The Immune Response and
immune system
The immune system (IS) maintains the integrity of the
organism; recognizes harmful from harmless and protects the
organism from ex- and endogenous harmful substances. It
belongs together with the nervous system and the endocrine
system between the regulatory systems.
Basic concepts:
• Immunity: protect the organism against pathogenic
microorganisms and their toxins.
• Auto-tolerance: recognizes its own tissue.
• Immune surveillance: recognizes internal pollutants;
removes old, damaged, mutated cells.
• Antigens (Ag): substances that the IS recognizes and
reacts to.
Communication within the immune system
Communication between cells of the immune system
occurs through signaling molecules:
• as direct interactions of molecules in membranes,
• through secreted molecules, including:
• cytokines - protein molecules,
• arachidonic acid derivatives (eicosanoids) prostaglandins,
leukotrienes, thromboxanes,
• NO,
• and oth.
Typical properties of the immune system
• Individual signals usually does not respond (is necessary the
presence of costimulatory signals, otherwise usually leads to
attenuation)
• Signal amplification (the signal is amplified over the signal path)
• The presence of signal transduction systems (termination of the
immune response)
• Cell proliferation (cell number changes as needed)
• Diffusion arrangement (high probability of encountering a stimulus)
+ cell migration (which allows targeted response at the site where it
is needed)
Local specificity of the immune response
Immune reactions occur mainly in mesenchymal tissues. Each reaction is
associated with damage to your own structures! If there is a stimulus on
the mucosa, it will usually be attenuated. If something goes into the subligament,
it will probably be pathogenic and the response will take place
(see mucosal immune system).
Immune-privileged areas are areas where some immune mechanisms are
missing. Immune reactions always damage their own structures, so they
are areas with low tissue regeneration capabilities (eg, CNS).
Non-specific immunity
• It recognizes dangerous from harmless by Pathogen-Associated Molecular
Pattern (PAMP) - phylogenetically conserved molecules that are typical for
pathogens (eg viral RNA, lipopolysaccharide).
• It works with specific immunity (it gives information about what is dangerous).
Specific immunity
• T-lymphocytes recognize only linear peptide fragments processed and presented by
antigen-presenting cell (APC), in particular dendritic cells in the presence of
costimulatory signals. They help cells with nonspecific immunity in killing
pathogens.
• B-lymphocytes recognize native antigen and receive costimulation from T-
lymphocytes.
• Autoreactive lymphocytes are eliminated.
• It responds only against dangerous stimuli (this gives information non-specific
immunity and apparently tissue that is pathogen-damaged).
• It has an immunological memory (use in active immunization).
Identification of Pathogenic Patterns
Pathogens are identified based on the presence of PAMP (Pathogen-Associated
Molecular Pattern) - phylogenetically highly conserved structures. Their carriers are
only microorganisms and are essential for their survival. Is part of them:
• bacterial wall - peptidoglycan, lipoteic acid, lipopolysaccharide,
• bacterial DNA - many cytosine and guanine, without methylation,
• dsRNA - viral.
• These patterns are recognized by PTH (Pathogen Pattern Receptor) = PRR
(Pathogen Recognition Receptor) receptors. There are the following types:
• secreted - opsonins (e.g., MBL) complement activation,
• endocytic - on phagocytes, mediate phagocytosis (eg MMR), MSR (macrophage scavenger
receptor) - cleans up bacterial residues),
• signaling - activate the signaling pathway leading to cytokine production (e.g., Toll-like receptor
(TLR).
• Identification of endogenous patterns
In connection with apoptosis, APOP (Apoptotic Cell Associated Molecular Pattern) patterns, such as the
phospholipids of the inner membrane of the cell membrane, are exhibited. Apoptotic Cell Receptor
(ACR) receptors are recognized, producing rather anti-inflammatory cytokines.
• Antigen presentation
Antigen Presenting Cells (APCs) absorb antigens, process them in lysosomes and present on HLA II
molecules. class. Thus treated, antigens (or antigenic epitopes) are presented along with costimulatory
signals to T lymphocytes.
Note: If any cell, not just antigen presenting, is infected with an intracellular parasite, the antigen is
presented on HLA class I.
