Antigen Recognition in the Adaptive Immune System

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Chapter 4

• Antigen Recognition in the Adaptive Immune System

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Ag Recognition

• Specific Ag recognition is the task of 2
  structurally similar types of cell surface
  protein of lymphocytes
• membrane bound Ab on B-cell (BCR)
• T-cell receptors (TCR) on T-cells
• Function to 1) detect external stimuli and 2)
  trigger response of the cell on which the
  receptor is expressed
• Ag receptors are clonally distributed each
  clone of lymphocytes having a particular
  specificity has a unique receptor different
  from receptors of all other clones
• clone cell and all of its progeny
• each clone recognizes a different Ag B or T
  cells respond in the same way transmit
  biochemical signals

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Ag ReceptorFunctions in Adaptive Immunity(must
know)
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Function 1

• Ag receptors of B and T cells recognize
  chemically different structures
• B-cells are able to recognize shapes or
  conformations of native macromolecules
• most T-cells recognize peptide Ag and only on APC
  bound to MHC

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Function 2

• Ag-receptor has domains
• regions that are involved in Ag recognition
• vary between clones of lymphocytes
• other regions are required for structural
  integrity
• others for effector functions
• conserved among all clones
• Ag recognizing portion of the receptors are
  called variable region and conserved portion are
  called constant region
• can maximize variability without changing basic
  structure
• variable region has short stretches of
  hypervariable regions CDR (complementary
  determining regions)
• special genetic mechanisms to develop

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Function 3

• Ag receptors are non-covalently linked to other
  invariant molecules which deliver message to
  inside of cell activation signal
• 2 functions of B-cell and T-cell receptors
  specific Ag recognition and signal transduction
• different polypeptides to do each function
• Receptors with Ag bound will aggregate
  (cross-link 2 or more Ag), causing signaling
  molecules to be close together, enzyme will
  attach on cytoplasmic portion the protein and
  phosphorylation of other proteins complex
  signaling cascade started mediate the lymph
  response
• T-cell signaling (Chapter 5)
• B-cell signaling (Chapter 7)

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Function 4

• Ab can be membrane bound or secreted (BCR) but
  TCR are only membrane bound
• Ab or immunoglobulins in the blood neutralize
  microbes and toxins
• recognize microbial Ag and toxins by variable
  domains constant domain binds other molecules
  (receptors on macrophages and complement
  proteins) that participate in eliminating Ag
• Chapter 8
• BCR functions to initiate humoral immune response
  and secreted Ab eliminates Ag in the effector
  phase of humoral response
• TCR function only in Ag recognition and T-cell
  activation do not mediate effector functions,
  done by the T-cell itself

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Antibodies

• 4 polypeptide chains 2 identical heavy (H)
  chains and 2 identical light (L) chains
• each chain has 1 variable and 1 constant
• L chain is attached to the H chain and the 2 H
  chains are linked by disulfide bonds intrachain
  and interchain

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Antibodies Secreted BCR

• 2 distinct regions
• constant region 1 type of 4 or 5 kinds,
  determines how pathogen is disposed of after
  binding of Ab part L and H chain
• variable region infinite number of forms, both
  arms are identical part L and H chain
• Characteristic folding pattern in each region
  Ig domain and it is found in other proteins in
  and out of the immune system

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Ab Regions

• Variable region is made up of VH and VL and has 3
  hypervariable regions called CDR
• CDR3 is most variable and contributes the most to
  Ag binding between V and C region
• Fab region is made up of VH,VL, CH1 and CL1
  fragment Ag binding (single arm of Y)
• Fc is made up of CH2 and CH3 fragment
  crystalline region
• F(ab)2 both arms and hinge region of Fc
• Between Fc and Fab is the hinge region that
  allows the Ab some flexibility for binding Ag
• Fc region is what dictates whether the BCR is
  anchored in the membrane or secreted into the
  intercellular space, also responsible for
  effector function

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Proteins of Ab

• Light chain has 2 classes
• ? and ? have different C regions but the same
  function
• Heavy chain has 5 classes
• ?, ?, ?, ? and ? that correspond to IgE, IgA,
  IgM, IgD and IgG respectively
• Many combinations of light and heavy chains
  contribute to the repertoire

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Isotypes (Classes)

