Transcript 9 Lymphatic System and Immunology

Lymphatic System and
Immunity:
Lymphatic System
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Lymph
Lymphatic vessels
Lymphatic tissue
Lymphatic nodules
Lymph nodes
Tonsils
Spleen
Thymus
Lymphatic Vessels
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Carry lymph away from tissues
Lymphatic capillaries
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More permeable than blood capillaries
Epithelium functions as series of one-way valves
Functions of the Lymphatic
System
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Fluid balance
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Fat absorption
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Excess interstitial fluid enters lymphatic
capillaries and becomes lymph
Absorption of fat and other substances from
digestive tract
Defense
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Microorganisms and other foreign substances are
filtered from lymph by lymph nodes and from
blood by spleen
Lymphatic Tissue and Nodules
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Lymphatic tissue
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Consists mainly of
lymphocytes
Encapsulated or not
Lymphatic nodules
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Numerous in loose
connective tissue of
digestive (Peyer’s
patches), respiratory,
urinary, reproductive
systems
Tonsils
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Large groups of lymphatic
nodules in nasopharynx
and oral cavity
Provide protection against
bacteria and other harmful
material
Groups
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Palatine
Pharyngeal
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Lingual
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Lymph Nodes
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Organized in cortex and medulla
Substances removed by phagocytosis or stimulate
lymphocytes or both
Only structures to filter lymph
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Afferent and efferent vessels
Figure 25-16 Molecular Biology of the Cell (© Garland Science 2008)
Spleen
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Located in left superior side of abdomen
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Blood flows through at 3 different rates
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Can be ruptured in traumatic abdominal injuries
resulting in bleeding, shock, death
Fast (most), slow, intermediate
Functions
Destroys defective RBCs
 Detects and responds to foreign substances
 Limited reservoir for blood
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Spleen
Thymus
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Located in superior mediastinum
Divisions: Cortex and medulla
Site of maturation of T cells
Hassall's corpuscle
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Found in the central region of each thymic lobule
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Sometimes referred to as a thymic corpuscle
Function is unknown
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Known source of Thymic Stromal Lymphopoietin (TSLP)
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TSLP is a Cytokine which activates Antigen Presenting Cells
(APCs), which in turn play a strong role in T-lymphocyte
selection.
Immunity
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Ability to resist damage from foreign substances as
microorganisms and harmful chemicals
Categories
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Innate or nonspecific resistance
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Mechanical mechanisms: Prevent entry or remove microbes
Chemical mediators: Promote phagocytosis and inflammation
Cells: Involved in phagocytosis and production of chemicals
Adaptive or specific immunity
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Specificity: Ability to recognize a particular substance
Memory: Ability to remember previous encounters with a particular
substance and respond rapidly
An Overview of the Immune
Response
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Innate immune Responses
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Innate immune responses provide the first line of
defense
The response lack specificity.
 An invading agent first encounters a phagocytic cell.
 Phagocytes have receptor proteins such as the Toll-like
receptors (TLRs).
 Activation of such receptors play a role in promoting
immunity , by initiating secretion of inflammatory
mediators (such as cytokines).
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Model of a TLR3 bound to a dsRNA molecule
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Innate responses are typically accompanied by
the concentration of defensive agents at the site
of infection—inflammation.
Another mechanism produces proteins called
complement that bind to pathogens and initiate
their lysis.
Innate responses against viruses include natural
killer (NK) cell to induce apoptosis in the
infected cell.
Inflammatory Response
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Tissue injury regardless of type can cause inflammation
Response initiated by chemical mediators that produce
vasodilation, chemotactic attraction, increased vascular
permeability
Types
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Local: Symptoms are redness, heat, swelling, pain, loss of
function
Systemic: Symptoms are increase in neutrophil numbers,
fever and shock
Inflammatory Response
C3a stimulates mast cells
and basophils, which
then secrete
inflammatory mediators
Innate Immunity: Cells
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White blood cells
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Most important cellular
components of immune
system
Methods
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Chemotaxis
Phagocytosis
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Phagocytic and first
cells to enter infected
tissue
Promote inflammation
Eosinophils
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Monocytes that leave
blood, enter tissues
Large phagocytic cells
Basophils and mast cells
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Neutrophils
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Macrophages
Reduce inflammation
Natural killer cells
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Lyse tumor and virusinfected cells
Innate immunity
Antigenic Determinants
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Antigenic determinants
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Specific regions of a given
antigen recognized by a
lymphocyte
Antigenic receptors
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Surface of lymphocyte
that combines with
antigenic determinant
An Overview of the Immune
Response
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Another innate antiviral response is initiated by
virus-infected cells that produce interferon.
