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Chapter 7. Humoral Immune Response Activation of B Lymphocytes and Production of Antibodies. Antibodies. Part of the adaptive immune response functions to neutralize and eliminate extracellular microbes and microbial toxins

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chapter 7

Chapter 7

Humoral Immune Response

Activation of B Lymphocytes and Production of Antibodies

  • Part of the adaptive immune response functions to neutralize and eliminate extracellular microbes and microbial toxins
  • More useful against polysaccharide and lipids and these types of toxins – B cells respond to many Ag types
  • Naïve B cells recognize Ag but can’t make Ab until activation allows differentiation to Ab secreting plasma cells
phases and types of hir
Phases and Types of HIR
  • Naïve B-cells have 2 classes of membrane bound Ab – IgM and IgD
    • act as receptor for Ag
  • Activation of Ag specific cells leads to clonal expansion
    • Go from 1 to 4000 Ab secreting cells
  • Differentiation into effector cells called plasma cells
    • secreted Ab is same specificity of as naïve membrane bound receptor but during differentiation can cause Ab with different heavy chain and effector function – heavy chain class (isotype) switching
    • can handle different types of microbes
  • Repeated exposure to causes Ab with increasing affinity to Ag – affinity maturation
    • improved capacity to bind and neutralize Ag
t cell dependence
T-Cell Dependence??
  • Ab response to different Ag may depend on the requirement of T-cell help or not
  • B-cells recognize many Ags – protein, polysaccharide, lipid and small chemicals
  • Protein Ag makes poor or no Ab response when T-cells are absent = T-dependent Ab response
    • T-helper cells play role in activation and powerful inducer of isotype switching
  • Polysaccharidde, lipid and non-protein Ag stimulate Ab production without T helper cells = T independent Ab response
    • little to no heavy chain switching or affinity maturation
b cell subsets respond differently
B-Cell Subsets Respond Differently
  • Protein and non-protein Ag result in different responses
  • Majority are follicular B-cells (follicles of lymph organs) make the majority of T-dependent, class-switched ans high-affinity Ab to protein Ag
    • also long-lived plasma cells
  • Marginal zone B-cells (marginal zone of spleen white pulp) respond to blood bourne-polysaccharide Ag
  • B-1 B-cells respond to non-protein Ag in mucosa and peritoneum
  • Marginal zone and B-1 B-cells have Ag receptors of limited diversity and mainly IgM response
  • Ab responses differ qualitatively and quantitatively
  • 1 response is the first time exposed
    • small amounts of Ab produced
  • 2 response is the subsequent exposure
    • more Ab produced
    • if to a protein, see isotype switching and affinity maturation
    • increase in TH cells with repeated stimulation
  • Ag recognition ACTIVATES B-lymphocytes
stimulation of b cells by ag
Stimulation of B-Cells by Ag
  • Initiated when Ag-specific B-cells in lymphoid follicles of the spleen, LN and mucosal lymphoid tissues recognize Ag
  • Ag of microbes in tissues or blood are transported and concentrated in B-cell rich follicles by possible method of:
    • macrophages in subcapsular sinus may capture Ag and display to B-cells in adjacent follicles
    • use BCR to recognize Ag in native conformation – triggers pathway for signal transduction
    • require additional signals from innate system
  • Ag without processing – NATIVE CONFORMATION
ag induced signaling in b cells
Ag-Induced Signaling in B-Cells
  • Membrane Ig receptors cluster (bind and move together) and trigger biochemical signals that are transduced by receptor-associated signal molecules
    • similar to T-cells activation
    • must cross-link 2 or more receptors for signal transduction – 2 or more Ag in an aggregate or repeating epitopes of one Ag molecule – binds adjacent Ig molecules
  • Polysaccharide, lipid and other non-protein Ag have multiple identical epitopes in each molecule (bind numerous Ig receptors on B-cell)
    • transduced by receptor-associated proteins
  • Receptor IgM and IgD – highly variable with short cytoplasmic domains
    • recognize Ag but do not transduce signals
  • IgM and IgD are non-covalently linked to Ig and Ig to make the B-cell receptor (BCR) complex
    • Ig and Ig contain conserved immunoreceptor tyrosine-based activation motifs (ITAM) – seen in other activation receptors
    • 2 or more Ag receptors cluster, Tyr in ITAM of Ig and Ig are phosphorylated by kinase associated with BCR complex
    • Tyr-PO4 is the docking sites for adaptor protein which gets phosphorylated and recruits a number of signal molecules
  • Signal cascade not as well understood as T-cells but essentially similar – activates trnscription factor that turn on genes whose proteins involved in B-cell proliferation and differentiation
b cell activation
