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SPECIFIC ACQUIRED IMMUNITY

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SPECIFIC ACQUIRED IMMUNITY Microbes evade, hosts respond Recall that innate immunity is based on recognition of molecular patterns in microbial cell walls, which sets off – PowerPoint PPT presentation

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Title: SPECIFIC ACQUIRED IMMUNITY


1
SPECIFIC ACQUIRED IMMUNITY
Microbes evade, hosts respond
  • Recall that innate immunity is based on
    recognition of molecular patterns in microbial
    cell walls, which sets off
  • Phagocytic cells
  • Complement
  • Killer cells
  • Microbes evolved to evade this primitive level of
    detection
  • Higher organisms evolved adaptor molecules, to
    connect specific microbial structures to these
    defense mechanisms

2
The adaptor molecules Ig and TCR
  • One end is specific to the invading microbe
  • The other end mediates cellular function
  • Alternative way to set off the immune responses
  • T-cell Receptor has structure similar to Ig
    and mediates a cytotoxic response

3
The Antibody molecule
  • B cells undergo rearrangement of DNA in the Ig
    genes all possible combinations of V, D and J
    segments into Heavy (VHDHJH) and light (VLJL)
    chain
  • These create the CDRs that form the antigen
    binding site
  • Millions of different combinations are possible
    many (nearly all?) are made by different B cell
    lines
  • B cells with rearranged Ig genes make just that
    one Ig molecule, and initially put it out on the
    surface as a membrane bound Ig molecule

4
Clonal Expansion and 1Response
  • When antigen interacts with an Ig on a B-cell
    surface, that B-cell is stimulated to
  • Proliferate (clonal expansion)
  • Differentiate into plasma cells, that make tons
    of secreted immunoglobulin of that exact
    antigenic specificity, and then die.
  • This is the primary immune response. It is
    relatively slow because there are very few of
    each version of naïve B-cell sitting around

5
Memory, and Adaptive response
  • When B-cells are stimulated to proliferate, some
    do not differentiate into plasma cells. They
    withdraw from the cell cycle
  • This is a larger number of cells than were
    present before the clonal expansion .. if the
    same microbe/antigen comes again, there will be
    more cells that are able to see it
  • When memory cells bind antigen, they are
    stimulated to proliferate and differentiate and
    because there are more of them around, the
    response is much quicker.

6
Memory, and Adaptive response
  • When B-cells are stimulated to proliferate, some
    do not differentiate into plasma cells. They
    withdraw from the cell cycle
  • This is a larger number of cells than were
    present before the clonal expansion .. if the
    same microbe/antigen comes again, there will be
    more cells that are able to see it
  • When memory cells bind antigen, they are
    stimulated to proliferate and differentiate and
    because there are more of them around, the
    response is much quicker.
  • The host has adapted to the microbe, making a
    faster response the second time
  • The secondary response is often also better
    because the cells displaying the highest affinity
    antibody are the ones that are most likely to
    bind Ag the second time, and be stimulated

7
Vaccination is based on this more rapid secondary
response
  • Challenge host with antigen that is similar to
    something dangerous toxin or pathogen
  • Altered toxin (toxoid, such as Tetanus toxoid)
  • Related but non-pathogenic virus (Vaccinia for
    smallpox)
  • Killed Virus (Salk polio)
  • Attenuated virus (Sabin polio, egg-passaged
    influenza)
  • Recombinant pathogenic marker (Hep B protein
    expressed in yeast, Strep M protein?)
  • Immune response will give protection because Abs
    will recognize epitopes on these similar antigens
  • Immune response can remove antigen or pathogen
    before it does damage to the host.

