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
* Basic metabolic panel
normal
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