B-Cell Activation
  • Syk is similar to ZAP-70
complement and b cell activation
Complement and B-Cell Activation
  • B-cells express receptor for a complement protein which provides signals to activate B-cells when bound to ligand
  • Complement is activated by microbes and Ab attached to microbes – functions as effector mechanism of host defense (Chapter 8)
complement activation of b cells
Complement Activation of B-Cells
  • Microbe has C3d (cleavage product of C3) coating the surface
  • B-cells has type 2 complement receptor (CR2 or CD21) and it binds to C3d
  • B-cells recognize microbe Ag by the Ig receptor and also recognizes C3d on CR2 receptors
    • C3d acts as the 2nd signal for B-cell activation
    • CR2 enhances Ag-dependent activation of B-cells
    • Ag recognition is 1st step and C3d-CR2 binding is the 2nd signal
  • Microbes themselves or innate immune response to microbes provide signals in addition to Ag recognition to activate lymphocytes or microbial products attaching to TLR on B-cell
  • C3d is similar to co-stimulators in T-cell activation
consequences of ag mediated b cell activation
Consequences of Ag-Mediated B-Cell Activation
  • Initiate B-cell proliferated and differentiation and prepare B cells to interact with TH cells if protein Ag
  • B-cell enters cell cycle and proliferates – clonal expansion
  • Produces more IgM and secrete IgM – early phase immune response induced
early phase is greatest
Early Phase is Greatest
  • Response is greatest for polysaccharide and T-independent Ag
    • multivalent
    • cross-links many Ag-receptors
    • activates C’ strongly
  • Proteins can’t do the 1st 2 so make weak response without TH response
    • lack multiple, identical epitopes
additional steps
Additional Steps
  • At least 3 other changes to the B-cell to enhance ability to interact with TH cells – acting as APC
    • increase the expression of B7 costimulator molecule (2nd signal for T-cells), may amplify helper T-cell response and expression of cytokine receptors – cytokine mediators of TH cell functions
    • decrease the expression of chemokine receptors – chemokines keep B-cell in follicles, without chemokines they can migrate out of follicle to where TH cells are concentrated
function of t helper cells
Function of T-Helper Cells
  • Required for strong response to protein Ag
  • B-cell and T-cell must recognize protein Ag and come together to stimulate B-cell proliferation and differentiation in the lymphoid tissue
    • takes 3-7 days for Ab response
activation and migration
Activation and Migration
  • Activated helper T-cells (effector cells) interact with Ag-stimulated B-cells at edge of follicles in lymphoid tissue
t h and b cell interaction
TH and B-Cell Interaction
  • Naïve CD4+ T-cell is stimulated to proliferate and differentiate into cytokine secreting effector cell
    • Ag recognition and co-stimulation
      • microbial Ag and protein Ag with adjuvants that cause expression of co-stimulators on APC
    • extracellular microbes and vesicular microbes on MHC II in T-cell rich zones in LN
      • depending on Ag – become TH1, TH2 or TH17 subset
      • portion of cells move out of LN to look for Ag
    • T-cells move out of LN to circulation – remove microbes CMI
    • some T-cells migrate to the edge of lymphoid follicles while B-cells are moving outward; dependent on changes in chemokine receptors on activated lymphocytes and the chemokines are also expressed to bind receptors
ag presentation by b cells
Ag Presentation by B-Cells
  • B-cells bind protein Ag (extracellular) by specific receptors and endocytose them – process in endosome vesicles and display on MHC II for recognition by helper T-cells
  • Membrane bound Ig can bind Ag with high affinity (low Ag concentration); very efficiently endocytosed and processed to be peptide on MHC II = act as APC
    • specific recognition of Ag by Ig on the surface
  • B-cells have ability to display multiple Ag for T-cell recognition – B and T cells can recognize different epitopes of same Ag
    • interactions remains Ag specific
  • Ag-activated B-cells also express co-stimulators such as B7 to stimulate T-cells that recognize Ag on B-cells
    • cannot activate naïve T-cells
t h cell mediated activation
TH-Cell Mediated Activation
  • TH-cell recognize Ag on APC B-cell and activate it by expressing CD40L and secreting cytokines – similar to T-cell activation of macrophages in CMI
  • CD40L binds CD40 on B-cell – sends signals for B-cell expansion and for synthesis and secretion of Ab
    • Cytokines made in the T-cell bind to the B-cell and enhance proliferation and Ig production
    • CD40L:CD40 interaction insures that B-cells are activated only when they come in contact with T-cell
  • Helper T- cell signals trigger heavy chain switching and affinity maturation – as seen in T-dependent protein Ag recognition
isotype switching
Isotype Switching
  • Heavy class chain is switched to a different isotype to broaden functional capabilities
