Transcript 10_14_immuno~4

Innate and adaptive immunity
• The immune system has various mechanisms to eliminate
pathogens that get past physical barriers. These include
both innate and adaptive immune responses. These work
together to result in the destruction of invading pathogens.
• Innate immunity (natural immunity):
– not specific for a given microbe
– act quickly, without the need for amplification of microbespecific cells that is seen in adaptive responses, providing
the first line of defense to microbial infection
• Adaptive immunity (acquired immunity):
– highly specific for a given infectious agent,
– more vigorous on subsequent exposure to the same
agent
– characterized by memory, amplification of responses,
and specificity
Recognition of Antigen by T and B cell Receptors
• T cell receptor (TCR) and the B cell
receptor (BCR, or surface
immunoglobulin) for antigen appear to
have a similar structure
• Also, both exhibit significant diversity,
with somatic recombination (DNA
rearrangements) being responsible
for most of this diversity
• However, there are several
fundamental differences between
these molecules:
• One important difference:
– the B cell antigen receptor (surface immunoglobulin), when
secreted and present in serum or other fluids as an
antibody, can exert its effector function,
– the T cell antigen receptor is found only as a cell surfaceassociated molecule
• Antibodies can:
– neutralize bacterial toxins by binding directly to these
molecule
– enhance phagocytosis by inducing opsonization
– activate the complement cascade, resulting both in lysis of
pathogens, as well as in their enhanced opsonization and
chemotaxis
• The T cell antigen receptor operates only as a cell surfaceassociated antigen-recognition molecule, and is not
secreted
• In fact, T cell-mediated effector functions are not actually
carried out by the TCR itself, in contrast to antibody
molecules, which can carry out several types of effector
functions in dealing with pathogens
• T cells exert their effector functions primarily by secreting
cytokines, or by acting as cytotoxic cells
• While these functions do involve the TCR as a means of
restricting specificity, the TCR itself does not exert these
activities
• Antibodies (Ab) are soluble
antigen-reactive molecules,
which are found in high
concentration in serum, and
are produced by B cells.
• An antibody molecule has
two antigen-binding sites
per molecule (variable
regions), and a constant
region, which plays important
roles in antibody effector
function.
• Antibodies are composed of two identical heavy chains and two
identical light chains
• Each light and heavy chain has a variable and constant
domain(s) - these combine to give a molecule with a constant
and variable regions (form the antigen-binding site).
• A cell surface-associated form of the immunoglobulin molecule
acts as the cell-surface receptor for antigen on B cells
• Cross-linking of surface Ig by antigen initiates the activation of B
cells
• When B cells are stimulated to make and secrete antibodies,
these secreted antibody molecules correspond to the surface
immunoglobulin expressed by those cells
• There are various immunoglobulin classes, or isotypes subtypes of antibody molecules
• The constant region of each of these immunoglobulin subclasses
differs, resulting in different biological functions
• The TCR forms part of the T
cell receptor complex on T
cells.
• This TCR complex is involved
not only in recognizing
antigen, but also participates
in the stimulation of signaling
that results in T cell activation.
• Another significant difference between
antibodies/immunoglobulins and the T cell receptor is that
antibodies (and B cells) can recognize intact antigens from
pathogens, while T cells do not
• The T cell receptor can only recognize antigens when fragments of
these antigens are displayed by specialized antigen-presenting
molecules on the surface of antigen-presenting cells (APC) MHC (major histocompatibility) molecules
• This difference is what allows antibody molecules to interact with
antigen when in solution, while T cells have to “see” antigen in the
context of an antigen-presenting cell
• Antigen-presenting
cells (APC) take-up
and process antigen,
allowing antigenderived peptides to
associate with MHC
molecules
• There are two types
of MHC molecules
that are important in
presenting antigen to
T cells:
– MHC class I
– MHC class II
• MHC class I molecules present antigens from intracellular
pathogens, such as antigens encoded by viruses
• Since MHC class I molecules operate as a sort of surveillance
system for intracellular pathogens, especially viruses, these
molecules are expressed on all nucleated cells
• MHC class II is involved in presenting antigens that antigenpresenting cells take up from their extracellular environment,
such as antigens that are produced by bacteria.
• Expression of MHC class II is restricted to specialized
antigen-presenting cells, so MHC class II is not expressed as
widely as MHC class I.
• Immune responses are sometimes
categorized as humoral responses or
cellular responses.
• The term humoral immunity refers to
forms of immune function that can be
transferred with the transfer of serum –
primarily antibody-mediated immunity,
since antibodies are soluble molecules
present in serum.
• Serum therapy, the passive transfer of
humoral immunity by giving patients serum
from an immune animal or person, was
common some years ago, and is still
utilized in some situations.
• Immune responses that could be
transferred by the transfer of cells, but
not of serum, from one animal to another
were referred to as cellular immunity, or
cell-mediated immunity.
• Cellular immunity is primarily due to the
actions of T cells, which do not secrete
their antigen receptor, and which need to
be present to exert the types of immune
responses that they are responsible for.
A N O V ER V IEW O F N O R M A L IM M U N E R ESP O N S ES
T Cell Subsets
cytokines
M onocyte
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• There are two major
subsets of T cells,
CD4-positive cells
and CD8-positive
cells.
