Download The Immune Response

The immune response
Anca Bacârea, Alexandru Schiopu
The importance of immune system
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The immune system is clearly essential for survival.
It constantly defends the body against bacteria, viruses, and other
foreign substances it encounters.
It also detects and responds to abnormal cells and molecules that
periodically develop in the body so that diseases such as cancers
do not occur.
An essential aspect of the immune response is the ability to
recognize almost limitless numbers of foreign cells and nonself
substances, distinguishing them from self molecules that are native
to the body – it distinguishes self from nonself.
Definitions
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The immune system consists of the central and peripheral lymphoid
tissues.
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The individual components of the substance that the immune
system recognizes as foreign are called antigens.
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The interaction of the collective and coordinated components of the
immune system and the antigens of a foreign agent is called the
immune response.
The immune
system
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The central lymphoid organs
 the bone marrow and the
thymus
 provide the environment for
immune cell production and
maturation
The peripheral lymphoid organs
 Lymph nodes, spleen, tonsils,
appendix, Peyer’s patches in
the intestine, and mucosaassociated lymphoid tissues in
the respiratory,
gastrointestinal, and
reproductive systems
 function to trap and process
antigen and promote its
interaction with mature
immune cells
The immune system - classification
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The immune system
 Nonspecific or innate defense system
 Cellular
 Humoral
 Specific or acquired immune system
 Cellular
 Humoral
Nonspecific or innate defense system
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First line of defense system
It distinguishes self from non-self but does not distinguish one type
of pathogen from another.
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Components:
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skin and mucous membranes
inflammatory response
phagocytic and non phagocytic leukocytes cells
Nonspecific defense system
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1. Mechanical factors
 The epithelial surfaces form a physical barrier that is very
impermeable to most infectious agents.
 The skin acts as our first line of defense against invading
organisms. The desquamation of skin epithelium also helps
remove bacteria and other infectious agents that have adhered to
the epithelial surfaces.
 Movement due to cilia or peristalsis helps to keep air passages
and the gastrointestinal tract free from microorganisms.
 The flushing action of tears and saliva helps prevent infection of
the eyes and mouth.
 The trapping effect of mucus that lines the respiratory and
gastrointestinal tract helps protect the lungs and digestive
systems from infection.
Nonspecific defense system
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2. Chemical factors
Fatty acids in sweat inhibit the growth of bacteria.
 Lysozyme and phospholipase found in tears, saliva and nasal
secretions can breakdown the cell wall of bacteria and destabilize
bacterial membranes.
 The low pH of sweat and gastric secretions prevents growth of
bacteria.
 Defensins (low molecular weight proteins) found in the lung and
gastrointestinal tract have antimicrobial activity.
 Surfactants in the lung act as opsonins (substances that promote
phagocytosis of particles by phagocytic cells).
3. Biological factors
 The normal flora of the skin and in the gastrointestinal tract can
prevent the colonization of pathogenic bacteria by secreting toxic
substances or by competing with pathogenic bacteria for
nutrients or attachment to cell surfaces.
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Nonspecific defense system
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The anatomical barriers are very effective in preventing colonization
of tissues by microorganisms.
However, when there is damage to tissues the anatomical barriers
are breached and infection may occur. Once infectious agents have
penetrated tissues, another innate defense mechanism comes into
play, namely acute inflammation.
Humoral factors play an important role in inflammation, which is
characterized by edema and the recruitment of phagocytic cells.
Nonspecific humoral immune system
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The complement system
 The complement system is a primary mediator of the humoral
immune response that enables the body to produce an
inflammatory response, lyse foreign cells, and increase
phagocytosis.
 The complement system, like the blood coagulation system,
consists of a group of proteins that normally are present in the
circulation as functionally inactive precursors. These proteins
make up 10% to 15% of the plasma protein fraction.
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a complement reaction to occur, the complement
components must be activated in the proper sequence.
 Uncontrolled activation of the complement system is prevented
by inhibitor proteins.
Complement activation
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The classic pathway of complement activation is initiated by
antibody bound to antigens on the surface of microbes or through
soluble immune complexes.
The alternate and the lectin pathways do not use antibodies and are
part of the innate immune defenses.
 The alternate pathway of complement activation is initiated by the
interaction with certain polysaccharide molecules characteristic of
bacterial surfaces.
 The lectin-mediated pathway is initiated following the binding of a
mannose-binding protein to mannose-containing molecules
commonly present on the surface of bacteria and yeast.
The activation of the three pathways produces similar effects on C3
and subsequent complement proteins.
