THE LYMPHATIC SYSTEM

LYMPHATIC SYSTEM AND IMMUNITY

- Our body’s lymphatic system and immunity serve as protection or defense

systems against disease-producing microbes and threats arising both inside and
outside the body. In this lecture, we will talk about the organization and
components of the lymphatic system and its role in keeping us healthy.
- The lymphatic system includes a fluid called lymph, vessels called lymphatic
vessels that transport the lymph, a number of lymphatic tissues, lymphatic
nodules, lymph nodes, and lymphatic organs that include the tonsils, the spleen,
and the thymus.

FUNCTIONS OF THE LYMPHATIC SYSTEM

- Fluid balance: Lymphatic vessels drain excess interstitial fluid from tissue
spaces and return it to the blood. This function closely links it with the
cardiovascular system. In fact, without this function, the maintenance of
circulating blood volume would not be possible.
- Lipid absorption: Lacteals are lymphatic vessels located in the lining of the
digestive tract. The lymphatic system absorbs lipids and other substances from
the digestive tract through the lacteals. Lipids enter the lacteal and pass through
the lymphatic vessels to the venous circulation. The lymph passing through these
lymphatic vessels, called chyle, appears white because of its lipid content.
- Carries out immune responses: Lymphatic tissue initiates highly specific
responses directed against particular microbes or abnormal cells.
- Defense: Microorganisms and other foreign substances are filtered from lymph
by lymph nodes and from blood by the spleen. In addition, lymphocytes and other
cells are capable of destroying microorganisms and other foreign substances.
Because the lymphatic system fights infections and filters blood and lymph to
remove microorganisms, many infectious diseases produce symptoms
associated with the lymphatic system.

LYMPHATIC VESSELS

- The inner layer of the lymphatic vessel consists of endothelium surrounded by an

elastic membrane; the middle layer consists of smooth muscle cells and elastic
fibers; and the outer layer is a thin layer of fibrous connective tissue.
 - Small lymphatic vessels have one-way valves that cause small lymphatic vessels
to form a clumped appearance.
- Lymphatic vessels originate as lymphatic capillaries, which are located in the
spaces between cells and are closed at one end. These capillaries and vessels
are not found in some parts of the body like the central nervous system, the bone
marrow, and tissues without blood vessels, such as cartilage, epidermis, and the
cornea. As these capillaries start to combine to form venules and then veins,
lymphatic vessels begin to form, which look like small veins but have thinner
walls and more valves.

Difference of Lymphatic Capillaries from Blood Capillaries

- Lymphatic capillaries are better absorbents than blood capillaries and thus can
absorb large molecules such as proteins and lipids. Lymphatic capillaries are
also slightly bigger in diameter than blood capillaries and have a unique one-way
structure that permits interstitial fluid to pass into them but not out.

Process of the flow of lymph in the Lymphatic Capillaries

- The ends of endothelial cells that make up the wall of a lymphatic capillary
overlap. When pressure is greater in the interstitial fluid than in lymph, the cells
separate slightly, like the opening of a one-way swinging door, and interstitial fluid
enters the lymphatic capillary. When pressure is greater inside the lymphatic
capillary, the cells adhere more closely, and lymph cannot escape back into the
interstitial fluid. The pressure is relieved as lymph moves further down the
lymphatic capillary. Attached to the lymphatic capillaries are anchoring filaments,
which contain elastic fibers. They extend out from the lymphatic capillary,
attaching lymphatic endothelial cells to surrounding tissues. When excess
interstitial fluid accumulates and causes tissue swelling, the anchoring filaments
are pulled, making the openings between cells even larger so that more fluid can
flow into the lymphatic capillary.
- Lacteals: transports dietary fluids into lymphatic vessels into the blood.
- Chyle: creamy-white lymph caused by the draining of the lymph from the small
intestine.
FORMATION AND FLOW OF LYMPH THROUGH LYMPHATIC VESSELS

Lymph can pass through lymphatic vessels using three mechanisms:

1. Contraction of lymphatic vessels: In many parts of the body, lymphatic vessels

pump lymph. The unidirectional valves divide lymphatic vessels into a series of
chambers, which function as “primitive hearts.” Lymph moves into a chamber,
smooth muscle in the chamber wall contracts, and lymph moves into the next
chamber.
2. Contraction of skeletal muscles: When surrounding muscle cells contract,
lymphatic vessels are compressed, causing lymph to move.
3. Thoracic pressure changes: During inspiration (breathing in), pressure in the
thoracic cavity decreases, lymphatic vessels expand, and lymph flows into them.
During expiration (breathing out), pressure in the thoracic cavity increases, and
lymphatic vessels are compressed, causing lymph to move.
After the lymph passes through the lymphatic capillaries, and into the lymphatic vessels,
it will then pass into lymph nodes, one of the lymphatic organs. As lymphatic vessels
exit lymph nodes in a particular region of the body, they converge to form larger vessels
called lymph trunks, which drain lymph from a major portion of the body.

PRINCIPAL TRUNKS

Lumbar trunk: drains lymph from the lower limbs, pelvic and abdominal walls, pelvic
organs, ovaries or testes, the kidneys, and the adrenal glands.

Intestinal trunk: drains lymph from abdominal organs, such as the intestines, stomach,
pancreas, spleen, and liver.

Bronchomediastinal trunk: drains lymph from the thoracic organs such as the heart
and lungs, and the thoracic wall.

Subclavian trunk: drains lymph from the upper limbs, superficial thoracic wall, and
mammary glands.

Jugular trunk: drains lymph from the head and neck.

The lymphatic trunks either connect to large veins in the thorax or join to yet larger
vessels called lymphatic ducts, which are the largest lymphatic vessels, then connect
to the large veins.
Right lymphatic duct: forms a single junction with the venous system.
Thoracic (left lymphatic) duct: forms the main vessel or passage for the return of
lymph to the blood.

Note: All lymph returns to the bloodstream through the thoracic (left ) lymphatic
duct and right lymphatic duct.

LYMPHATIC ORGANS AND TISSUES

The widely distributed lymphatic organs and tissues are classified into two groups
based on their functions. Primary lymphatic organs are the sites where stem cells divide
and become immunocompetent, that is, capable of mounting an immune response. The
primary lymphatic organs are the red bone marrow (in flat bones and the epiphyses of
long bones of adults) and the thymus. Pluripotent stem cells in red bone marrow give
rise to mature, immunocompetent B cells and to pre-T cells. The pre-T cells in turn
migrate to the thymus, where they become immunocompetent T cells. The secondary
lymphatic organs and tissues are the sites where most immune responses occur. They
include lymph nodes, the spleen, and lymphatic nodules (follicles). The thymus, lymph
nodes, and spleen are considered organs because each is surrounded by a connective
tissue capsule; lymphatic nodules, in contrast, are not considered organs because they
lack a capsule.

● TONSILS
 - are large groups of lymphatic nodules and diffuse lymphatic tissue located
deep in the mucous membranes within the pharynx that form a ring at the
junction of the oral cavity and oropharynx and at the junction of the nasal
cavity and nasopharynx.
- The tonsils are strategically positioned to participate in immune responses
against inhaled or ingested foreign substances entering the pharynx from
the nasal or oral cavity.
- There are three groups of tonsils: (1) the palatine tonsils, is set in the
posterior wall of the nasopharynx (2) the pharyngeal tonsil, these are the
tonsils commonly removed in a tonsillectomy, positioned at the posterior
region of the oral cavity, one on each side, and (3) the lingual tonsil,
which lie at the base of the tongue, may also require removal during a
tonsillectomy.

