Humoral Response

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Humoral Response

• Reading
• Chapter 11

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• Antigen selection and clonal expansion

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• Humoral Response
• Immunologic memory
• First exposure Primary response lag of
  5-7 days and peaks at 10-17 days while TH cells
  activate B cells
• Second exposure Induction of a rapid response
  lag of 1-2 days lasts months to years due to
  clonal expansion and activation of memory B cells

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• Primary response following activation of naive
  lymphocyte
• Lag phase
• Highly variable
• Characteristic antibody production, Ex. soluble
  antigens
• Primary humoral response and antibody production
• IgM that may switch to IgG
• Generation of memory B cells in G0

• Secondary Response following activation of
  memory lymphocytes

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• Known reasons for difference between primary and
  secondary response
• Size of B cell population
• Activation rate of memory B cells
• Synthesis of high affinity antibodies
• Due to affinity maturation and class switching
• Provides specificity for epitopes

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• Humoral response requires activation of both TH
  cells and B cells
• Experiments using hapten-carrier conjugates have
  shown that both TH and B cells must recognize
  antigenic determinants (epitopes) on the same
  antigen for activation of B cells
• Requirement of coupling to a carrier
• Secondary response and the carrier effect
• Separate populations recognize epitope on the
  carrier and hapten

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Removal of T cells
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• TH cells population generated from the mouse
  primed with the unrelated carrier BGG are
  required for B cell activation and the secondary
  immune response
• TH cell population is specifically generated in
  the mouse primed with the unrelated carrier BGG
• Response of hapten-primed B cells to
  hapten-carrier conjugates reuiqres the presence
  of carrier-primed CD4 TH cells specific for
  carrier epitopes

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• In vivo induction of humoral responses
• Spleen and lymph nodes are sites where antigen
  can be pooled and interact with lymphocytes
• Lymph Nodes
• Filters gt90 of antigen
• Antigen transporting cells
• Cells encountered in specific regions of the
  lymph node

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• Overview of the generation of a humoral response
  in the lymph node
• Ag-mediated B cell activation
• Proliferation of B cells at edge of T cell rich
  zone
• B cells differentiate and secrete antibody for
  primary response
• Migration of activated B and TH cells to follicle
• Development of a secondary follicle and
  importance of follicular dendritic cells
• Formation of the germinal center

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• Celluar interactions in the Germinal Center
• Developed 7-10 days after TD Ag exposure
• Centroblast proliferation in the dark zone
• Characteristics of centroblasts
• Development of centrocytes
• Migration to the light zone and interaction with
  follicular dendritic cells
• Events within the light zone

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• Generation of high affinity antibodies
• Primarily due to somatic hypermutation (SH) and
  selection process
• Intense SH in germinal center (H or L chain
  mutated/2 cell divisions)
• SH concentrated in CDRs of V region

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• Some comments on Ag selection
• mIg molecules of centrocyte bind Ag on follicular
  dendritic cells in the light zone
• Binding provides a survival signal
• Centrocytes with high affinity mIg are more
  likely to receive survival signal
• Surviving centrocytes must interact with CD40L of
  TH cells and TCR
• CD40-CD40L
• Class II MHC-Ag TCR-CD3

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• Cytokines affect what Ig class is chosen when
  IgM- cell undergoes class switch
• Requires CD40-CD40L interaction, without CD40L
  X linked hyper IgM syndrome
• (Class switch allows any given VH domain to
  associate with the constant region of any
  isotype antibody specificity remains constant
  while effectory functions can change.)

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• Memory and plasma cells are generated in germinal
  centers
• Differentiation requires a change in RNA
  processing of H chain from membrane bound form to
  the secreted form
• Regulation of B cell Development primarily
  controlled by transcription factors
• Ex. BSAP, c-Jun, E2A, Ikaros etc.
• BSAP (B cell specific activator protein) is a
  master B cell regulator

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• Regulation of Immune Effector Response
• Final outcome of immunity or tolerance depends
  upon several factors
• immunologic history of the animal
• presence of competing antigen
• antibody- mediated suppression