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Interferon binds to the surface of non-infected cells
making them resistant to infection.
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A type of interferon may induce synthesis of
miRNAs that target viral RNA genomes.
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Adaptive Immune Responses
Adaptive (or acquired) immune responses
require a lag period for an attack against a foreign
agent.
 This response is specific and occurs only in
vertebrates.
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immunity:
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Humoral immunity
 Cell-mediated immunity
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Humoral immunity is carried out by antibodies,
which are globular proteins of the
immunoglobulin superfamily (IgSF).
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Cell-mediated immunity is carried out by cells.
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Both types of immunity are mediated by
lymphocytes, which are leukocytes that
circulate between the blood and lymphoid
organs.
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Humoral immunity is mediated by B
lymphocytes, which differentiate into antibodysecreting plasma cells when activated.
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Cell-mediated immunity is carried out by T
lymphocytes (or T cells), which recognize and
kill infected cells when activated.
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B and T cells arise from hematopoietic stem cells.
Origin and Development
of Lymphocytes
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B and T cells
 Originate in red bone
marrow
 Move to lymphatic
tissue from processing
sites and continually
circulate
 Clones are small
groups of identical
lymphocytes
Adaptive immunity involves the ability to recognize,
respond to, and remember a particular substance
(stimulant).
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Stimulants
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Antigens: Large molecules
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Foreign: Not produced by body, introduced from outside
Self-antigens: Produced by body
Haptens: Small molecules and capable of combining
Types
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Humoral or Antibody-mediated: B cells
Cell-mediated: T cells
Major Histocompatability
Complex (MHC)
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Most lymphocyte activation involves
glycoproteins of cell surfaces called MHC
molecules
Class I molecules display antigens on surface of
nucleated cells, resulting in destruction of cells
 Class II molecules display antigens on surface of
antigen-presenting cells (APCs), resulting in
activation of immune cells
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The MHC proteins hold fragments of antigen in
place on APCs.
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The TCR interacts with an APC when it docks with
MHC proteins.
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Cytotoxic T cells recognize their antigen in
association with MHC I molecules.
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Helper T cells recognize their antigen in association
with MHC II molecules.
Peptides produced by antigen processing bind
within a groove of the MHC protein molecule
MHC class I
Origin and Development
of Lymphocytes
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Positive selection
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Negative selection
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Eliminates lymphocytes that react against self-antigens
Primary lymphatic organs (red bone marrow, thymus)
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Ensures survival of lymphocytes that react against
antigens
Where lymphocytes mature into functional cells
Secondary lymphatic organs
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Where lymphocytes produce an immune response
Thymus
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Located in superior mediastinum
Divisions: Cortex and medulla
Site of maturation of T cells
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T-cells, activated by clonal selection, interact
with antigens through a surface protein called a
T-cell receptor.
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T cells are activated by fragments of antigens that are
displayed on the surface of antigen-presenting
cells (APCs).
Dendritic cells ingest antigens by endocytosis.
 Macrophages ingest antigens by phagocytosis.
 These cells process and present the antigen to other cells.
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T cells release
cytokines that
alter the activity
of the target cell.
Any students interested in partaking in a directed
study group led by a past graduate of the course
(one of the good ones), on Fridays from 1-2:30
pm, Please email Sorouch Safa at:
[email protected]
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Three classes of T cells are distinguished by the
proteins on their surfaces and their biological
functions:
Cytotoxic T lymphocytes (CTLs) kill target cells
by inducing apoptosis.
 Helper T (TH) lymphocytes are regulatory cells
activated by APCs.
 Regulatory T lymphocytes (TReg cells) suppress
the activities of other immune cells.
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T-cell receptor synthesis
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The ability of T cells to recognize foreign antigens is mediated by
the T-cell receptor (TCR).
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Unlike most genes, the TCR gene is made up of a series of
alternative gene fragments.