ADDITIONAL INFORMATION:
Tonsillitis is an infection or inflammation of the tonsils. Most often, it is
caused by a virus, but it may also be caused by the same bacteria that
cause strep throat. The principal symptom of tonsillitis is a sore throat.
Additionally, fever, swollen lymph nodes, nasal congestion, difficulty in
swallowing and headaches may also occur. Tonsillitis of viral origin usually resolves on
its own. Bacterial tonsillitis is typically treated with antibiotics. Tonsillectomy, the removal
of a tonsil, may be indicated for individuals who do not respond to other treatments.
Such individuals usually have tonsillitis lasting for more than 3 months (despite
medication), obstructed air pathways, and difficulty in swallowing and talking.
 ● LYMPH NODES

- are about 600 round, oval, or bean-shaped bodies distributed along the
various lymphatic vessels, both superficial and deep, and usually transpire
in large groups. Large groups of lymph nodes are present near the
mammary glands and in the axillae and groin.
- Lymph nodes have a capsule that extends into the node, and a
trabeculae (capsular extensions) that divide the nodes into sections,
provide support, and provide a passage for blood vessels into the interior
of a node. Inside the capsule, is a supporting network of reticular fibers
and fibroblast, which together with the capsule and trabeculae, form a
strata, which is the supporting network of connective tissues of a lymph
node.
- The parenchyma (functioning part) of a lymph node is divided into a
superficial cortex and a deep medulla.
- The cortex consists of an outer cortex and an inner cortex. In the outer
cortex are egg-shaped bundles of B cells called lymphatic nodules
(follicles). A lymphatic nodule consisting mainly of B cells is called a
primary lymphatic nodule, while the lymphatic nodules in the outer cortex
are secondary lymphatic nodules. They initiate response to an antigen (a
foreign substance) and are sites of plasma cell and memory B cell
formation. The center of a secondary lymphatic nodule contains a region
of light-staining cells called a germinal center, where B cells, follicular
dendritic cells (a special type of dendritic cell), and macrophages are
found. The region of a secondary lymphatic nodule enveloping the
germinal center is composed of dense accumulations of B cells that have
relocated away from their site of origin within the nodule. The inner cortex
consists mainly of T cells and dendritic cells that enter a lymph node from
other tissues and do not contain lymphatic nodules. The dendritic cells
introduce antigens to T cells, causing their reproduction, then the newly
formed T cells then transport from the lymph node to areas of the body
where there is antigenic activity. The medulla of a lymph node contains B
cells, antibody-producing plasma cells that have moved out of the cortex
into the medulla, and macrophages.
Route of lymph flow through a lymph node:

Afferent lymphatic vessel to Subcapsular sinus to Trabecular sinus to Medullary

sinus to Efferent lymphatic vessel

Lymph flows in one direction only, it enters through several afferent lymphatic vessels,
which puncture the convex surface of the node at some points. The valves of these
vessels open towards the center which causes the node to move inwards. Inside the
node, the lymph enters the sinuses which are a series of irregular channels that contain
branching reticular fibers, lymphocytes, and macrophages. Lymph begins to flow to the
subcapsular sinus, beneath the capsule, then moves towards the trabecular sinus
which extends through the cortex parallel to the trabeculae, and moves into medullary
sinuses, which expands through the medulla. The medullary sinuses sinuses drain into
one or two efferent lymphatic vessels, which are wider and fewer in number than
afferent vessels. They also contain valves that open away from the center of the lymph
node to transport lymph, antibodies produced by plasma cells, and activated T cells out
of the node. Efferent lymphatic vessels emerge from one side of the lymph node at a
slight depression called a hilum. Blood vessels also enter and leave the node at the
hilum.

- An important function of lymph nodes is to filter the lymph, removing

bacteria and other materials. The lymph nodes are connected in a series
so that lymph leaving one lymph node is carried to another lymph node
and so on.
- The foreign substances are trapped by the reticular fibers within the
sinuses of the node. Macrophages knock down some foreign substances
by phagocytosis, a process wherein a cell binds to the item it wants to
engulf on the cell surface and draws the item inward while engulfing
around it while lymphocytes destroy others by immune responses. The
filtered lymph then leaves the other end of the lymph node. In addition,
lymphocytes congregate, function, and proliferate within lymph nodes.
- Lymph nodes are categorized as superficial or deep. Superficial lymph
nodes are in the subcutaneous tissue beneath the skin, and deep lymph
nodes are everywhere else.
 ● SPLEEN

