B-CELLS

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B-CELLS

• Origin
• Development
• SelectionS
• ActivationS

• Progenitor B cells (pro-B-cells) bearing a CD45R
  marker develop in the bone marrow into
  immature and then mature B cells.
• Then, they migrate to peripheral lymph nodes.
• Those developmental events are physically and
  physiologically distinct the former are antigen
  independent the latter are antigen dependent.

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NEGATIVE selection

• crosslinkage of mIgM on immature B cells can
  cause cells to die within the bone marrow
• aka CLONAL DELETION

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Nota bene

• Prior to clonal deletion, development is antigen
  independent.
• Negative selection and positive selection are
  antigen dependent.
• Recognition of the ANTIGEN in the periphery leads
  to positive selection
• aka CLONAL EXPANSION

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SELECTION does not equal ACTIVATION

• Recall that a B-CELL needs a signal from a
  T-HELPER CELL

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SELECTION does not equal ACTIVATION

• Recall that a B-CELL needs a signal from a
  T-HELPER CELL

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Signaling is synergistic
Consider how cytokines function.
Remember their potency and locality.
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SELECTION does not equal ACTIVATION

• Recall that a B-CELL needs a signal from a
  T-HELPER CELL

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Activation.

• Activation occurs when a B-cell associates with a
  T-helper cell through a ternary complex this
  association establishes specificity (the B-cell
  will have processed the antigen and presented it
  through MHC-II, thus selecting a specific
  T-helper cell lineage).
• Pairing between B7 on the B-cell and CD28 on the
  T-helper cell constitutes a co-stimulatory signal
  which will activate the T-helper cell. (The
  identities of the co-stimulatory proteins are
  specific but these same proteins are involved
  regardless of the identity of the antigen).
• The T-helper cell , once activated, synthesizes
  CD40L. Now, pairing occurs between CD40 on the
  B-cell and CD40L on the T-helper cell . This
  association constitutes a co-stimulatory signal
  which activates the B-cell.
• Thus, there is mutuality between the B-cell
  activating the T-helper cell and the activated
  T-helper cell, in turn, activating the B-cell.
• (This mutuality should not obscure that the
  process is antigen-driven.)

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• Cytokines of various types are secreted by
  T-helper cell and are received by
  differentiating B-cells.
• The various cytokines affect what immunoglobulin
  isotypes will be produced by plasma cells.

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Where is activation happening?And what is
happening?

• The primary response is initiated in the
  paracortex.
• T-cells respond to processed antigen that is
  typically delivered from a site of origin by
  dendritic cells.
• B-cells see the same antigen in an unprocessed
  form in the lymph.
• The T-cells and B-cells, now both activated,
  form associations which allow proper signaling.
• The B-cells migrate to the periphery of the
  paracortex and form foci where they mature into
  plasma cells which secrete, first, IgM and then
  IgG.
• Some B-cells along with some T-helper cells
  migrate to primary follicles in the cortex.

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Primary follicles develop into secondary follicles

• The secondary follicles have an area of
  proliferation (a germinal center) where B-cells
  proliferate and differentiate.

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Follicular dendritic cells not an APC!

• The follicular dendritic cells do not originate
  in the bone marrow and do not have MHC-II.
• Rather, the follicular dendritic cell contains Fc
  receptors, receptors which can capture
  immunoglobulins through their constant region.

Thus, the follicular dendritic cells become
decorated with Ab complexed to whole
(unprocessed) antigen. Stated another way, these
follicles have a rich supply of the filtered
antigen The dendrites are fragile and can break
in to (non-nucleated) beads (about 0.3-0.4 µm in
diameter) these beads are called iccosomes
(immune-complex coated bodies) they can persist
for several months.
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How do the primary and secondary responses differ?
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How do the primary and secondary responses differ?

• The secondary response is more intense because
• there are more memory cells specific for an
  antigen than there are naive cells,
• (ii) the immunoglobulins of memory cells have
  experienced affinity maturation and bind to
  antigen more strongly,
• (iii) memory cells have a much more extensive
  exposure to antigen (presented by follicular
  dendritic cells), and
• (iv) activation of memory cells requires a less
  strong stimulation.