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In order to create a functional T cell receptor, immature Tlymphocyte precursors use a series of DNA-interacting enzymes
to bring separate gene fragments together.
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The outcome of this process is that the TCR for EACH and
EVERY T-lymphocyte has a different sequence.
DNA
rearrangements that
lead to the
formation of genes
for an
immunoglobulin
(such as the T-cell
receptor)
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DNA Rearrangement of Genes Encoding Band T-Cell Antigen Receptors
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Two separate genes (a C gene and V gene) are
combined (with a joining segment) through
rearrangement to form one continuous gene that
encodes one antibody chain.
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DNA rearrangement (continued)
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The process is catalyzed by V(D)J recombinase which
joins V and J segments of the gene, and deleting the
intervening DNA.
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Rearrangement is facilitated by signal sequences
which are similar in V and J segments.
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DNA rearrangement (continued)
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Variability in polypeptide chains is achieved by:
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The variety of V and J exons in the DNA of the germ
line.
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Varying the site at which J and V sequences are joined.
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The enzymatic insertion of nucleotides.
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Somatic hypermutation refers to a high mutation rate in V elements
of B cells.
T-cell receptor assembly
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The TCRβ chain is paired with the pre-Tα to generate the preTCR.
 The disadvantage in the gene-rearrangement process is that
many of the combinations of the TCR gene fragments are
non-functional.
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Cells that fail to produce a functional pre-TCR are eliminated by
apoptosis (β-selection).
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Following β-selection, the cells undergo TCRα rearrangement,
resulting in completely assembled TCR in its final form.
T-cell receptor (general structure)
TCR interactions with MHC I and MHC II
Positive T-cell receptor selection
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Thymocytes which pass ‘β-selection’ now express a TCR which
is capable of assembling on the cell surface.
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However many of these TCRs will still be non-functional (unable to bind
MHC I or II).
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Thymocytes that have a T cell receptor incapable of binding
MHC class I or class II undergo apoptosis (panel b).
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The remaining thymocytes will undergo negative selection.
Negative T-cell receptor selection
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The key disadvantage in the process of TCR assembly is that by
random chance, some arrangements will create a TCR capable of
binding self-peptides presented on MHC class I or II.
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Such T cells would be capable of activating an immune response against
self, resulting in an autoimmune disease.
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During negative selection, all thymocytes with a high affinity for
binding self peptides presented on MHC class I or class II are
induced to undergo apoptosis (panel a).
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Cells which do not have a high affinity for self antigens survive
negative selection (panel c).
Determining the fate of a newly formed
T cell in the thymus
B-cells undergo a process of positive
selection to eliminate self-recognition.
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Features of the B-cell clonal selection:
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Antibody production follows selection of B cells
by antigen.
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Each B cell becomes committed to produce one
species of antibody.
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B cells become committed to antibody formation in
the absence of antigen.
Antigen Processing
Phagocytosis
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Phagocytosis also involves membrane
invagination.
This process does not involve clathrin.
Pseudopods extend around a particle,
forming a phagosome.
Phagosome will fuse with a lysosome,
containing digestive enzymes.
There are smaller transport mechanisms
in the wall of the secondary lysosome.
Costimulation
Proliferation of Helper T Cells
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Binding of an antigen
to the B-cell receptor
“primes” the B-cell
Proliferation of B Cells
Comparison of the structure of a B cell
and a plasma cell
Antibody-Mediated Immunity
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Antibodies or
Immunoglobulins (Ig)
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Classes: IgG, IgM, IgA,
IgE, IgD
Structure
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Variable region: Part that
combines with anitgenic
determinant of antigen
Constant region:
Responsible for activities
Actions of Antibodies
Figure 25-11 Molecular Biology of the Cell (© Garland Science 2008)
Antibody Production
Ways to Acquire
Adaptive Immunity
Effects of Aging
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Little effect on lymphatic system
Decreased ability of helper T cells to
proliferate in response to antigens
Decreased primary and secondary antibody
responses
Decreased ability of cell-mediated immunity
to resist intracellular pathogens
Immune System Problems
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Hypersensitivity reactions
Autoimmune disease
Severe combined immunodeficiency disease
(SCID)
Transplantation
Acute rejection
 Chronic rejection
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