• Ab with different heavy chains that differ in
  properties and effector functions
• All BCR (attached to membrane) are either IgM or
  IgD heavy chains
• it is only after Ag recognition that you will
  have a switch to a different heavy chain and lead
  to secretion from the B-cell heavy chain class
  (isotype) switching (Chapter 7)
• B cells retain specificity because it is only the
  constant region that is changing, not the
  variable region light chain is fixed in each
  clone

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Ag Binding

• Can bind a variety of Ag large macromolecules
  or small chemicals and many shapes
• allowed for the hinge region
• Ag-Ab reaction is created by H-bonds and charge
  interactions

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Ag Recognition Types

• Recognized components of Ag are called epitopes
  or determinants
• linear determinants AA are all in a row
• conformational determinants dependent on shape
  of Ag and may be AA at distant sites on the
  polypeptide
• neo-determinant hidden Ag that are exposed
  after physicochemical change

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Ag-Ab Attraction

• Affinity strength of the attraction between
  epitope and variable region of Ab
• Dissociation constant is the molar concentration
  required to occupy ½ of available Ab the lower
  the KD the higher the affinity
• 1 Ab response is in the range of 10-6 to 10-9
  but the 2 response can boost it to 10-8 to 10-11
  affinity maturation (Chapter 7)
• Avidity total strength of binding for all
  binding sites and the Ag
• dependent on Affinity and valence ( of binding
  sites)
• IgM avidity gt IgG
• Cross-reaction Ab that recognizes an Ag that is
  structurally similar to Ag it was made against

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BCR Ag Recognition

• BCR (membrane bound) will recognize Ag but they
  require Ig? and Ig? as part of the complex
• Ig? and Ig? transmit signals to interior so
  B-cell can be activated (Chapter 7)
• Monoclonal Ab is one that is made by 1 B-cell to
  recognize 1 Ag
• make by fusing a B-cell with a myeloma cell to
  make a hybridoma that will make just that Ab the
  B-cell is specific for

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T-Cell Receptor for Ag

• ? and ? chain with 1 variable and 1 constant
  region each homologous to Ig V and C regions
  (heterodimeric)
• V region has 3 hypervariable or complementary
  regions CDR3 is most important and most
  variable
• Always membrane bound, never secreted
• No class switching or affinity maturation

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TCR Recognition

• ? and ? chain participate in specific
  interactions with MHC and bound peptides
• Recognize as few as 1-3 residues in the
  MHC-associated peptide
• usually immuno-dominant epitope
• can tell difference between complex microbes by
  only 1-3 AA

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Subpopulations of T-cells

• TCR made of ? and ? chains
• 10 of T-cells have
• have different specificities
• abundant in epithelia
• may recognize a variety of protein/nonprotein Ag
  not displayed by classical MHC molecules
• Natural Killer T-cells
• lt5
• express markers of NK cells
• ??TCR can recognize glycolipid or other
  nonpeptide Ag displayed on non-polymorphic
  MHC-like molecules

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TCR Recognition

• TCR can recognize Ag but cant activate T cell
  requires CD3 and ? chain
• CD3 and ? chain passes message on into the cell
• Also requires CD4 or CD8 as accessory molecules
  which recognize the non-polymorphic parts of MHC
  (Chapter 5)

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Development of Immune Repertoires

• We get the enormous diversity in immune responses
  because of the maturation of the lymphocyte
• 3 processes involved
• proliferation of immature lymphocyte
• expression of Ag receptor genes
• selection of lymphocytes expressing useful
  receptors
• Common to B-cells (in BM) and to T-cells (in
  thymus)

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Immature Lymphocyte Proliferation

• Maximizes the numbers of cells available to
  express useful Ag receptors and mature into
  functionally mature lymphocytes
• IL-7 (growth factor) produced by stromal cells in
  the BM and thymus
• help lymphocytes proliferate without expressing
  Ag receptors
• later Ag receptors are expressed and then
  regulate signals for proliferation

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Ag Receptor Genes

• Ag receptor gene segments are separated in the
  germline, recombine during lymphocyte maturation
• Various nucleotide sequence changes at site of
  recombination
• Central to lymphocytes maturation

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Maturing Lymphocytes

• Selection at several steps to preserve usefulness
• based on expression of intact Ag receptor
  components and what they recognize, others will
  die by apoptosis
• Positive selection immature T-cells recognize
  self MHC molecules and then must recognize the
  same MHC to be activated delivers the signals
  for survival and proliferation
• Negative selection eliminates lymphocytes that
  recognize self antigens with high affinity

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