- The spleen is a soft, encapsulated organ of variable size, roughly the size
of a clenched fist, and is located on the left, superior part of the abdominal
cavity, between the stomach and diaphragm. It is the largest single mass
of lymphatic tissue in the body. It has a small amount of smooth muscle,
and the superior surface of the spleen is smooth and convex and
conforms to the concave surface of the diaphragm. Like lymph nodes, the
spleen has a hilum, where the splenic artery, splenic vein, and efferent
lymphatic vessels pass through.
- The spleen has an outer capsule of dense irregular connective tissue
surrounding it and is covered in turn by a serous membrane, the visceral
peritoneum.
- Bundles of connective tissue fibers from the capsule form trabeculae,
which expand into the organ, dividing it into small, interconnected parts.
The capsule with the trabeculae, reticular fibers, and fibroblasts forms the
stroma of the spleen; the parenchyma of the spleen contains different
kinds of tissue called white pulp and red pulp. White pulp is a lymphatic
tissue, consisting mostly of lymphocytes and macrophages arranged
around branches of the splenic artery called central arteries. The red pulp
consists of blood-filled venous sinuses and cords of splenic tissue called
splenic cords or Billroth’s cords. Splenic cords consist of red blood cells,
 macrophages, lymphocytes, plasma cells, and granulocytes. Veins are
closely related to the red pulp. Blood flowing into the spleen through the
splenic artery enters the central arteries of the white pulp. In the white
pulp, B cells and T cells conduct immune functions, similar to lymph
nodes, while spleen macrophages remove blood-borne pathogens by
phagocytosis.
- Within the red pulp, the spleen performs three functions related to blood
cells: (1) elimination by macrophages of ruptured, worn out, or defective
blood cells and platelets; (2) storage of platelets, up to one-third of the
body’s supply; and (3) production of blood cells or hemopoiesis during
fetal life.

● THYMUS GLAND

- The thymus is a bilobed organ located in the superior mediastinum, the

partition dividing the thoracic cavity into the left and right parts, between
the sternum and aorta. It expands from the top of the sternum or the
inferior cervical region to the level of the fourth costal cartilage, nearer to
the top of the heart and its great vessels. A confining layer connects the
 thymus together but a connective tissue called the capsule surrounds
each lobe separately. In addition to the capsule is the trabeculae, which
probe inward and divide each lobe into lobules.
- Each lobule consists of the cortex and central medulla. A cortex is
composed of large numbers of T cells and scattered dendritic cells,
epithelial cells, and macrophages. Immature T cells or pre-T cells move
from red bone marrow to the cortex of the thymus, where they proliferate
and mature. Dendritic cells are cells that assist during the maturation
process of the T- T-cells. Epithelial cells surround and serve as the
framework for as many as 50 T cells. They help “educate” the pre-T cells
in a process known as positive selection, a process of targeting the
desired cell population with an antibody specific to a cell surface marker.
Additionally, they produce thymic hormones that are thought to support the
maturation of T cells. Thymic macrophages help eliminate the debris of
dead and dying cells, then the surviving T cells enter the medulla, which
consists of widely scattered, more mature T cells, epithelial cells, dendritic
cells, and macrophages.
- Some of the epithelial cells become arranged into concentric layers of flat
cells called thymic (Hassall’s) corpuscles that degenerate and become
filled with keratohyalin granules and keratin. They may also serve as sites
of T cell death in the medulla. T cells that leave the thymus through the
blood migrate to lymph nodes, the spleen, and other lymphatic tissues,
where they take control of parts of these organs and tissues.
- The thymus has a reddish appearance in a living body because of its high
content of lymphoid tissue and a rich blood supply. As people get older,
however, fatty infiltrations replace the lymphoid tissue and the thymus
takes on more of the yellowish color of the invading fat, giving the false
impression of reduced size. The actual size of the thymus, defined by its
connective tissue capsule, does not change. In infants, the thymus has a
mass of about 70 g. It is after puberty that adipose and areolar connective
tissue begin to replace the thymic tissue. By the time a person matures,
the functional portion of the gland is reduced considerably, and in old age,
the functional portion may weigh only 3 g.
NOTE: The bilobed thymus is largest at puberty and then the functional portion withers
with age.