8
The T-cell Receptor (TCR)
  • T-cells are lymphocytes that develop in the
    thymus. Do not make soluble Ig, but they do make
    a membrane protein (the TCR) with similar
    structure and recognition capabilities
  • T-cells are part of an adaptive and specific
    response
  • Specific Recognition site involves two
    polypeptide chains that result from gene
    rearrangement to provide many possible
    combinations in the variable region (sound
    familiar?)
  • Adaptive Clonal expansion of T-cells occurs
  • There are different kinds of T-cells with
    particular functions. The two best studied are
    Helper T-cells and Cytotoxic cells

9
Adaptor molecules trigger some of the same kinds
of responses seen in innate immunity
  • Antibodies
  • Phagocytosis
  • Complement-mediated killing
  • T-cell receptor
  • Cytotoxic lymphocytes

10
Phagocytosis
  • Antibodies can directly activate macrophages by
    their Fc regions
  • Polyvalent binding can enhance this dramatically

11
Complement alternative pathway
  • Alternative pathway ( innate immunity) is set
    off by repetetive patterns on microbes
  • C3bBb (C3 convertase) is stabilized by microbes,
    and catalyzes
  • C3 C3b C3a
  • C5 C5b C5a
  • C6789 and MAC
  • C3a and C5a
  • Chemotactic for Mf (phagocytosis)
  • Activate mast cells (inflammation)

12
The Classical Pathway has a molecule that
responds to Antibody recognition of microbes
C1r and C1 s have enzymatic activity, cleaving C4
to C4b, and C4b2 to C4b2a
13
Ig activates the classical pathway of
complement
  • Classical pathway is set off by Antibody
    interacting with C1, a large molecule with
    subunits q, r and s
  • C1qrs catalyzes C4 to C4b, and then C4b2 to C4b2a
  • C4b2a is a C3 convertase, and catalyzes
  • C3 C3b C3a
  • C5 C5b C5a
  • C6789 and MAC
  • C3a and C5a
  • Chemotactic for Mf (phagocytosis)
  • Activate mast cells (inflammation)

14
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15
Cell-mediated adaptive immunityCytotoxic
lymphocytes
  • Dont have antibodies but T-cell receptors,
    which are similar to antibodies
  • Paired polypeptide chains, a and b domain
    structure with C and V regions
  • Gene rearrangements that provide many versions of
    the V regions that have exquisite specificity
  • Non-specific end of molecules mediates the host
    response
  • TCRs are membrane-bound molecules when engaged,
    cell responds to try to eliminate the foreign
    entity

16
Cytotoxic Lymphocytes (CTLs)
  • Some pathogens live inside host cells and thus
    are difficult for the immune system to detect
    (viruses are obligate, some parasites are
    facultative)
  • CTLs are T-cells lymphocytes that
  • to recognize foreign things
  • see them really only when they are in normal
    cells. Cell surface proteins seen in the same
    cells that contain normal cell proteins eg
    virally infected cells or tumor cells)
  • Respond to foreign in the context of normal by
    killing the cell. Cytotoxic T-cells (CTLs kill
    cells they recognize as bearing foreign antigens
    (such as virally infected cells, or tumor cells)

17
What CTLs recognize
  • Normal host cells have a set of proteins that are
    present on the surface of nearly all cells of
    that organism
  • These are Class 1 Antigens (from the major
    histocompatiblity complex, or MHC)
  • T cells have T Cell receptors that are similar in
    structure (and function) to Ig molecules
  • T cell receptors see (bind to) Class 1 antigens
    that look strange because they have foreign
    molecules lose by. What we say is that they
    recognize foreign proteins in the context of
    class 1 molecules (more on that later)
  • T cells undergo clonal expansion when they
    recognize foreign antigens together in the
    context of Class 1 MHC proteins this
    recognition triggers proliferation of this
    particular line of cells (sound familiar??)

18
Summary
  • Antibodies (and T-cell receptors) serve as
    specific adaptors to recognize invaders and make
    them subject to the hosts defense system,
    consisting of phagocytic cells, complement and
    killer cells
  • Acquired immunity is specific because the the
    adaptor molecules are highly variable in
    structure
  • It is adaptive because clonal selection and
    proliferation enhance the response over time and
    multiple challenges.
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