Transcript Specific Immunity

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
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
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
Clonal Expansion and 1°Response
• 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
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.
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
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.
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 Tcells and Cytotoxic cells
Adaptor molecules trigger some of
the same kinds of responses seen
in innate immunity:
• Antibodies
– Phagocytosis
– Complement-mediated killing
• T-cell receptor
– Cytotoxic lymphocytes
Phagocytosis
• Antibodies can directly activate
macrophages by their Fc regions
• Polyvalent binding can enhance this
dramatically
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)
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
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)
Cell-mediated adaptive immunity:
Cytotoxic lymphocytes
• Don’t 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
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 Tcells (CTLs kill cells they recognize as
bearing foreign antigens (such as virally
infected cells, or tumor cells)
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??)
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.