Complement activation
Immune Cells
Nonspecific immune cells
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Phagocytes:
 Neutrophyles – bacteria
 Eosinophyles – enzymes that kills parasites
 Macrophages - "big eaters"
Non phagocytic leukocytes:
 Basophiles – role in allergic response
 Mastocytes
 Natural killer lymphocytes – antiviral and anti-tumor activity
Nonspecific immune cells
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Macrophages have important functions in both innate and antigenspecific immune responses.
As phagocytic cells with antigen nonspecific activity, they help to
contain infectious agents until specific immunity can be marshaled.
In addition, early in the host response, the macrophage functions as
an accessory cell to ensure amplification of the inflammatory
response and initiation of specific immunity.
Macrophages are activated by the presence of antigen to engulf and
digest foreign particles.
Activated macrophages act as antigen presenting cells (APCs)
that break down complex antigens into peptide fragments that can
associate with class I or II Major Histocompatibility Complex (MHC)
molecules. Macrophages can then present these complexes to the
helper T cell so that nonself-self recognition and activation of the
immune response can occur.
Presentation of antigen to helper T cell by an
antigen-presenting cell (APC)
NK cells
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The NK cell is a nonspecific effector cell that can kill tumor cells and
virus-infected cells.
They are called natural killer cells because, unlike T cytotoxic cells,
they do not need to recognize a specific antigen before being
activated.
NK cells kill after contact with a target cell. The NK cell is
programmed automatically to kill foreign cells.
Programmed killing is inhibited if the NK cell membrane molecules
contact MHC self-molecules on normal host cells.
The mechanism of NK cytotoxicity depends on production of poreforming proteins (i.e., NK perforins), enzymes, and toxic cytokines.
Specific Immunity
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Specific or acquired immunity develops during an individual’s lifetime.
It distinguishes self from nonself, and responds specifically to different
pathogens and foreign molecules.
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Components:
 Lymphocytes are key players in the specific or acquired immune
response:
 Lymphocytes represent 20% to 40% of blood leukocytes;
 T lymphocytes (also called T cells), which participate in cell-mediated
immunity (60-70%);
 B lymphocytes (also called B cells), which participate in humoral
immunity (10-20%);
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Cell-mediated immunity involves the production of cytotoxic T cells, which
have the ability to destroy antigen-bearing cells.
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Humoral immunity is characterized by the transformation of B cells into
plasma cells, which secrete immunoglobulins (antibodies) that have specific
activity against the inciting antigen.
T cells
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T cells are maturated in the thymus.
There, they learn how to distinguish self from nonself. Only the T
cells that ignore self antigen molecules are allowed to mature and
leave the thymus. Without this training process, T cells could attack
the body's cells and tissues.
Mature T cells are stored in secondary lymphoid organs (lymph
nodes, spleen, tonsils, appendix, and Peyer's patches in the small
intestine).
These cells circulate in the bloodstream and the lymphatic system.
After they first encounter a foreign or abnormal cell, they are
activated and search for those particular cells.
Immune Cells
Pathway for Tcell differentiation
Types of T cells
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Helper T (CD4) cells help other immune cells. Some helper T cells help B
cells produce antibodies against foreign antigens. Others help activate killer
T cells to kill foreign or abnormal cells or help activate macrophages
enabling them to ingest foreign or abnormal cells more efficiently.
 The Th1 response is characterized by the production of interferon gamma, which activates the bactericidal activities of macrophages, and
induces B-cells to make opsonizing (coating) antibodies, and leads to
cell mediated immunity.
 The Th2 response is characterized by the release of interleukin 4, which
results in the activation of B-cells to make neutralizing (killing)
antibodies, leading to humoral immunity.
 Generally, Th1 responses are more effective against intracellular
pathogens (viruses and bacteria that are inside host cells), while Th2
responses are more effective against extracellular bacteria, parasites
and toxins.
Types of T cells
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Th1 cells:
 secrete IL-2, IL-12, IFN gamma, TNF-beta;
 activate macrophages, amplifying their cytokine secretion
capacity and potential for presentation of antigens;
 activate synthesis of IgG but not IgE;
 are involved in delayed hypersensitivity reactions;
 are activated by signals from intracellular bacteria and viruses;
Th2 cells:
 secrete IL-4, IL-5, IL-6, IL-10;
 activate the synthesis of IgE;
 stimulate proliferation and activation of eosinophils;
 are stimulated by allergens or parasite components.
Types of T cells
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Killer (cytotoxic) T cells (CD8) attach to particular foreign or
abnormal (for example infected) cells because they have
encountered them before. Killer T cells may kill these cells by
making holes in their cell membrane and injecting enzymes into the
cells or by binding with certain sites on their surface called death
receptors.
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Suppressor (regulatory) T cells produce substances that help end
the immune response or sometimes prevent certain harmful
responses from occurring.
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Sometimes T cells—for reasons that are not completely understood
- do not distinguish self from nonself. This malfunction can result in
an autoimmune disorder, in which the body attacks its own tissues.
