Innate and Adaptive

Immunity
 The immune system
The immune system includes all of the structures and processes that provide
a defense against potential pathogens.
Can be grouped in two overlapping categories:

1. Innate (or nonspecific ) immunity

2. Adaptive (or specific ) immunity
 Innate (or nonspecific ) immunity
• Immediate defense
• Protects without prior exposure to infectious agents
• Is non-specific
• No long lasting immunity = no memory
• Activates adaptive immunity
2nd line of defense:
• Phagocytic Cells: Neutrophils,
1st line of defense: macrophages, monocytes,
• Skin • NK cells
• Mucous membranes/Secretions • Complement system
• Stomach acid • Inflammation
• Inflammatory Cytokines
Innate (or nonspecific ) immunity
 Neutrophil, Polymorphonuclear (PMN) cell
• Most Abundant circulating cell
• Granulocyte with segmented nuclei (2-5 lobes)
• Function: Phagocytosis;
Monocyte - circulating cell; Monocyte
• Precursor of tissue macrophages
• Kidney-shaped nucleus
Macrophages - Residents in all tissues
• Phagocyte
• Antigen presenting cell = T-cell activator
Dendritic Cell Dendritic Cell
• Phagocyte
• Antigen presenting cell = T cell activator
Eosinophils, Basophills, Mast cells
• Elimination of large extracellular parasites
• Hypersensitivity type 1 = allergic reaction
 Phagocytosis
• The phagocyte “eats” the microbe by
engulfing it - the microbe is internalized.
• The microbe is surrounded by a membrane
and is contained within a vacuole -
phagosome
• Phagosome fuses with a lysosome, which
contains digestive enzymes = formation of
phagolysosome
• the lysosomal enzymes may be released
before the fusion is complete, killing the
cell causes the inflammation of the
infected area.
 Phagocytosis
Three major groups of phagocytic cells:
1. neutrophils;
2. The cells of the mononuclear
phagocyte system - monocytes
in the blood and macrophages
(derived from monocytes),
dendritic cells in the connective
tissues
3. Organ-specific phagocytes in
the liver, spleen, lymph nodes,
lungs, kidneys and Brain - are
functionally related to
macrophages
 Chemotaxis
• Neutrophils and monocytes are
recruited to the site of an infection
by a process called chemotaxis—
movement toward chemical
attractants.
• Chemokines – subclass of cytokines
that attract the WBCs
• Neutrophils are the first to arrive at
the site of an infection;
• monocytes arrive later and can be
transformed into macrophages as
the battle progresses
Attraction and Rolling

Invading bacteria secrete

chemoattractants - attract and
activate the white blood cells.
a neutrophil – undergoes:
1. rolling,
2. capture,
3. adhesion
4. activation,
5. extravasation (diapedesis)
through the blood vessel wall.
 Fever
• Body temperature is regulated by the hypothalamus thermoregulatory
center (a “thermostat”) that maintains body temperature at about 370 C.
• endogenous pyrogens - interleukin-1 beta - produced as a by leukocytes
– resets this thermostat upward
• The cell wall of gram-negative bacteria contains endotoxin - stimulates
monocytes and macrophages to release cytokines. These cytokines,
interleukin-1, interleukin-6, and tumor necrosis factor - produce fever,
sleepiness, and a fall in the plasma iron concentration.
a mild to moderate fever may be a beneficial response in infections. The fall
in plasma iron concentrations can inhibit bacterial activity;
fever also induces increased activity of neutrophils and increased
production of interferons
 Local Inflammation
• When the microbe enters the tissue, Tissue macrophages and mast cells
are activated and release chemicals (cytokines and chemokines) that
attract neutrophils to the site of the infection
Mast cells produce histamine, serotonin, and other chemicals that cause
the endothelial cells to contract away from each other:
1. This increases the permeability of the capillaries
2. Allows more fluid and plasma proteins into the extracellular space - a
local edema ensues
3. Allow the extravasation of leukocytes into the inflamed area
 Local Inflammation
• The leukocytes move to the area by
chemotaxis
• The leukocytes squeeze between adjacent
endothelial cells and enter the
subendothelial connective tissue.
The first to arrive are:
1. neutrophils, followed by:
2. Monocytes (which can change into
macrophages)
3. T lymphocytes
 Local Inflammation
• Neutrophils phagocytose microorganisms and release enzymes and
antimicrobial peptides.
They also release NETs—neutrophil extracellular traps— composed of
extracellular fibers
• The NETs immobilize the bacteria,
• facilitate their phagocytosis,
• may kill them directly by antimicrobial enzymes.
Through the action of proteases the neutrophils degrade and liquefy the
surrounding tissues
• viscous, protein-rich fluid, together with dead neutrophils, forms pus
1. The neutrophils release granules and attract monocytes
2. Monocytes transform into macrophages
Macrophages phagocytose microorganisms and fragments of the extracellular
matrix, they also release nitric oxide, which aids in the destruction of bacteria.
3. Later, B lymphocytes are stimulated to produce antibodies against specific
antigens of the invading bacteria.
Binding of antibodies to antigens in the bacteria amplifies the previously
nonspecific response:
• Antibody-antigen binding causes activation of complement - directly destroys
the bacteria
• Antibody-antigen binding promotes the phagocytic activity of neutrophils,
macrophages, and monocytes
• The ability of antibodies to promote phagocytosis is called opsonization
Characteristic symptoms of a local inflammation:

• Redness and Warmth (due to histamine-stimulated vasodilation);

• Swelling (edema) and pus;
• Pain
“rubor, calor, dolor, and tumor” (redness, heat, pain, and swelling)
• If the infection continues, endogenous pyrogen from leukocytes and
macrophages may also produce a fever,
• Excessive inflammation can sometimes harm the host tissues than the
pathogens themselves.
 Interferons
Cells infected with a virus, produce polypeptides that interfere other
strain of virus to infect other cells - These interferons - a nonspecific,
short-acting resistance to viral infection.
Alpha interferon and beta interferon are produced by almost all cells
in response to infections - act as messengers that protect other cells
from viral infection.
The viruses are still able to penetrate other cells, but the ability of the
viruses to replicate is inhibited.
Gamma interferon is produced only by particular lymphocytes and
natural killer cells - defense against infection and cancer.
 Adaptive / Acquired Immunity

• Develops over time

• Highly specific for particular antigen
Has Memory cells – stronger, quicker response to previously encountered
antigen:
B Lymphocytes – produce Circulating antibodies - gamma globulins that
attack the invading agent = humoral immunity or B-cell immunity
 T lymphocytes - specifically crafted in the lymph nodes to destroy the
foreign agent - cell-mediated immunity or T-cell immunity:
1. Helper CD4+ T cells: stimulate B cells - production of immunoglobulins
2. Cytotoxic CD8+ T cells: directly attack and destroy cells that express
foreign antigens
 Acquired immunity
after invasion by an organism or toxin, body recognizes this invasion:
• Each toxin or each organism almost always contains specific chemical
compounds, that is perceived as foreign – acquired immunity is activated
• These foreign substances are called antigens - they initiate activation of
acquired immunity.
• Antigens stimulate the production of specific antibodies
• Antigenic determinant sites (epitopes ) - are areas that stimulate production
of different antibodies. Most antigens have many epitopes and stimulate the
production of many different antibodies
 T and the B Lymphocytes.
• Both types of lymphocytes are derived from pluripotent
hematopoietic stem cells.
Almost all of the lymphocytes eventually end up in the lymphoid tissue,
but before doing so, they are further differentiated
• T lymphocytes migrate to and are preprocessed in the thymus gland -
responsible for cell-mediated immunity
• the B lymphocytes that form antibodies—are preprocessed in the
liver during mid-fetal life and in the bone marrow in late fetal life and
after birth - responsible for humoral immunity.
Thymus

• below the thyroid in the neck into the thoracic cavity.