The main components of the immune system
Immune reactions are ensured by different kinds of cells and molecules and their interactions.
IS cells + connective tissue cells → lymphatic tissue, lymphatic organs.
Immune system cells
Myeloid
• Monocytes (macrophages), neutrophils, basophils (mast cells), eosinophils, dendritic cells →
non-specific IS component; phagocytosis, cytokine producers, soluble mediators.
• Dendritic cells, monocytes and macrophages = antigen presenting cells (APC); the basis of
the antigen-specific part of IS.
• Myocytes also include erythrocytes and thrombocytes.
Lymphoid
• NK cells, lymphocytes B and T.
• The development of B-lymphocytes takes place in the bone marrow and is completed after
encountering Ag in secondary lymphatic organs; the final stage is the antibody-producing
plasma cells.
• Development of T-lymphocytes occurs mainly in thymus; 2 major phenotypically different
subpopulations: precursors of helper cells (on CD4 receptor surface), cytotoxic cell precursors
(CD8): upon aging with Ag on the surface of suitable APCs differentiate into mature effector
T lymphocytes.
• The part of T and B lymphocytes, after meeting Ag, is differentiated in a memory cell
responsible for immunological memory.
Basic molecules of the immune system
• TCR, BCR (antigen-specific receptors on the surface of T and B
lymphocytes);
• MHC I, II. (HLA molecule);
• Fc receptors (bind Fc parts of immunoglobulin molecules);
• adhesive and costimulatory molecules;
• immunoglobulins;
• cytokines;
• components of the complement system.
The Immune System is the Third Line
of Defense Against Infection
Barrier Defenses
 Barrier defenses include the skin and mucous
membranes of the respiratory, urinary, and
reproductive tracts
 Mucus traps and allows for the removal of microbes
 Many body fluids including saliva, mucus, and tears
are hostile to many microbes
 The low pH of skin and the digestive system
prevents growth of many bacteria
Mucosal immune system
The mucosal immune system, or MALT mucosa associated lymphoid tissue (in GIT
called GALT (gut), BALT (bronchus)) is the lymphatic tissue in the mucosal or sublymphatic
ligament.
Peyer's plaques in the distal section of the ilea, histological specimen
d-MALT - diffuse lymphatic tissue (cells are dispersed in the mucosa or submucosa)
o-MALT - Organized lymphatic tissue (cells are arranged in lymphatic follicles that
can be isolated (folliculi lymphatici aggregati) or associated with so-called follicular
lymphatic aggregates.
Over the lymphatic follicles, the intestinal wall is covered with FAE (epithelium
associated with follicles), which contains a large number of M-cells (membrane cells
- from the intestinal lumen endocytopes the antigens and transmit it to lymphocytes).
The First Line of Defense
~Skin~
- The dead, outer
layer of skin, known
as the epidermis,
forms a shield
against invaders and
secretes chemicals
that kill potential
invaders
- You shed between
40 – 50 thousand
skin cells every day!
Immune function of GIT
 Large surface
 The significance of intact gastrointestinal
mucosa
 Mucosal barrier - mucus, lysozymes,
phagocytes, pH of environment, humoral
factors
 The immune system of the digestive tract:
 Peyer plaques - lymphoid follicles, antibody
production
 Immune cells - intraepithelial lymphocytes, the
lymphocytes in the lamina propria immunoglobulin
production
 Drainage system of portal blood and lymph
The First Line of Defense
~Saliva~
What’s the first thing you do when you
cut your finger?
- Saliva contains many
chemicals that break down
bacteria
- Thousands of different types
of bacteria can survive these
chemicals, however
- Swallowed bacteria are
broken down by HCl in
the stomach
- The stomach must produce
a coating of special mucus
or this acid would eat
through the stomach!
The First Line of Defense
~Stomach Acid~
• Goblet cells – mucins
• M cells - ability to take up antigen from the lumen via endocytosis, phagocytosis,
or transcytosis to antigen presenting cells, such as dendritic cells, and
lymphocytes
• Paneth cells - synthesize and secrete substantial quantities of antimicrobial
peptides and proteins
Lungs and immunity
= opsonins to coat bacteria and viruses, thereby
promoting phagocytosis by macrophages resident in
the alveoli
Innate or Genetic Immunity: Immunity an
organism is born with.
