Transcript Path_ggf_9g

The Adaptive Immune
Response
FUNCTIONS OF THE IMMUNE SYSTEM:
• Recognize, destroy and clear a diversity of pathogens.
•
Initiate tissue and wound healing processes.
• Recognize and clear damaged self components.
Exhibit “tolerance” to innocuous material including self
The Normal Immune Response
The normal immune response is best understood in the
context of defense against infectious pathogens, the
classical definition of immunity.
Innate immunity refers to defense mechanisms that have
evolved to specifically recognize microbes and protect
individuals against infections.
Adaptive immunity consists of mechanisms that are
stimulated and are capable of recognizing microbial and
nonmicrobial substances.
Innate immunity
The first line of defense always ready to prevent
and eradicate infections.
Adaptive immunity
Develops later, after exposure to microbes, and
is even more powerful than innate immunity in
combating infections.
By convention, the term “immune response”
refers to adaptive immunity.
Innate and Adaptive immunity represent two different arms of the
immune system that work together in host defense.
Innate Immunity (natural/native):
• Provides immediate protection from infection.
• Is broadly specific to microbes and tissue damage products.
• Does not change in response to reinfection (nonadaptive)
• Initiates processes that lead to activation of adaptive immune
responses.
Adaptive Immunity (specific/acquired):
• Appears to adapt to a variety of non-self components (acquired)
• Is highly specific to a particular molecule “antigen”
• Responses upon reinfection are faster, better and stronger
(memory)
• Generates proteins and cells that enhance innate immune function.
The innate immune system provides immediate protection.
The adaptive response takes time to develop and is antigen specific.
Activation of B and T lymphocytes
Naive
Naive
Plasma cells
ADAPTIVE IMMUNITY
The adaptive immune system consists of lymphocytes and their
products, including antibodies.
The receptors of lymphocytes are much more diverse than
those of the innate immune system, but lymphocytes are not
inherently specific for microbes, and they are capable of
recognizing a vast array of foreign substances.
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There are two types of adaptive Immunity
Cellular immunity : mediated by T lymphocytes and is responsible
for defense against intracellular microbes.
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Humoral immunity: mediated by B lymphocytes and their
secreted products, antibodies (also called immunoglobulins, Ig)
that protects against extracellular microbes and their toxins.
Types of Adaptive Immune Reponses
Lymphocytes
Although lymphocytes appear morphologically unimpressive and similar to
one another, they are actually remarkably heterogeneous and specialized
in molecular properties and functions.
Lymphocytes and other cells involved in immune responses are not fixed in
particular tissues (as are cells in most of the organs of the body) but are
capable of migrating among lymphoid and other tissues and the vascular
and lymphatic circulations.
This feature permits lymphocytes to home to
any site of infection.
In lymphoid organs, different classes of
lymphocytes are anatomically segregated in such
a way that they interact with one another only
when stimulated to do so by encounter with
antigens and other stimuli.
http://www.nature.com/nri/journal/v12/n1/images/nri3128-f5.jpg
Mature lymphocytes that have not encountered the antigen for
which they are specific are said to be naive (immunologically
inexperienced).
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After they are activated by recognition of antigens and other
signals lymphocytes differentiate into:
effector cells, which perform the function of eliminating microbes.
memory cells, which live in a state of heightened awareness and
are better able to combat the microbe in case it returns.
http://www.nature.com/nri/journal/v7/n12/images/nri2204-f1.jpg
B Lymphocytes
B lymphocytes develop from precursors in the bone marrow.
Mature B cells constitute 10% to 20% of the circulating peripheral lymphocyte
population and are also present in peripheral lymphoid tissues such as lymph
nodes, spleen, and mucosa-associated lymphoid tissues.
B cells recognize antigen via the B-cell antigen receptor complex.
Membrane-bound antibodies called IgM and IgD, present on the surface of all
mature, naive B cells, are the antigen-binding component of the B-cell receptor
complex.
Each B-cell receptor has a unique antigen specificity, derived from RAGmediated rearrangements of Ig genes.
After stimulation by antigen and other signals, B cells develop into plasma
cells that secrete antibodies, the mediators of humoral immunity.