• Lymphocytes seed the thymus and become transformed into T cells.
• Grows during childhood but gradually regresses after puberty.
thymus of adults becomes a fatty organ
• Production of T lymphocytes occurs more slowly in adulthood -
mostly by secondary lymphoid organs rather than in the thymus.
 Thymus Gland Processes the T Lymphocytes
after origination in the bone marrow, T Lymphocytes migrate to the thymus
gland – to develop extreme diversity for reacting against different antigens
• Mature T lymphocytes leave the thymus and spread throughout the lymphoid
tissue
T lymphocytes leaving the thymus, must not react against body’s own tissue
proteins;
• If a T lymphocyte reacts with “self-antigens” - it is destroyed - This happens
to 90 % of the T cells.
• the T cells that are released are non-reactive against the body’s own
antigens—they react only against antigens from an outside source
 Secondary Lymphoid
Organs
About 450 lymph nodes, spleen, tonsils,
and Peyer’s patches under the mucosa
of the intestines
• strategically located in areas where
antigens could enter the blood or
lymph.
• The spleen filters blood,
• Other secondary lymphoid organs filter
lymph
• They capture pathogens, present them
to macrophages and other cells,
• sites where lymphocytes can come
into contact with the foreign antigens
 T LYMPHOCYTES
T lymphocytes kill their victim cells by cell-mediated destruction
• Killer (cytotoxic) T Lymphocytes
• Helper T Lymphocytes
• Regulatory T Lymphocytes
 Antigen Presenting Cells
• T lymphocytes need to be activated first;
• T lymphocytes to respond to foreign antigens, the antigens must be
presented to the T cells on the membrane of antigen-presenting
cells:
1. dendritic cells
2. macrophages
3. B lymphocytes
• Most invading organisms are first
phagocytized and digested by the
macrophages,
• Digested parts of an invading organism are
liberated into the macrophage cytosol.
• The macrophages expose these antigens on
their surface receptors
• Present the antigen to the lymphocytes and
activate them
macrophages, secrete a special substance
interleukin-1 = promotes growth and
reproduction of lymphocytes.
 Human leukocyte antigens (HLAs) - MHC molecules

Class-1 MHC molecules - on all the

nucleated cells
• MHC 1 Present polypeptides that have
entered the cell
• Antigens derived from proteins in the
cell’s cytoplasm
• If any cell presents foreign antigens
on class-1 MHC molecules, Killer T
lymphocytes are activated and
destroy a cell
• class-1 MHC molecules interact with
CD8 receptor on Cytotoxic T cells
 Class-2 MHC molecules
Class-2 MHC - present only on antigen
presenting cells —dendritic cells,
macrophages, and B lymphocytes
• APCs capture the foreign proteins,
process them and present the foreign
antigens on their MHC class-2
molecules
• class-2 MHC molecules interact with
CD4 receptor on helper T lymphocytes
• The helper T lymphocytes can only be
activated if the antigens are presented
to them with class-2 MHC molecules
 Cytotoxic T lymphocytes
The killer T lymphocytes defend against viral and fungal infections and
destroy cancer cells
• Destroy the cells that harbor foreign molecules
• Have a surface molecule called CD8.

The activated killer cells secrete perforins

and granzymes.
• The perforins enter the plasma
membrane of the victim cell - form a
large pore - osmotic destruction of the
victim cell.
• The granzymes enter the victim cell and
cause the destruction of the victim
cell’s DNA
 Helper T lymphocytes
are identified in the laboratory by a surface molecule called CD4
These cells enhance the immune response;
Stimulate B lymphocytes to differentiate into plasma cells and
secrete antibodies
Stimulate killer lymphocytes to mount a cell-mediated immune
response.
Helper T lymphocytes aid the specific immune response through
secretion of chemical regulators called lymphokines
 Lymphokines

• T lymphocytes, secrete a
number of polypeptides that
regulate immune system
Activity
• lymphokine is often used to
refer to the cytokines of
lymphocytes.
 Subtypes of helper T lymphocytes:
TH1, TH2, TH17
TH1 produce interleukin-2 and gamma interferon:
• activate killer T cells and promote cell-mediated immunity against
intracellular pathogens.
• stimulate macrophages – greatly increasing their activity.

The TH2 lymphocytes secrete interleukin-4, interleukin-5, interleukin-13,

• stimulate B lymphocytes against extracellular pathogens.

