Activation and Migration

1
Activation and Migration

• Activated helper T-cells (effector cells)
  interact with Ag-stimulated B-cells at edge of
  follicles in lymphoid tissue

2
TH and B-Cell Interaction

• Naïve CD4 T-cell is stimulated to differentiate
  into cytokine secreting effector cell
• Ag recognition and costimulation
• 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 and TH2 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

3
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
• Activated B-cells express co-stimulators B7 to
  stimulate T-cells that recognize Ag on B-cells

4
B- and T-Cell Interaction
5
TH-Cell Mediated Activation

• TH-cell recognize Ag on APC B-cell and activate
  it by expressing CD40 ligand (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
• CD40LCD40 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 see in
  T-dependent protein Ag

6
Isotype Switching

• Heavy class chain is switched to a different
  isotype
• 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 with IgG1
  and IgG3
• bind the Fc receptor on the phagocyte with high
  affinity and specificity for ? heavy chain
• IgE is used to fight helminths with eosinophils
  which recognize the ? heavy chain by way of Fc
  receptor

7
Effector Functions of Ab
Know cytokines and which Ab
8
Reasons for Switching

• Need to make a response that can remove various
  microbes needs to be more than IgM and IgD
• heavy class switching gives us plasticity
  greater flexibility in combating microbes
• Class switching is mediated by CD40L mediated
  signals different cytokines involved
• cytokines and CD40L activate B-cells for some
  progeny of some cells
• No CD40L or CD40 B-cells secrete only IgM

9
X-Linked Hyper IgM Sndrome

• Inactivating mutations in CD40L gene on the
  X-chromosome
• 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)

10
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
• combines with light chain to make IgM always
  1st
• 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
• enzyme activation-induced deaminase plays a role
  in switch recombination

11
Switching

• 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

12
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 cells may act as master controller of
  the immune response
• Also influenced by site of immune response
• mucosal epithelium has IgA B cells and
  cytokines to switch to IgA

13
Affinity Maturation

• Affinity of Ab produced to protein Ag increases
  with prolonged or repeated exposures
• Ab binding to microbe or Ag increases if
  infection is persistent or recurrent
• due to point mutations in the V region Ag binds
  in the hypervariable region
• happens only in T-dependent protein Ag

14
Mutation Accumulation
15
Helper Cells Are Critical

• Affinity maturation occurs in germinal center of
  lymphoid follicles Somatic Hypermutation of Ig
  genes in dividing B-cells followed by 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
• AgAb complex can activate complement

16
Affinity Maturation
17
Where??

• Occurs in different parts of lymphoid tissue
• 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 to the BM continue to secrete
  Ab even when Ag is gone
• immediate protection if see microbe again
• Fraction of cells after heavy class switching
  (occurs outside of follicle) will become memory
  cells and wander until contact the Ag again

18
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

19
Ab Feedback

• Most B-cells will die by apoptosis except for
  memory and plasma cells
• Removal comes from the B-cell having a Fc
  receptor that will bind Fc part of Ab and
  receptor mediated signaling
• terminates the humoral immune response