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Immunoglobulin
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Immunoglobulins (cont.)
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µ-mRNA
B Lymphocytes
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In addition to membrane Ig, the B-cell antigen receptor complex
contains a heterodimer of two invariant proteins called Igα and Igβ.
B cells also express several other molecules that are essential for their
responses. These include complement receptors, Fc receptors, and
CD40.
Upon activation, B lymphocytes proliferate and then differentiate into
plasma cells that secrete different classes of antibodies with distinct
functions (Fig. 6-12).
Upon activation, B lymphocytes proliferate and then differentiate into
plasma cells that secrete different classes of antibodies with distinct
functions (Fig. 6-12).
Many polysaccharide and lipid antigens have multiple identical
antigenic determinants (epitopes) that are able to engage many antigen
receptor molecules on each B cell and initiate the process of B-cell
activation.
Typical globular protein antigens are not able to bind to many antigen
receptors, and the full response of B cells to protein antigens requires
help from CD4+ T cells.
B cells ingest protein antigens into
vesicles, degrade them, and display
peptides bound to MHC molecules
for recognition by helper T cells.
The helper T cells express CD40L
and secrete cytokines, which work
together to activate the B cells.
http://upload.wikimedia.org/wikipedia/commons/thumb/f/f7/B_cell_activation.png/300px-B_cell_activation.png
Immunoglobulins
• IgG, IgM and IgA constitute 95% of serum
immunoglobulins
• IgE trace, IgD B cell membrane associated
• Monomeric IgM on B cell surface
constitutes B cell receptor
• B cell antigen receptor complex contains
nonpolymorphic transmembrane proteins
like the CD3 proteins of TCR, Iga and Igb
Each plasma cell secretes antibodies that have the same antigen binding
site as the cell surface antibodies (B-cell receptors) that first recognized
the antigen.
Polysaccharides and lipids stimulate secretion mainly of IgM antibody.
Protein antigens, by virtue of CD40L- and cytokine-mediated helper T-cell
actions, induce the production of antibodies of different classes, or
isotypes (IgG, IgA, IgE).
Cytokines that induce isotype switching include IFN-γ and IL-4.
Helper T cells also
stimulate the production of
antibodies with high
affinities for the antigen.
This process, called affinity
maturation, improves the
quality of the humoral
immune response.
Isotype switching and
affinity maturation occur
mainly in germinal centers,
which are formed by
proliferating B cells,
especially in helper T celldependent responses to
protein antigens.
http://www.cs.unm.edu/~immsec/html-imm/AFF-MAT1.JPG
Helper T cells are required for efficient isotype switching, affinity
maturation and generation of long lived memory B cells
Signal 1
Signal 2
Antibodies bind to microbes and prevent them from infecting cells,
thus “neutralizing” the microbes. IgG antibodies coat (“opsonize”)
microbes and target them for phagocytosis, since phagocytes
(neutrophils and macrophages) express receptors for the Fc tails of
IgG. IgG and IgM activate the complement system by the classical
pathway, and complement products promote phagocytosis and
destruction of microbes.
The production of most
opsonizing and
complement-fixing IgG
antibodies is stimulated
by TH1 helper cells,
which respond to many
bacteria and viruses;
thus, the protective
response to most
bacteria and viruses is
driven by TH1 cells.
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Some antibodies serve special roles at particular anatomic sites.
IgA is secreted from mucosal epithelia and neutralizes microbes
in the lumens of the respiratory and gastrointestinal tracts (and
other mucosal tissues).
IgG is actively transported across the placenta and protects the
newborn until the immune system becomes mature.
IgE and eosinophils
cooperate to kill parasites,
mainly by release of
eosinophil granule contents
that are toxic to the worms.
TH2 cells secrete cytokines
that stimulate the
production of IgE and
activate eosinophils, and
thus the response to
helminths is orchestrated by
TH2 cells.
http://faculty.ccbcmd.edu/courses/bio141/lecguide/unit5/humoral/5classes/images/u3fig2t.jpg
Most circulating IgG antibodies have half-lives of about 3 weeks.
Some antibody-secreting plasma cells migrate to the bone marrow and
live for years, continuing to produce low levels of antibodies.
