IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES
IMMUNITY MEDIATED BY B LYMPHOCYTES AND ANTIBODIES
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
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
Figure 7-2 part 1 of 2
Figure 7-2 part 2 of 2
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
Figure 7-3
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
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
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
Figure 7-5
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
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
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
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
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
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
Figure 7-10
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
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
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
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
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
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
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)
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
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)
ANTIBODIES PROTECT AGAINST VIRAL AND BACTERIAL INFECTION
* Initial step in microbial pathogenesis is attachment to host tissues mediated by adhesins
* Microbial adhesins * Molecules
* Gp120 of HIV* Hemagglutinin (HA) of Influenza viruses
* Organelles* Fimbriae of Escherichia coli
* Neutralizing antibodies against adhesins prevent attachment
DESTRUCTION OF ANTIBODY COATED PATHOGENS
* Phagocytes are agents of destruction* Macrophages and neutrophils
* Mechanism* Antibodies bind to pathogens* Phagocytes have Fc-gamma receptors on surface * Fc-gamma receptor of phagocytes binds to Fc region of antibody
* Low affinity binding
* Antibody coating of pathogens enhances phagocytosis* Encapsulated pathogens
DESTRUCTION OF ANTIBODY COATED PARASITES
* Adult parasites are the largest of microorganisms* Diphyllobothrium latum (5 - 10 meters)
* Ascaris lumbricoides (20 – 35 cm)
* Mechanism of destruction* IgE coating of parasites
* Binding of mast cells, basophils and activated eosinophils * Release of granules contents onto surface
* Mechanism of elimination* Inflammatory mediators promote physical removal
* Constriction of smooth muscle
* Increased blood vessel permeability
CASE STUDY
* 45 year old white female
* Presents to family physician with complaint* Mild fatigue for one month
* Passed “Ribbon-like worm” with bowel movement
* Patient history * No exotic travel
* No pets
* Eats out 3 to 4 times a week (patron of sushi / sashimi)
CASE STUDY
* Laboratory testing* CBC with differential normal* Basic metabolic panel normal
* Physical examination* Extraction from rectum of ribbon-like worm* Approximately 80 cm
* Specimen (worm) sent to laboratory
CASE STUDY – QUESTIONS
* What is the diagnosis
* What is the etiological agent
* How is the etiological agent transmitted
* What is the recommended treatment* United States* Japan
CASE STUDY – ANSWERS TO QUESTIONS
* Diagnosis* Diphyllobothriasis
* Etiological agent* Diphyllobothrium latum
* Transmission* Ingestion of raw fish containing plerocercoid larvae
CASE STUDY – ANSWERS TO QUESTIONS
* Treatment in the United States* Praziquantel* Niclosamide
* Treatment in Japan* Amidotrizoic (diatrizoic) acid (Gastrografin)* Administered either orally or by injection into
duodenum by endoscopy
CASE STUDY
* 87 year old female presents to family physician with
* Erythematous lesion on left thigh
* Three weeks duration
* Lesion biopsy submitted for pathology exam
* Pathology report
* Subcutaneous Dirofilaria infestation with granulomatous and eosinophilic dermatitis
MAST CELLS, EOSINOPHILS, BASOPHILS AND IgE ANTIBODY
* Mast cells, basophils and activated eosinophils have IgE receptor* Fc-epsilon-RI
* High affinity for Fc region of IgE
* Mast cells * Fc-epsilon-RI receptors and cytoplasmic granules are constitutive
* Cytoplasmic granules contain “inflammatory mediators”* Histamine
* Antigen binding initiates degranulation of mast cells
Fc RECEPTORS AND NATURAL KILLER CELLS
* NK cells * Express Fc-gamma-RIII receptor for IgG1 and IgG3
* Fc-gamma-RIII important in ADCC
* ADCC* Mediated primarily by NK cells* Illustrates that antibody can direct specific attack by effector cells that
have no specificity for antigen
* Mechanism* Virus infected cells express viral proteins on surface* Antibodies bind viral proteins* NK cells bind to antibodies, release granules, kill cells