Types of T cells
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Γδ T cells (gamma delta T cells) represent a small subset of T cells,
which possess a different receptor on the surface (TCR). Most T
cells receptor consists of two chains α-and β-gp. Unlike T cells, γδ
cells have a TCR composed of gamma and a delta chains. This
group is more poorly represented than beta alpha cells. They are
abundant in the intestinal mucosa.
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Natural killer T cells (NKT) are a heterogeneous group of T cells,
which have properties of both NK cells and T cells and represents
only 0.2% of all circulating T lymphocytes in the blood.
The central role of Thelper cells (CD4)
B cells
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B cells are formed in the bone marrow. B cells have particular sites
(receptors) on their surface where antigens can attach.
B cells are the major cells involved in the creation of antibodies that
circulate in blood plasma and lymph, known as humoral immunity.
In mammals there are five types of antibody IgA, IgD, IgE, IgG, and
IgM, differing in biological properties.
Each has evolved to handle different kinds of antigens.
Upon activation, B cells produce antibodies, each of which
recognizes a unique antigen, and neutralize specific pathogens.
B cells
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The B-cell response to antigens has two stages:
 Primary immune response:
 When B cells first encounter an antigen, the antigen attaches to a
receptor, stimulating the B cells.
 Some B cells change into memory cells, which remember that
specific antigen, and others change into plasma cells. Helper T cells
help B cells in this process.
 Plasma cells produce antibodies that are specific to the antigen that
stimulated their production. After the first encounter with an antigen,
production of enough of the specific antibody takes several days.
Thus, the primary immune response is slow.
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Secondary immune response
 Whenever B cells encounter the antigen again, memory B cells very
rapidly recognize the antigen, multiply, change into plasma cells, and
produce antibodies. This response is quick and very effective.
B cells
Primary and secondary phases of the humoral
immune response to the same antigen.
Antigens
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Antigens or immunogens are substances foreign to the host that can
stimulate an immune response.
Most antigens are macromolecules such as proteins and
polysaccharides, although lipids and nucleic acids occasionally can
serve as antigens.
Antigens include:
 bacteria
 fungi
 viruses
 protozoans
 parasitic worms
 substances such as pollen
 venom
 transplanted organs
Antigens
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Antigens, which in general are large and complex, are biologically
degraded into smaller chemical units or peptides.
These discrete, immunologically active sites on antigens are called
antigenic determinants or epitopes.
It is the unique molecular shape of an epitope that is recognized by
a specific receptor found on the surface of the lymphocyte or by the
antigen-binding site of an antibody.
A single antigen may contain several antigenic determinants; each
can stimulate a distinct clone of lymphocytes to respond.
Smaller substances (molecular masses <10,000 daltons) usually are
unable to stimulate an adequate immune response.
Low–molecular-weight compounds, known as haptens, combine
with larger protein molecules they function as antigens.
Antigens
Multiple epitopes on a complex antigen being recognized by their respective (A,
B, C) antibodies
Immunoglobulins - structure
Classes and Characteristics of Immunoglobulins
Class
Percentage of
Total
Characteristics
Ig G
75%
•
Ig A
15%
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Ig M
10%
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Ig D
0.2%
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Ig E
0.004%
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Displays antiviral, antitoxin, and antibacterial properties
• Only Ig G crosses the placenta
• Responsible for protection of newborn
• Activates complement and binds to macrophages
Predominant in body secretions, such as saliva, nasal and
respiratory secretions, and breast milk
• Protects mucous membranes
Forms the natural antibodies such as those for ABO blood
• Antigens
• Prominent in early immune responses
• Activates complement
Found on B lymphocytes
• Needed for maturation of B cells
Binds to mast cells and basophils
• Involved in parasitic infections, allergic and hypersensitivity
reactions
Active Versus Passive Immunity
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Active or acquired immunity
 Can be achieved through exposure to a specific antigen.
 It is acquired through immunization or actually having a disease.
 Active immunity, although long lasting once established, requires
a few days to weeks after a first exposure to become sufficiently
developed to contribute to the destruction of the pathogen.
Active Versus Passive Immunity
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Passive immunity
 Is immunity transferred from one source to another source. (e.g.
An infant receives passive immunity naturally from the transfer of
antibodies from its mother in utero and through a mother’s breast
milk.)
 Passive immunity also can be artificially provided by the transfer
of antibodies produced by other people or animals.
 Some protection against infectious disease can be provided by
the injection of hyperimmune serum, which contains high
concentrations of antibodies for a specific disease, or immune
serum or gamma globulin, which contains a pool of antibodies for
many infectious agents.
 Passive immunity produces only short-term protection that lasts
weeks to months.