IMMUNITY

Immunity is the ability to resist damage from foreign substances, such as

microorganisms; harmful chemicals, such as toxins released by microorganisms; and
internal threats, such as cancer cells.

Types of Immunity

1. Innate

2. Adaptive

INNATE IMMUNITY

In innate immunity, the body recognizes and destroys certain pathogens, but the
response to them is the same each time the body is exposed.

Innate immunity includes body defenses that are present at birth and genetically
determined.
Main components of innate immunity

1. Physical barriers prevent microbes from entering the body.

2. Chemical mediators act directly against microorganisms, leading to the
destruction of the microorganisms.
3. Cells involved in phagocytosis and the production of chemicals that
participate in the immune response.

Chemical Mediators of Innate Immunity and Their Functions

Surface chemicals - lysozymes (in tears, saliva, nasal secretions, and sweat) lyse
cells; acid secretions (sebum in the skin and hydrochloric acid in the stomach) prevent
microbial growth or kill microorganisms; mucus on the mucous membranes traps
microorganisms until they can be destroyed.

Histamine - an amine released from mast cells, basophils, and platelets; it causes
vasodilation, increases vascular permeability, stimulates gland secretions, causes
smooth muscle contraction of airway passages in the lungs, and attracts eosinophils.

Kinins - are polypeptides derived from plasma proteins; kinins cause vasodilation,
increase vascular permeability, stimulate pain receptors, and attract neutrophils.

Interferons - are proteins produced by most cells that interfere with virus production
and infection.

Complement - a group of plasma proteins that increase vascular permeability, stimulate

the release of histamine, activate kinins, lyse cells, promote phagocytosis, and attract
neutrophils, monocytes, macrophages, and eosinophils.

Prostaglandins - are a group of lipids, some of which cause smooth muscle relaxation
and vasodilation, increase vascular permeability, and stimulate pain receptors.

Leukotrienes - a group of lipids, produced primarily by mast cells and basophils, that
cause prolonged smooth muscle contraction and attract neutrophils and eosinophils.

Pyrogens - are chemicals released by neutrophils, monocytes, and other cells that
stimulate fever production.
MECHANICAL MECHANISM

Mechanical barriers are the first line of defense against pathogens, physically
preventing pathogens from entering the body.

Skin and mucous membranes act as barriers, the skin is the most important mechanical
barrier. The epidermis, the skin's outer layer, is tough and difficult for pathogens to
penetrate.

Mucous membranes provide a mechanical barrier to pathogens and other particles at

body openings.

Other mechanical defenses

The pathogens are washed from the eyes by tears, from the mouth by saliva, and from
the urinary tract by urine.

CHEMICAL MEDIATORS

Chemical mediators are molecules responsible for many aspects of innate immunity.

Some chemical mediators on the surface of cells kill micro-organisms or prevent them
from entering the cells.

Other chemical mediators, such as histamine, complement, and eicosanoids, promote

inflammation by causing vasodilation and increasing vascular permeability, attracting
white blood cells, and stimulating phagocytosis.

Cytokines

Are proteins or peptides secreted by cells that bind to receptors on cell surfaces,
stimulating a response. They usually bind to receptors on neighboring cells, but
sometimes they bind to receptors on the secreting cell.

Regulates the intensity and duration of immune responses and stimulates the
proliferation and differentiation of cells. Examples of cytokines are interferons,
interleukins, and lymphokines.

Complement

Complement is a group of about 20 proteins that protect the body by destroying

abnormal cells or enhancing other components of immunity. Complement proteins make
up approximately 10% of the globulin part of plasma proteins. They include proteins
named C1–C9 and factors B, D, and P (properdin).
Normally, complement proteins circulate in the blood in an inactive, nonfunctional form.
They become activated in the complement cascade, a series of reactions in which each
component of the series activates the next component. The complement cascade
begins through either the alternative pathway or the classical pathway.

Interferons

Interferons are proteins that protect the body against viral infections. When a virus
infects a cell, the infected cell produces viral nucleic acids and proteins, which are
assembled into new viruses.