The majority of effector lymphocytes induced by an infectious
pathogen die by apoptosis after the microbe is eliminated, thus
returning the immune system to its basal resting state, called
homeostasis.
The initial activation of lymphocytes also generates long-lived memory
cells, which may survive for years after the infection.
Memory cells are an expanded pool of antigen-specific lymphocytes
(more numerous than the naive cells specific for any antigen that are
present before encounter with that antigen), and that respond faster
and more effectively when re-exposed to the antigen than do naive
cells. This is why the generation of memory cells is an important goal
of vaccination.
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T Lymphocytes
T lymphocytes develop from precursors in the thymus. Mature T
cells are found in the blood, where they constitute 60% to 70% of
lymphocytes, and in T-cell zones of peripheral lymphoid organs
(described below).
Each T cell recognizes a specific cell-bound antigen by means of
an antigen-specific T-cell receptor (TCR). In approximately 95% of
T cells the TCR consists of a disulfide-linked heterodimer made up
of an α and a β polypeptide chain, each having a variable (antigenbinding) region and a constant region.
The αβ TCR recognizes peptide
antigens that are displayed by
major histocompatibility complex
(MHC) molecules on the surfaces
of antigen-presenting cells
(APCs).
By limiting the specificity of T cells
for peptides displayed by cell
surface MHC molecules, called
MHC restriction, the immune
system ensures that T cells see
only cell-associated antigens
(e.g., those derived from
microbes in cells).
http://life.nthu.edu.tw/~b861610/seminar/2000-4-13/tcr-mhc.JPG
TCR diversity is generated by somatic rearrangement of the genes
that encode the TCR α and β chains.
All cells of the body, including lymphocyte progenitors, contain
TCR genes in the germ-line configuration, which cannot be
expressed as TCR proteins.
During T cell development in the thymus, the TCR genes rearrange
to form many different combinations that can be transcribed and
translated into functional antigen receptors.
The enzyme in developing lymphocytes that mediates
rearrangement of antigen receptor genes is the product of RAG-1
and RAG-2 (recombination activating genes); inherited defects in
RAG proteins result in a failure to generate mature lymphocytes.
Whereas each T cell expresses TCR molecules of one specificity,
collectively, the full complement of T cells in an individual is
capable of recognizing a very large number of antigens. It is
important to note that unrearranged (germ-line) TCR genes are
present in all non-T cells in the body, but only T cells contain
rearranged TCR genes.
Hence, the presence of rearranged TCR genes, which can be
demonstrated by molecular analysis, is a marker of T-lineage
cells. Furthermore, because each T cell and its clonal progeny
have a unique DNA rearrangement (and hence a unique TCR), it is
possible to distinguish polyclonal (non-neoplastic) T-cell
proliferations from monoclonal (neoplastic) T-cell proliferations.
Thus, analysis of antigen receptor gene rearrangements is a
valuable assay for detecting lymphoid tumors.
http://wenliang.myweb.uga.edu/mystudy/immunology/ScienceOfImmunol
ogy/NotesImages/Topic174NotesImage5.gif
A small population of mature T cells expresses another type of
TCR composed of γ and δ polypeptide chains.
The γδ TCR recognizes peptides, lipids, and small molecules,
without a requirement for display by MHC proteins.
γδ T cells tend to aggregate at epithelial surfaces, such as the skin
and mucosa of the gastrointestinal and urogenital tracts,
suggesting that these cells are sentinels that protect against
microbes that try to enter through epithelia.
However, the functions of γδ T cells are not clearly understood.
Another small subset of T cells expresses markers that are found
on NK cells; these cells are called NK-T cells. NK-T cells express a
very limited diversity of TCRs, and they recognize glycolipids that
are displayed by the MHC-like molecule CD1. The functions of NKT cells are also not well defined.
