • Tyrosine kinases phosphorylates Ig-alpha and Ig-beta proteins initiating intracellular signaling • Additional signals are required and provided by • B cell co-receptor • CD4 TH2 lymphocytes

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6. SIGNAL ENHANCEMENT BY B CELL CO-RECEPTOR • B cell co-receptor is complex of 3 proteins • CD21 [Complement receptor 2 (CR2)] • Binds to complement on pathogen • CD19 • CD81 • Signal enhancement results from juxtaposition of receptor and co-receptor • 1,000 to 10,000 X • Additional signals required depending on nature of antigen and provided by CD4 TH2 cells

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9. FINAL OUTCOME OF B CELL ACTIVATION • Proliferation and differentiation of B cells into antibody producing plasma cells • Morphology of B cells and plasma cells • B cells • Large nucleus and small cytoplasm • Plasma cells • Large nucleus and large cytoplasm packed with ER

13. THE NATURE OF ANTIGENS AND THE ANTIBODY RESPONSE • Thymus independent antigens (TI antigens) • Activate naïve B cells without help from CD4 cells • Classification into • TI-1 antigens (Lipopolysaccharides) • TI-2 antigens (Polysaccharides) • Minority of antibody production • Thymus dependent antigens (TD antigens) • Activation of naïve B cells requires help from CD4 cells • Majority of antibody production

14. THYMUS INDEPENDENT ANTIGENS AND ANTIBODY PRODUCTION • TI-1 antigens • Lipopolysaccharide of gram-negative bacteria • Stimulate production of IgM only • LPS specific activation • LPS non-specific co-activation • Repeating epitopes not required • TI-2 antigens • Polysaccharides and proteins of bacteria • Stimulate production predominately of IgM • Repeating epitopes required

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18. MECHANISM OF CD4 T CELL AND B CELL INTERACTION TO TD ANTIGENS • TD antigens transported to secondary lymphoid tissues for meeting with CD4 T cells and B cells • CD4 T cells are activated in T cell zone by APC • B cells enter T cell zone and bind same antigen • Antigen bound to B cell is internalized by • Receptor mediated endocytosis

19. MECHANISM OF CD4 T CELL AND B CELL INTERACTION TO TD ANTIGENS • Antigen is processed and presented on B cell surface with MHC class II molecules • T cell and B cell interact via CD40L and CD40 • T cell produce cytokine (interleukin-4) which activates B cell • Cognate interaction • Interaction of B and T cells specific for same antigen

21. COGNATE INTERACTION OF CD4 TH2 CELLS AND B CELLS • CI results in primary focus of B lymphoblasts in T cell area • Some B lymphoblasts move to medullary cords and differentiate into plasma cells • IL-5 and IL-6 from TH2 cells • Some B lymphoblasts move to primary follicles and differentiate into centroblasts • Centroblasts proliferate and follicle changes morphology • Germinal center

24. GERMINAL CENTERS IN SECONDARY LYMPHOID TISSUES • Mantle zone • Resting B cells present in follicle prior to arrival of activated B cells and T cells • Light zone • Non-dividing centrocytes associated with • Follicular dentritic cells • Stromal cells of lymphoid follicles • Dark zone • Proliferating centroblasts

26. GERMINAL CENTERS IN SECONDARY LYMPHOID TISSUES • Site for somatic hypermutation and affinity maturation • Initiated by cytokines of T cells • Begins with centroblasts in dark zone • Results in centrocytes with mutated receptors in light zone • B cells (centrocytes) which undergo somatic hypermutation • Produce receptor with range of affinities • Highest affinity receptors are selected • Must bind antigen or face apoptosis • Antigen provided by follicular dentritic cells

27. PRESENTATION OF ANTIGEN BY FDC’S • Follicular dentritic cells (FDC’s) • Bind antigen in form of immune complexes • Bound immune complexes are not internalized and become clustered as • Iccosomes (Immune complex coated bodies) • Iccosomes are shed from FDC’s and taken up by centrocytes • Centrocytes must obtain, internalize and present antigen for differentiation into plasma cells

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32. COMPARISON OF RESTING B CELLS AND PLASMA CELLS • Differentiation based on intrinsic and inducible properties • Intrinsic • Surface IG • Surface MHC class II molecules • High rate of antibody secretion • Inducible • Growth • Somatic hypermutation • Isotype switching

34. ISOTYPE SWITCHING IN B CELLS • Takes place primarily in germinal centers • Determined by • Cognate interaction with CD4 T cells • Induction requires CD40L to CD40 • T cell cytokines • Induction or inhibition of isotypes • Hyper-IgM Syndrome • Genetic immunodeficiency from no CD40L • B cells cannot switch isotypes • No response to TD antigens

37. GENERAL EFFECTOR FUNCTIONS OF ANTIBODIES • IgM • Protection of blood • IgG and IgA (monomeric) • Protection of blood and extracellular fluids • IgA (dimeric) • Protection mucous membranes and secretions • IgE • Protection of connective tissues

38. PROTECTION OF BLOOD BY IgM ANTIBODIES • Primary function • Early protection against blood-borne pathogens • Characteristics • First antibody produced • Secreted form is pentamer with 10 binding sites • Penetration of tissue fluids is limited • Phagocytic cells have no IgM Fc receptors • Fc region can bind complement

39. PROTECTION OF MUCOUS MEMBRANES BY DIMERIC IgA • Dimeric IgA made by plasma cells in mucosal-associated lymphoid tissues • GALT and BALT • Dimeric IgA transfer to epithelial surface • Transcytosis • Receptor mediated transport of macromolecules across epithelial cells • Mechanism of transcytosis • Binding to poly-Ig receptor on basolateral epithelium • Endocytotic vesicle transport to apical epithelium • Protease cleavage of receptor to secretory piece

41. IgG TRANSPORT FROM BLOOD TO EXTRACELLULAR FLUIDS • Transport mediated by endothelial receptor • Brambell receptor (FcRB) • Structure of receptor • Similar to MHC class I molecule • Mechanism • Binding to FcRB on apical endothelium • Endocytotic vesicle transport to basolateral endothelium

43. ANTIBODIES PROTECTING FETUS AND NEWBORN • IgG • Protects fetus and newborn • Maternal circulation to fetal circulation • Transfer across placenta mediated by FcRB • IgG levels similar in mothers and newborns • IgA • Protects GI tract of newborn • Transfer by breast milk • Dimeric form (IgA2 subclass)

45. DISTRIBUTION OF ANTIBODIES IN HUMAN BODY • Plasma • IgM, IgG and IgA (monomeric) • Extracellular fluids • IgG and IgA (monomeric) • Mucous membranes and secretions • IgA (dimeric) • Connective tissues • IgE

47. ANTIBODIES PROTECT AGAINST BACTERIAL EXOTOXINS • Number of bacteria cause disease by secreting exotoxins • Many toxins have receptor-binding and toxic functions on separate polypeptide chains • Exotoxin disease prevented by antibodies that block toxin binding • Neutralizing anitbodies • Antibodies raised by vaccination against toxins using • Toxoids (modified toxins)