Adaptive Immunity to Infection
a.
Adaptive immunity is triggered when an infection eludes the innate
defense mechanisms and generates a threshold dose of antigen.
b.
This antigen then initiates an adaptive immune response, which becomes
effective only after several days, the time required for antigen-specific T and
B cells to proliferate and differentiate into effector cells.
c.
Meanwhile, the pathogen continues to grow in the host, held in check
mainly by innate and non-adaptive mechanisms.
d.
The first step in any adaptive immune response leading to protective
immunity is the activation of T cells in the draining lymphoid organs.
e.
The trapping of antigen by antigen-presenting cells that migrate to these
lymphoid tissues and the continuous recirculation of T cells through the tissues
ensures that rare antigen-specific T cells will encounter their specific antigen
on an antigen-presenting cell.
2.
Clonal selection of Lymphocytes
a.
Limitations of innate immunity:
i.
the defense systems of innate immunity are limited to those that bear
surface molecules that are common to many pathogens and can be recognized by
neutrophils and macrophages.
ii.
many bacteria have evolves capsules that enable them to conceal these
molecules and thereby avoid provoking phagocytic cells.
iii.
viruses carry no such unvarying molecules and are rarely recognized by
phagocytic cells.
iv.
moreover, the surface molecules of pathogens evolve at a very fast rate.
v.
the recognition mechanism used by lymphocytes has evolved to overcome
these problems.
b.
Diversity of Lymphocyte receptors:
i.
instead of bearing several receptors each specifically recognizing a
conserved surface molecule of a pathogen, each naive lymphocyte entering the
bloodstream bears receptors of only a single specificity.
ii.
however, the specificity of these receptors is determined by a unique
genetic mechanism that operates during the development of lymphocytes in the
bone marrow and thymus to generate hundreds of different variants of the
receptor gene.
iii.
thus, although individual lymphocytes carries receptors of only one
specificity, the specificity of each lymphocyte is different.
c.
Since each lymphocyte has a different antigen-binding specificity, the
fraction of lymphocytes that can bind and respond to any given antigen is very
small.
d.
To generate sufficient specific effector lymphocytes to fight an
infection, an activated lymphocyte must proliferate before its progeny finally
differentiate into effector cells.
e.
Lymphocyte activation and proliferation:
i.
initiated in the lymphoid tissues where phagocytic cells carrying antigen
are trapped.
ii.
these display the antigen to the naive recirculating lymphocytes as they
migrate through the lymphoid tissue before returning to the bloodstream via the
lymph.
iii.
when antigen interacts with the receptor on a mature lymphocyte, that
cell is activated to form a lymphoblast and then starts to divide.
iv.
it gives rise to a clone of identical progeny, all of whose receptors
bind the same antigen.
v.
these then differentiate into B cells or T cells.
f.
Cessation of Lymphocyte action:
i.
after a lymphocyte has been activated, it takes 4-5 days of proliferation
before clonal expansion is complete and the lymphocytes have differentiated into
effector cells.
ii.
that is why adaptive immune responses occur only after a delay of several
days.
iii.
effector cells only have a limited lifespan and once antigen is removed,
most of the antigen-specific cells undergo apoptosis.
iv.
however, some persist after the antigen has been eliminated.
v.
this is the basis of immunologic memory, which ensures a more rapid and
effective response on a second encounter with a pathogen and thereby provides
lasting immunity.
g.
Antigen-presenting cells:
i.
peripheral lymphoid tissues are specialized to trap phagocytic cells and
to promote interactions between cells that are necessary for the initiation of
the adaptive immune responses.
ii.
dendritic cells, macrophages and B cells trap antigen in the periphery
and migrate to lymphoid tissues where they present antigens to T cells.
iii.
dendritic cells are the most important antigen-presenting cell, playing a
central role in the initiation of the adaptive immune responses.
iv.
macrophages mediate innate immune responses directly and make a crucial
contribution to the effector phase of the adaptive immune response.
v.
antigen born by antigen-presenting cells may be swept into the spleen by
the blood or into the lymph nodes by the lymph or taken up by the M cells of the
gut-associated lymphoid tissue and trapped by antigen-presenting cells already
present there.
3.
Differentiation of CD4 T cells
a.
It is during the initial response of naive CD4 T cells to antigen in the
peripheral lymphoid tissues that the differentiation of these cells into the two
major classes of CD4 effector T cells occurs.
b.
This has a critical impact on the outcome of an adaptive immune response,
determining whether it will be dominated by macrophage activation or by antibody
production.
c.
Origin of TH1 cells:
i.
viruses and some bacteria induce IL-12 secretion by macrophages that can
activate NK cells to produce IFN-g.
ii.
naive CD4 T cells, activated in the presence of IL-12 and IFN-g
are committed to differentiate into TH1 cells that produce gamma interferon and
IL-2.
iii.
these interleukins activate macrophages and cytotoxic T cells
respectively, and cell-mediated immunity occurs.
d.
Origin of TH2 cells:
i.
other pathogens (e.g. worms) do not induce IL-12 expression by macrophage
but may cause NK1.1 CD4 T cells to synthesize and secrete IL-4 and IL-5.
ii.
these interleukins activate B cells to become plasma cells and antibodies
are produced.
e.
Activation of T cells:
i.
the activation of helper T cells requires that they recognize a complex
on the surface of antigen-presenting cells, e.g. macrophages consisting both the
antigen and a class II MHC protein.
ii.
within the cytoplasm of the macrophage, the foreign protein is cleaved
into small peptides that associate with class II MHC proteins.
iii.
the complex is transported to the surface of the macrophage, where the
antigen, in association with a class II MHC protein, is presented to the
receptor on the CD4-positive helper cell.
4.
Activation of Humoral response
a.
The most important functions of TH2 cells depend upon their interactions
with B cells, and these interactions occur in the lymphoid tissue.
b.
B cells specific for protein antigens cannot be activated to proliferate,
form germinal centers or differentiate into plasma cells until they encounter a
TH2 cell that is specific for one of the peptides derived from that antigen.
c.
B cells migrate through the peripheral lymphoid organs and it is thought
that the trapping and activation of naive CD4 T cells in the T-cell areas of
lymphoid tissues provide a concentration of antigen-specific helper T cells to
activate the B cells.
5.
Cellular Immunity
a.
Cooperation of T cells with B-cells to enhance the production of
antibodies; helper T cells function by releasing cytokines that provide various
activation signals for the B cells.
b.
Inflammatory effects:on activation, a certain T-cell subpopulation
releases cytokines that induce the migration and activation of monocytes and
macrophages, leading to the so-called delayed-type hypersensitivity
inflammatory reactions.
c.
Cytotoxic effects: killer T cells kills target cells on contact.
d.
Regulatory effects: suppressor T cells suppress the immune response
leading to a downward modulation or a shutoff in reactivity of other effector
cells.
e. Signal via cytokines through cytokines, T cells communicate and modulate activities of other lymphoid and nonlymphoid cells.