 Genetically determined.
 May be due to lack of receptors or other
molecules required for infection.
 Innate human immunity to canine distemper.
 Immunity of mice to poliovirus.
Acquired Immunity:Immunity that an
organism develops during lifetime.
 Not genetically determined.
 May be acquired naturally or artificially.
 Development of immunity to measles in response to
infection or vaccination.
Innate versus acquired immunity
Innate immunity
 neutrophils, macrophages, NK cells
 Toll and toll-like receptors = affinity to bacterial lipopolysaccharides,
lipoproteins, peptidoglycans, DNA = molecular patterns expressed by
pathogens
Innate versus acquired immunity
Acquired
immunity
 Ability of lymphocytes to
produce antibodies (B cells)
or cell-surface receptors (T
cells) = specific!
 Antigens (proteins,
polypeptides, nucleic acids,
lipids)
 Humoral immunity –
circulating antibodies
(plasma cells, activation of
complement system,
bacterial infection)
 Cellular immunity – T-
lymphocytes
Reticuloendothelial system – tissue macrophage system
Types of Acquired Immunity
I. Naturally Acquired Immunity: Obtained in
the course of daily life.
A. Naturally Acquired Active Immunity:
 Antigens or pathogens enter body naturally.
 Body generates an immune response to antigens.
 Immunity may be lifelong (chickenpox or mumps)
or temporary (influenza or intestinal infections).
B. Naturally Acquired Passive Immunity:
 Antibodies pass from mother to fetus via placenta
or breast feeding (colostrum).
 No immune response to antigens.
 Immunity is usually short-lived (weeks to months).
 Protection until child’s immune system develops.
Types of Acquired Immunity (Continued)
II. Artificially Acquired Immunity: Obtained by
receiving a vaccine or immune serum.
1. Artificially Acquired Active Immunity:
 Antigens are introduced in vaccines (immunization).
 Body generates an immune response to antigens.
 Immunity can be lifelong (oral polio vaccine) or temporary
(tetanus toxoid).
2. Artificially Acquired Passive Immunity:
 Preformed antibodies (antiserum) are introduced into body
by injection.
 Snake antivenom injection from horses or rabbits.
 Immunity is short lived (half life three weeks).
 Host immune system does not respond to antigens.
Duality of Immune System
I. Humoral (Antibody-Mediated) Immunity
 Involves production of antibodies against foreign
antigens.
 Antibodies are produced by a subset of lymphocytes
called B cells.
 B cells that are stimulated will actively secrete
antibodies and are called plasma cells.
 Antibodies are found in extracellular fluids (blood
plasma, lymph, mucus, etc.) and the surface of B cells.
 Defense against bacteria, bacterial toxins, and viruses
that circulate freely in body fluids, before they enter
cells.
 Also cause certain reactions against transplanted
tissue.
Antibodies are Proteins that Recognize Specific Antigens
Duality of Immune System II. Cell
Mediated Immunity
 Involves specialized set of lymphocytes called T cells
that recognize foreign antigens on the surface of cells,
organisms, or tissues:
 Helper T cells
 Cytotoxic T cells
 T cells regulate proliferation and activity of other cells
of the immune system: B cells, macrophages,
neutrophils, etc.
 Defense against:
 Bacteria and viruses that are inside host cells and are
inaccessible to antibodies.
 Fungi, protozoa, and helminths
 Cancer cells
 Transplanted tissue
Antigens
 Most are proteins or large polysaccharides from
a foreign organism.
 Microbes: Capsules, cell walls, toxins, viral capsids,
flagella, etc.
 Nonmicrobes: Pollen, egg white , red blood cell
surface molecules, serum proteins, and surface
molecules from transplanted tissue.
 Lipids and nucleic acids are only antigenic when
combined with proteins or polysaccharides.
 Molecular weight of 10,000 or higher.
 Hapten: Small foreign molecule that is not antigenic. Must be
coupled to a carrier molecule to be antigenic. Once antibodies
are formed they will recognize hapten.