• The TH17 cells secrete interleukin-17 - stimulates a different kind of

inflammatory response by neutrophils.
 Regulatory T lymphocytes (Treg)
Regulatory (suppressor) T lymphocytes provide a “brake” on the
specific immune response
• inhibit the activity of killer T lymphocytes and B lymphocytes.
• these cells has CD4 as well as CD25 surface markers.
• suppress inappropriate adaptive immune responses,
• required for immune tolerance to self-antigens
• prevention of autoimmune diseases
 T Cells in Activate B Lymphocytes
• Most antigens activate
both T lymphocytes and
B lymphocytes at the
same time.
• T helper cells, secrete
lymphokines - activate
the specific B
lymphocytes
• B lymphocytes
differentiate into plasma
cells and secrete
antibodies
Without the help of helper
T cells, B lymphocytes
form low amount of
antibodies
 Liver and Bone Marrow Preprocess the B
Lymphocytes
• B lymphocytes secrete antibodies
• Antibodies - are large protein molecules that are capable of
combining with and destroying the antigenic substance,
After preprocessing, the B cells migrate to lymphoid tissue throughout
the body, where they lodge near but slightly removed from the T-
lymphocyte areas.
 B lymphocytes
circulates throughout the body, until it encounters
the antigen
• Exposure to the appropriate antigen activates
the B cell
• B cell enters a germinal center of a secondary
lymphoid organ, where it undergoes divisions.
1. Some become memory cells - important in
forming active immunity.
2. Others transform into plasma cells that
produce about 2,000 antibody proteins per
second
The antibodies that are produced by plasma cells
react specifically with that antigen
• Opsonization - The ability of antibodies to
stimulate phagocytosis
 Antibody Structure
All antibody molecules consist of four
interconnected polypeptide chains
• Two long, heavy chains (the H chains ) are
joined to two shorter, lighter L chains.
• The stalk of the Y has been called the
“crystallizable fragment” (Fc ),
• The top of the Y is the “antigen-binding
fragment” ( Fab )
Fab regions are variable – depending on the
specific type of antigens
Antibody types
• Antibody proteins are also known as
immunoglobulins (Ig).
There are five Ig subclasses:
1. IgG - Most abundant in the
plasma, secreted during secondary
response
2. IgA - most abundant in the
secretions of mucosal membranes,
saliva and milk
3. IgM – serve as antigen receptors,
secreted during primary contact
with antigen
4. IgD – serve as antigen receptors
5. IgE - involved in allergic reactions
 Complement System
Cascade of Proteins acting together to attack the microorganism
• The complement proteins are named C1 through C9 - are
present in an inactive state in plasma and other fluids
There are two pathways of activation:
1. The classic pathway - initiated by the binding of IgG and IgM
antibodies to antigens on the invading cell’s membrane. This
is more rapid and efficient
2. Alternative pathway - initiated by the unique polysaccharides
that coat bacterial cells.
the complement proteins can be subdivided into three
components:
1. Recognition (C1);
2. Activation (C4, C2, and C3);
3. Attack (C5 through C9).
• The attack phase consists of complement fixation, in which
complement proteins attach to the cell membrane and destroy
the cell
 Complement pathway
Complement-dependent cytotoxicity (destruction of cells by complement) is
initiated by the binding of antibodies to antigens on invading cell surface
• Then protein C1 is activated –cleaves C4 into two fragments: C4a and C4b
• The C4b fragment is an active enzyme - binds to the cell membrane
• Then, C3 is cleaved into C3a and C3b
Alternative pathway also results in the conversion of C3 into C3a and C3b -
Acting through a different sequence of events
• The C3b converts C5 into C5a and C5b .
• C5 through C9 are inserted into the bacterial cell membrane to form a
membrane attack complex - large pore that can kill the bacterial cell through
the osmotic influx of water.
 Other functions of Complement fragments
Complement fragments that do not become fixed and have a number of
effects:
1. chemotaxis —attract phagocytic cells to the site of complement
activation;
• C3a and C5a - powerful chemokines to attract macrophages,
neutrophils, monocytes, and eosinophils to the site of the infection.
2. Opsonization —phagocytic cells have receptors for C3b - forms bridges
between the phagocyte and the victim cell - facilitating phagocytosis;
3. Stimulation of histamine release from mast cells and basophils by C3a
and C5a .
• Histamine causes vasodilation and increased capillary permeability.
• Blood flow to the infected area is increased - bring in more phagocytic
cells
• also result in edema through leakage of plasma proteins into the
surrounding tissue fluid
 References:
1. Human physiology - Stuart Ira Fox, Pierce College.—Fourteenth
edition.
2. Textbook of Medical Physiology – Arthur C. Guyton, John E. Hall.—
11th edition