Figure 1 Structure of the TCR
Tripodo, C. et al. (2009) Gamma-delta T-cell lymphomas
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2009.169
Figure legend for previous slide
During T-cell development, CD4−CD8− T-cells are committed either to an αβ
or γδ fate as a result of an initial β or δ TCR gene rearrangement. Cells that
undergo early β chain rearrangement express a pre-TCR structure composed of a
complete β chain and a pre-TCRα chain on the cell surface. Such cells switch to
a CD4+CD8+ state, rearrange the TCRα chain locus, and express a mature αβ
TCR on the surface. CD4−CD8− T cells that successfully complete the γ gene
rearrangement before the β gene rearrangement express a functional γδ TCR and
remain CD4−CD8−. The complete α, β, γ, and δ TCR chains display strong
structural homology with immunoglobulin light and heavy chains, as they consist
of a variable amino-terminal region and a constant region. Abbreviations: C,
constant; DN, double-negative (CD4−CD8−); DP, double-positive (CD4+CD8+);
pTα, pre-TCRα chain; TCR, T-cell receptor; V, variable.
http://www.nature.com/nri/journal/v2/n5/images/nri797-t1.gif
In addition to CD3 and ζ proteins, T cells express several other
proteins that assist the TCR complex in functional responses.
These include CD4, CD8, CD2, integrins, and CD28.
CD4 and CD8 are expressed on two mutually exclusive subsets of
αβ T cells.
CD4 is expressed on
approximately 60% of mature
CD3+ T cells, which function as
cytokine-secreting helper cells
that help macrophages and B
lymphocytes to combat infections,
whereas
During antigen presentation, CD4
molecules bind to class II MHC
molecules that are displaying
antigen.
http://ars.els-cdn.com/content/image/1-s2.0-S095279151200115X-gr2.jpg
CD8 is expressed on about 30% of T
cells, which function as cytotoxic
(killer) T lymphocytes (CTLs) to
destroy host cells harboring
microbes.
CD4 and CD8 serve as
“coreceptors” in T-cell activation,
so called because they work with
the antigen receptor in responses to
antigen.
When the antigen receptor of a T cell recognizes antigen, the CD4 or
CD8 co-receptor initiates signals that are necessary for activation of
the T cells.
Because of this requirement for co-receptors,
CD4+ helper T cells can recognize and respond to antigen displayed
only by class II MHC molecules, whereas CD8+ cytotoxic T cells
recognize cell-bound antigens only in association with class I MHC
molecules.
Dendritic Cells
There are two types of cells with dendritic morphology that are functionally quite
different. Both have numerous fine cytoplasmic processes that resemble
dendrites, from which they derive their name.
Interdigitating dendritic cells, or just dendritic cells.
These cells are the most important antigen-presenting cells
(APCs) for initiating primary T-cell responses against protein
antigens.
Several features of dendritic cells account for their key role in
antigen presentation.
http://www.nobelprize.org/educational/medicine/immunity//images/detail/agp.gif
First, these cells are located at the right place to capture antigens—under
epithelia, the common site of entry of microbes and foreign antigens, and in
the interstitia of all tissues, where antigens may be produced.
Immature dendritic cells within the epidermis are called Langerhans cells.
http://upload.wikimedia.org/wikipedia/commons/2/2e/Dendritic_cells.jpg
Second, dendritic cells express many receptors for capturing and
responding to microbes (and other antigens), including TLRs and
mannose receptors.
http://www.nature.com/nri/journal/v1/n2/images/nri1101-135a-f5.gif
Third, in response to microbes,
dendritic cells are recruited to the Tcell zones of lymphoid organs, where
they are ideally located to present
antigens to T cells.
Fourth, dendritic cells express high
levels of the molecules needed for
presenting antigens to and activating
CD4+ T cells.
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Follicular dendritic cell
These cells bear Fc receptors for IgG and receptors for
C3b and can trap antigen bound to antibodies or
complement proteins.
Such cells play a role in humoral immune responses by presenting antigens
to B cells and selecting the B cells that have the highest affinity for the
antigen, thus improving the quality of the antibody produced.
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MHC is HLA
HLA and Disease Association
Disease
HLA
Allele
Risk
(%)
Ankylosing spondylitis
B27
90–
100
Postgonococcal arthritis
B27
14
Acute anterior uveitis
B27
14
Rheumatoid arthritis
DR4
4
Chronic active hepatitis
DR3
13
Primary Sjogren
syndrome
DR3
9
Type 1 diabetes
DR3
5
DR4
6
DR3/DR4
20
APCs
All nucleated cells
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