Antigens
Epitope:
 Small part of an antigen that interacts
with an antibody.
 Any given antigen may have several
epitopes.
 Each epitope is recognized by a different
antibody.
Epitopes: Antigen Regions that Interact
with Antibodies
Antibodies
 Proteins that recognize and bind to a particular
antigen with very high specificity.
 Made in response to exposure to the antigen.
 One virus or microbe may have several antigenic
determinant sites, to which different antibodies
may bind.
 Each antibody has at least two identical sites
that bind antigen: Antigen binding sites.
 Valence of an antibody: Number of antigen
binding sites. Most are bivalent.
 Belong to a group of serum proteins called
immunoglobulins (IGs).
Antibody Structure
 Monomer: A flexible Y-shaped molecule with
four protein chains:
 2 identical light chains
 2 identical heavy chains
 Variable Regions: Two sections at the end of Y’s
arms. Contain the antigen binding sites (Fab).
Identical on the same antibody, but vary from
one antibody to another.
 Constant Regions: Stem of monomer and lower
parts of Y arms.
 Fc region: Stem of monomer only. Important
because they can bind to complement or cells.
Antibody Structure
Immunoglobulin Classes
I. IgG
 Structure: Monomer
 Percentage serum antibodies: 80%
 Location: Blood, lymph, intestine
 Half-life in serum: 23 days
 Complement Fixation: Yes
 Placental Transfer: Yes
 Known Functions: Enhances phagocytosis,
neutralizes toxins and viruses, protects fetus and
newborn.
Immunoglobulin Classes
II. IgM
 Structure: Pentamer
 Percentage serum antibodies: 5-10%
 Location: Blood, lymph, B cell surface (monomer)
 Half-life in serum: 5 days
 Complement Fixation: Yes
 Placental Transfer: No
 Known Functions: First antibodies produced
during an infection. Effective against microbes and
agglutinating antigens.
Immunoglobulin Classes
III. IgA
 Structure: Dimer
 Percentage serum antibodies: 10-15%
 Location: Secretions (tears, saliva, intestine, milk),
blood and lymph.
 Half-life in serum: 6 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: Localized protection of mucosal
surfaces. Provides immunity to infant digestive
tract.
Immunoglobulin Classes
IV. IgD
 Structure: Monomer
 Percentage serum antibodies: 0.2%
 Location: B-cell surface, blood, and lymph
 Half-life in serum: 3 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: In serum function is unknown.
On B cell surface, initiate immune response.
Immunoglobulin Classes
V. IgE
 Structure: Monomer
 Percentage serum antibodies: 0.002%
 Location: Bound to mast cells and basophils
throughout body. Blood.
 Half-life in serum: 2 days
 Complement Fixation: No
 Placental Transfer: No
 Known Functions: Allergic reactions. Possibly
lysis of worms.
How Do B Cells Produce Antibodies?
 B cells develop from stem cells in the bone
marrow of adults (liver of fetuses).
 After maturation B cells migrate to lymphoid
organs (lymph node or spleen).
 Clonal Selection: When a B cell encounters an
antigen it recognizes, it is stimulated and divides
into many clones called plasma cells, which
actively secrete antibodies.
 Each B cell produces antibodies that will
recognize only one antigenic determinant.
Humoral Immunity
Apoptosis
 Programmed cell death (“Falling away”).
 Human body makes 100 million lymphocytes
every day. If an equivalent number doesn’t die,
will develop leukemia.
 B cells that do not encounter stimulating antigen
will self-destruct and send signals to phagocytes
to dispose of their remains.
 Many virus infected cells will undergo apoptosis,
to help prevent spread of the infection.
Consequences of Antigen-Antibody Binding
Antigen-Antibody Complex: Formed when an
antibody binds to an antigen it recognizes.
Affinity: A measure of binding strength.
1. Agglutination: Antibodies cause antigens
(microbes) to clump together.
 IgM (decavalent) is more effective that IgG (bivalent).
 Hemagglutination: Agglutination of red blood cells.
Used to determine ABO blood types and to detect
influenza and measles viruses.