  • Helper T-cell help with the switch from IgM/IgD to another isotype
    • allows humoral immune response to adapt in order to combat microbe optimally
      • IgG is used to opsonize microbes and extracellular viruses – phagocytosed by neutrophils and macrophages; usually IgG1 and IgG3 classes
        • bind the Fc receptor on the phagocyte with high affinity and specificity for  heavy chain
      • IgE is used to fight helminths by recruiting eosinophils which recognize the  heavy chain by way of Fc receptor
effector functions of ab
Effector Functions of Ab
  • Know cytokines and which Ab
reasons for switching
Reasons for Switching
  • Need to make a response that can remove various microbes – needs to be more than IgM and IgD
  • Class switching is mediated by CD40L:CD40 mediated signals – different cytokines involved
    • cytokines influences which heavy chain class an individual B-cell and progeny will switch to
  • No CD40L or CD40 – B-cells secrete only IgM
x linked hyper igm syndrome
X-Linked Hyper IgM Syndrome
  • Inactivating mutations in CD40L gene on the X-chromosome – no functioning forms of CD40L
  • Mostly IgM Ab produced due to the defective heavy chain switching
  • Also defective CMI because of the effect on T-cell activation (use of CD40L)
class switching switch recombination
Class Switching (Switch Recombination)
  • Process is well understood
  • In IgM B-cells the VDJ region of variable portion is adjacent to C gene splice mRNA of VDJ RNA to CRNA = make  heavy chain
  • Cytokines and CD40 signals stimulate transcription thru a C gene segment to make something other than IgM – 5’ end intron has conserved sequence that is the switch region
    • activation causes 3’ switch region of C to link to 5’ switch region of downstream constant region and delete entire intron, removing the  gene RNA
      • switch region is not present for C gene
    • enzyme Activation-Induced Deaminase (AID) plays a role in switch recombination
  • VDJ region in contact with C regions downstream – Ab may have new heavy chain but the specificity in the variable region is the same as IgM
    • VDJ region stays the same (where Ab specificity resides)
cytokine impact
Cytokine Impact
  • INF complements both B-cells and phagocytes
    • INF makes opsonizing Ab (from TH1 cells)
      • promotes phagocytosis – also INF is phagocyte activating
    • bacteria and viruses stimulate the formation of TH1 cells (secretes INF)
  • IgE class switching is ruled by IL-4 (TH2 cytokine) and eosinophil activation by IL-5 (also from TH2 cells)
  • Nature of helper cell activity guides the Ab response
    • optimized for the microbe
    • helper T-cells may act as “master controller” of the immune response
  • Also influenced by site of immune response
    • mucosal epithelium has IgA – B cells and unknown cytokine to switch to IgA
affinity maturation
Affinity Maturation
  • Affinity of Ab produced to protein Ag increases with prolonged or repeated exposures to that Ag
    • Ab binding to microbe or Ag increases if infection is persistent or recurrent
    • due to point mutations in the V region – Ag binding hypervariable region
      • happens only in T-dependent protein Ag
      • mutation rate 1:1000 nucleotides – somatic hypermutation
helper cells are critical
Helper Cells Are Critical
  • Affinity maturation occurs in germinal center of lymphoid follicles – Somatic Hypermutation of Ig genes in dividing B-cells – followed by selection of high affinity B-cells by Ag displayed by follicular dendritic cells
  • As response goes on, increase in the level of Ab and decrease in the Ag so B-cells with high affinity Ab receptors will bind Ag on the FDC and therefore survive apoptosis
    • B cells are selected to survive must bind Ag at lower and lower Ag concentration
    • germinal center B-cells die unless rescued by Ag-recognition
    • Ag:Ab complex can activate complement
  • Occurs in different parts of lymphoid tissue
  • Mature naïve B-cell recognize Ag and move to peripheral edge of the follicle where it encounters the T helper cell and start to secrete Ab
  • Plasma cells move away from B-cell rich regions continue to secrete Ab even when Ag is gone
  • Fraction of cells after heavy class switching (occurs outside of follicle) will become memory cells and wander until contact the Ag again
t independent ab response
T-Independent Ab Response
  • Know the bottom part of this table
  • Needs no T-cell help
  • Polysaccharides, lipids and non-protein molecules
    • no T-cell recognition / no MHC
    • response happens because these Ag are multi-valent (have multiple identical epitopes) and can activate B-cell
  • Two types of Ab differ
ab feedback
Ab Feedback
  • Most B-cells will die by apoptosis except for memory and small number of plasma cells
  • Removal comes from the B-cell having a Fc receptor, FcRII that will bind Fc part of Ab and receptor mediated signaling
    • terminates the humoral immune response when sufficient IgG present