The new viruses are then released to infect other cells. Because infected cells usually
stop their normal functions or die during viral replication, viral infections are clearly
harmful to the body. Fortunately, viruses often stimulate infected cells to produce
interferons, which do not protect the cell that produces them. Instead, interferons bind to
the surface of neighboring cells, which then stimulate those cells to produce antiviral
proteins.

CELLS OF THE IMMUNE SYSTEM

White blood cells, also called leukocytes, are the most important cellular components
of immunity. They are produced in the red bone marrow and lymphatic tissue and help
defend the body against infection.

CHEMOTAXIS – The movement of white blood cells toward these chemicals

PHAGOCYTIC CELLS

Phagocytes

A type of white blood cell that uses phagocytosis to engulf bacteria, foreign particles,
and dying cells to protect the body. The two major types of phagocytes are neutrophils
and macrophages.

Phagocytosis - the ingestion of microbes or other particles such as cellular debris

Neutrophils

Small, phagocytic cells are produced in large numbers in red bone marrow and released
into the blood, where they circulate for a few hours.

They release chemical signals, such as cytokines and chemotactic factors, that increase
the inflammatory response by recruiting and activating other immune cells.
Macrophages

Large phagocytic cells. derived from monocytes, that leave the circulation to
differentiate into different tissues. and enlarge about fivefold.

CELLS OF INFLAMMATION

Basophils and mast cells

Are white blood cells derived from red bone marrow. Basophils are motile cells that can
leave the blood and enter infected tissues. Mast cells are nonmotile cells in connective
tissue, especially near capillaries.

Basophils and mast cells can be activated through innate immunity or through adaptive
immunity. When activated, they release chemicals that produce an inflammatory
response or activate other mechanisms, such as smooth muscle contraction in the
lungs.

Eosinophils

Eosinophils are white blood cells. They are produced in red bone marrow, enter the
blood, and within a few minutes enter tissues.

Eosinophil numbers increase in response to parasitic infections. Eosinophils secrete

enzymes that effectively kill some parasites. Also, eosinophil numbers greatly increase
in the case of an allergic reaction with much inflammation.

NATURAL KILLER (NK) CELLS

Natural killer (NK) cells are a type of lymphocyte produced in red bone marrow and
account for up to 15% of lymphocytes.

They are classified as part of innate immunity because they do not exhibit a memory
response.

NK cells use a variety of methods to kill their target cells, including releasing chemicals
that damage plasma membranes and cause the cells to lyse.

INFLAMMATORY RESPONSE

The inflammatory response is a complex sequence of events involving many of the

chemical mediators and cells of innate immunity.
Trauma, burns, chemicals, and infections can damage tissues, resulting in inflammation.

These chemicals produce several effects:

1. Vasodilation increases blood flow and brings phagocytes and other white blood cells
to the area.

Phagocytes - remove microorganisms and dead tissue, and damaged tissues are
repaired.

2. Phagocytes and other white blood cells leave the blood and enter the tissue

3. Increased vascular permeability allows fibrinogen and complement to enter the tissue
from the blood.

Fibrinogen is converted to fibrin, which walls off the infected area, preventing the
spread of infection.

TYPES OF INFLAMMATION

LOCAL INFLAMMATION - is an inflammatory response confined to a specific area of

the body. Symptoms of local inflammation include redness, heat, and swelling due to
increased blood flow and increased vascular permeability, as well as pain caused by
swelling and by chemical mediators acting on pain receptors. The tissue destruction,
swelling, and pain lead to loss of function.

SYSTEMIC INFLAMMATION - is an inflammatory response that is generally distributed

throughout the body. In addition to the local symptoms at the sites of inflammation.

Three additional features can be present:

1. Red bone marrow produces and releases large numbers of neutrophils, which
promote phagocytosis.

2. Pyrogens (PYE-roh-jens; fever-producing), chemicals released by microorganisms,

neutrophils, and other cells, stimulate fever production. Pyrogens affect the body’s
temperature-regulating mechanism in the hypothalamus in the brain. As a
consequence, heat production and conservation increase, raising body temperature.
Fever is beneficial because it promotes the activities of the immune system, such as
phagocytosis, and inhibits the growth of some microorganisms.
3. In severe cases of systemic inflammation, vascular permeability can increase so
much that large amounts of fluid are lost from the blood into the tissues. The decreased
blood volume can cause shock and death.