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TH
TH
CD4
cytokines
ACTIVATION
cytokines
• CD4-positive T cells
are helper/inducer
cells
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TH
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CT L -P
CD8
B
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TH
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cytokines
PR O LIFER A TIO N
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B
B
• CD8-positive T cells
are cytotoxic T cells
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C TL
C TL
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D IFFER EN TIA TIO N =
C ELL K ILLIN G
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Plasma
cell
Plasma
cell
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• These different T cell subsets interact with different MHC
molecules:
– helper/inducer T cells (CD4) : MHC class II
– cytotoxic T cells (CD8) : MHC class I
• CD4-positive T cells, which interact with MHC class II-positive
antigen-presenting cells, are specialized for the induction of
responses to extracellular antigens
• These are two types of CD4 helper T cells:
– TH1 cells
– TH2 cells
• These CD4 subsets are defined by the pattern of cytokines that
they produce, and they have markedly different biological
effects, and help induce different sorts of immune responses.
• CD8-positive T cells, which interact with MHC class I-positive
antigen-presenting cells, are specialized for the induction of
responses to intracellular antigens
• CD8 cells, when stimulated, become cytotoxic killer cells.
• There are different types cells that can function as of antigenpresenting cells.
• Specialized or professional APC include:
– dendritic cells
– macrophages
– B lymphocytes
• All of these cells express significant levels of MHC class II
molecules on their surface, and can take up and process and
present antigen to CD4-positive T cells.
• Dendritic cells also are very effective at stimulating CD8 T cell
activation, inducing these cells to become cytotoxic T cells.
• CD4 and CD8 molecules play a direct role in APC:T cell
interactions, binding to MHC class II and class I, respectively.
• This ensures that MHC class I presents peptides to, and stimulates,
CD8 T cells, and that MHC class II interacts only with CD4 cells.
Lymphoid Tissue
• The different types of cells that make up the immune system are
distributed in blood and tissues, as well as in lymphoid
tissues/organs.
• Cellular interactions are
necessary to kick-off
immune responses –
these interactions occur
in lymphoid tissues.
• In addition to this, the
development of the cells
of the immune system also
takes place in other types
of lymphoid tissue.
• Lymphoid organs can be divided into:
– primary lymphoid organs, such as the thymus and bone
marrow - where lymphocytes develop and undergo
maturation
– secondary lymphoid organs, such as the spleen and
lymph nodes - where mature lymphocytes hang out and
interact with antigen and with each other, in the course of
initiating and carrying out immune responses
• The cells of the immune system develop from pluripotent
stem cells, which reside in bone marrow. Differentiation of
these stem cells is induced by interactions with the bone
marrow stromal cells, especially by certain cytokines
produced by these cells.
• B and T cells undergo distinct differentiation pathways.
• B cells are generated in the bone marrow, with mature B cells,
which are ready to respond to antigen, migrating to lymph nodes
and spleen.
• Tolerance is the induction of non-responsiveness to a
particular antigen, resulting in the inability to respond to that
antigen.
• Tolerance to self-antigens is a central feature of the immune
system.
• Loss of tolerance to self antigens can result in the destruction
of self-tissues by the immune system, resulting in autoimmune
disease.
• Tolerance to self-antigens is induced in both B and T cells
during their development.
• The induction of tolerance to selected non-self antigens
(transplanted tissue) would be a great thing to be able to
achieve:
• T cell precursors leave the bone marrow, go to the thymus,
where they mature, with mature T cells then migrating to
secondary lymphoid organs.
• The thymus is a primary lymphoid organ that is specialized for
the generation of mature, antigen-responsive T cells.
thymus
bone marrow
2o lymphoid
organs
• The cellular interactions between
APC and helper T cells, and between
activated helper T cells and other
lymphocytes, involve both direct cellcell contact, mediated by cell-surface
stimulatory and adhesion molecules,
as well as the production of cytokines.
• These interactions occur primarily in
the peripheral lymphoid organs
(lymph nodes and spleen), also
called secondary lymphoid organs.
• These are specialized for the
trapping of antigen, and for allowing
interaction of APC and T cells, and
leading to the initiation of immune
responses.
• Lymph nodes are kidney shaped organs that filter lymph.
• Lymph nodes contain B cell-enriched areas (follicles in the
cortex) and dendritic cell and T cell-enriched areas (the
paracortical area).
• Germinal centers are areas of proliferating B cells interacting
with T cells and antigen.
• Lymph draining the
extracellular spaces carries
antigens from the tissues to
the lymph nodes, entering via
the afferent lymphatic vessel.
• This brings soluble antigen in
contact with various types of
APC, including dendritic cells,
macrophages, and B cells.
• The spleen is a fist-sized organ that filters antigens from blood,
and is composed of two types of tissue, white pulp and red pulp.
• The red pulp contains
erythrocytes.
• The white pulp
contains arterioles
surrounded by
lymphoid cells,
including T cell and a B
cell-enriched areas.
Introduction to immunology concepts
• innate and adaptive immunity
– rapid vs. slow
– not antigen-specific vs. highly-specific
– not amplified on 20 exposure vs. strongly amplified + memory
• cells involved in immune responses
– lymphocytes (B and T cells, T cell subsets)
– phagocytic cells, antigen-presenting cells
• specific recognition of antigen
– T cell receptor (TCR), B cell receptor and antibodies
– antibodies can “see“ antigens in their native form, the TCR “sees” Ag only
when processed and presented appropriately
– MHC – interactions with antigen and TCR
– clonal selection
• lymphoid tissue
– 10 lymphoid tissue – where lymphocytes develop
– 20 lymphoid tissue –lymphocytes & APC interact to initiate immune responses