2. Opsonization: Antigen (microbe) is covered with
antibodies that enhances its ingestion and lysis by
phagocytic cells.
Consequences of Antibody Binding
Humoral Immunity
3. Neutralization: IgG inactivates viruses by
binding to their surface and neutralize toxins by
blocking their active sites.
4. Antibody-dependent cell-mediated cytotoxicity:
Used to destroy large organisms (e.g.: worms).
Target organism is coated with antibodies and
bombarded with chemicals from nonspecific
immune cells.
5. Complement Activation: Both IgG and IgM
trigger the complement system which results in
cell lysis and inflammation.
Consequences of Antibody Binding
Immunological Memory
Antibody Titer: The amount of antibody in the
serum.
Pattern of Antibody Levels During Infection
Primary Response:
 After initial exposure to antigen, no antibodies are
found in serum for several days.
 A gradual increase in titer, first of IgM and then
of IgG is observed.
 Most B cells become plasma cells, but some B cells
become long living memory cells.
 Gradual decline of antibodies follows.
Immunological Memory (Continued)
Secondary Response:
 Subsequent exposure to the same antigen displays
a faster and more intense antibody response.
 Increased antibody response is due to the
existence of memory cells, which rapidly produce
plasma cells upon antigen stimulation.
Antibody Response After Exposure to Antigen
T Cells and Cell Mediated Immunity
Antigens that stimulate this response are mainly
intracellular.
Requires constant presence of antigen to remain
effective.
Unlike humoral immunity, cell mediated immunity
is not transferred to the fetus.
Cytokines: Chemical messengers of immune cells.
 Over 100 have been identified.
 Stimulate and/or regulate immune responses.
 Interleukins: Communication between WBCs.
 Interferons: Protect against viral infections.
 Chemokines: Attract WBCs to infected areas.
T Cells and Cell Mediated Immunity
Cellular Components of Immunity:
 T cells are key cellular component of immunity.
 T cells have an antigen receptor that recognizes
and reacts to a specific antigen (T cell receptor).
 T cell receptor only recognize antigens combined
with major histocompatability (MHC) proteins on
the surface of cells.
 MHC Class I: Found on all cells.
 MHC Class II: Found on phagocytes.
 Clonal selection increases number of T cells.
T Cells Only Recognize Antigen Associated
with MHC Molecules on Cell Surfaces
T Cells and Cell
Mediated Immunity
Types of T cells
1. T Helper (TH) Cells:
Central role in immune
response.
 Most are CD4+
 Recognize antigen on the surface of
antigen presenting cells (e.g.:
macrophage).
 Activate macrophages
 Induce formation of cytotoxic T cells
 Stimulate B cells to produce
antibodies.
Central Role of Helper T Cells
Types of T cells (Continued)
2. Cytotoxic T (Tc) Cells: Destroy target cells.
 Most are CD4 negative (CD4 -).
 Recognize antigens on the surface of all cells:
• Kill host cells that are infected with viruses or bacteria.
• Recognize and kill cancer cells.
• Recognize and destroy transplanted tissue.
 Release protein called perforin which forms a pore in
target cell, causing lysis of infected cells.
 Undergo apoptosis when stimulating antigen is gone.
Cytotoxic T Cells Lyse Infected Cells
Types of T cells (Continued)
3. Delayed Hypersensitivity T (TD) Cells: Mostly T
helper and a few cytotoxic T cells that are
involved in some allergic reactions (poison ivy)
and rejection of transplanted tissue.
4. T Suppressor (Ts) Cells: May shut down
immune response.
Humoral Response to T Dependent Antigens
Humoral Response to T Dependent Antigens
Relationship Between Cell-Mediated
and Humoral Immunity
2. Antibody Dependent Cell Mediated
Cytotoxicity (ADCC)
 Target cell is covered with antibodies, leaving Fc
portion sticking outwards.
 Natural killer and other nonspecific cells that have
receptors for Fc region are stimulated to kill targeted
cells.
 Target organism is lysed by substances secreted by
attacking cells.
 Used to destroy large organisms that cannot be
phagocytosed.
Destruction of Large Parasites by ADCC