ADAPTIVE IMMUNITY

Adaptive immunity is not necessarily present at birth and may be developed due to
disease exposure or vaccination.

Adaptive immunity can recognize, respond to, and remember a particular substance.

Two Important Characteristics:

Specificity - is the ability of adaptive immunity to recognize a particular substance. For

example, innate immunity can act against bacteria in general, whereas adaptive
immunity can distinguish among various kinds of bacteria.

Memory - is the ability of adaptive immunity to “remember” previous encounters with a

particular substance. Essentially the body is “trained,” and “better equipped” to deal with
the pathogen. As a result, future responses are faster, stronger, and longer-lasting.

ANTIGENS

substances that stimulate adaptive immune responses.

Antigens are divided into two groups:

FOREIGN ANTIGENS

Introduced from outside the body. Microorganisms, such as bacteria and viruses, and
chemicals released by microorganisms are examples of foreign antigens. Pollen, animal
hairs, foods, and drugs can cause an allergic reaction because they are foreign
antigens that produce an overreaction of the immune system.

ALLERGIC REACTION – caused by foreign antigens that produce an overreaction of

the immune system.

SELF-ANTIGENS

Molecules produced by body cells to identify them as “self” or part of the body. Some of
these self-antigens also provide important information about the health of the cell. Some
self-antigens are used by defense cells to determine if a cell is mutated or infected.
This is beneficial. For example, the recognition of tumor antigens can result in the
destruction of the tumor. But the response to self-antigens can also be harmful.
Autoimmune disease results when self-antigens stimulate the unwanted destruction of
normal tissue. An example is rheumatoid arthritis, which destroys the tissue within joints

AUTOIMMUNE DISEASE – results when self-antigens stimulate unwanted destruction

of normal tissue.

ORIGIN AND DEVELOPMENT OF LYMPHOCYTES

Lymphocytes - are white blood cells that serve as one of the body’s primary immune
cells. Originated from the bone marrow and mature in primary lymphatic organs which
are the red bone marrow and thymus.

STEM CELLS – Give rise to all the blood cells

CLONES – small groups of identical B cells or T cells that are formed during embryonic
development

2 MAJOR TYPES OF LYMPHOCYTES

B cells - give rise to cells that produce antibodies.

T cells - can promote or inhibit the activities of both antibody-mediated immunity and
cell-mediated immunity.

Both B cells and T cells originate from stem cells in red bone marrow. B cells are
processed from pre-B cells in the red bone marrow, whereas T cells are processed from
pre-T cells in the thymus. Both B cells and T cells circulate to other lymphatic tissues,
such as lymph nodes.
 DIFFERENCE BETWEEN B AND T CELLS

B CELLS T CELLS

Origin of cells Red bone marrow Red bone marrow

Site of Maturation Red bone marrow Thymus

Location of Mature Cells Blood and lymphatic tissue Blood and lymphatic tissue

Secretory Products Antibodies Cytokines

Each kind of lymphocyte, once developed and activated, produces a clone of cells
capable of recognizing specific antigens.

ACTIVATION AND REGULATION OF LYMPHOCYTES

Two general principles in lymphocyte activation:

1. Lymphocytes must be able to recognize the antigen.

This recognition will help the lymphocytes in determining the affected area and, from
there, they’ll be able to interact with the antigen.

2. After recognition, the lymphocytes must increase in number to destroy the

antigen.

Lymphocytes will go through a process that will result in cell division to make additional
cells, such as plasma cells, in order to build an effective immune response.
Antigenic Determinants and Antigen Receptors

An antigen has many antigenic determinants to which lymphocytes can respond. All
lymphocytes in a given clone have identical proteins on their surfaces called antigen
receptors, which combine with a specific antigenic determinant.

Antigen Receptors - proteins of the lymphocytes

T-Cell Receptors – antigen receptors on T cells

B-Cell Receptors – antigen receptors on B cells

Each clone consists of lymphocytes that have identical antigen receptors on their
surfaces. Activation of the lymphocytes of a particular clone occurs when antigens
combine with the antigen receptors of a clone. Once lymphocytes are activated, the
adaptive immune response begins.

MAJOR HISTOCOMPATIBILITY COMPLEX

● MHC (major histocompatibility complex) molecules are involved in the

majority of lymphocyte activation.
● MHC molecules are glycoproteins that have binding sites for antigens.
● MHC molecules are a different group of receptors found on the membrane of
many types of cells.

TWO CLASSES OF MHC MOLECULES:

1. MHC class 1 molecules

found on the membranes of most nucleated cells and display internal antigens.
2. MHC class 2 molecules

found on the membranes of antigen-presenting cells and display external antigens.

which include B cells, macrophages, monocytes, and dendritic cells.

Dendritic cells are large, motile cells with long cytoplasmic extensions. These cells are
scattered throughout most tissues (except the brain), with their highest concentrations in
lymphatic tissues and the skin. Dendritic cells in the skin are often called Langerhans
cells.

Similarities between MHC class I and MHC class II

● Both are synthesized in rough endoplasmic reticulum

● Both are found on the surface of APC surface
● Both are encoded by genes in HLA locus
● In both class I and class II, expression of genes is co-dominant

DIFFERENCE BETWEEN MHC CLASS I AND MHC CLASS II

MHC class I MHC class II

1. Have 8-10 amino acids Have 13-18 amino acids

2. Peptide binding domain alpha1, alpha2 Peptide binding domain alpha1, beta1

3. Present antigen to CD 8 T-cells Present antigen to CD 4 T-cells

4. Found on all surfaces of nucleated Found on the surface of APCs and

cells activated T cells

5. Composed of one peptide encoded by Composed of two peptides encoded by

HLA locus and beta 2 microglobulin HLA locus

6. Bind with endogenous antigen Bind with exogenous antigen

7. Has no invariant chain Has invariant chain

8. After binding to CD 8 T cells, cytokines After binding to CD4 T cells it triggers B

are produced that lead to the lysis of the cell response which results in antibody
entire cell formation.
COSTIMULATION

The combination of an MHC class II/antigen complex with an antigen receptor is usually
only the first signal necessary to produce a response from a B cell or a T cell.
In many cases, costimulation by additional signals is also required.

Costimulation is accomplished by cytokines released from cells as well as molecules

attached to the surfaces of cells. Cytokines produced by lymphocytes are often called
lymphokines

CYTOKINES AND THEIR FUNCTIONS

CYTOKINE DESCRIPTION

Interferon alpha (IFNα) Prevents viral replication and inhibits cell

growth; secreted by virus-infected cells

Interferon beta (IFNβ) Prevents viral replication, inhibits cell

growth, and decreases the expression of
major histocompatibility complex
(MHC) class I and II molecules; secreted
by virus-infected fibroblasts

Interferon gamma (IFNγ) About 20 different proteins that activate

macrophages and natural killer (NK) cells,
stimulate adaptive immunity by increasing
the expression of MHC class I and II
molecules, and prevent viral replication;
secreted by helper T, cytotoxic T, and NK
cells

Interleukin-1 (IL-1) Costimulation of B cells and T cells;

promotes inflammation through
prostaglandin production and induces
fever acting through the hypothalamus
(pyrogen); secreted by macrophages, B
cells, and fibroblasts

Interleukin-2 (IL-2) Costimulation of B cells and T cells and

activation of macrophages and NK cells;
secreted by helper T cells

Interleukin-4 (IL-4) Plays a role in allergic reactions by

 activation of B cells, resulting in the
production of immunoglobulin E (lgE);
secreted by helper T cells

Interleukin-5 (IL-5) Part of the response against parasites by

stimulating eosinophil production;
secreted by helper T cells

Interleukin-8 (IL-8) Chemotactic factor that promotes

inflammation by attracting neutrophils and
basophils; secreted by macrophages

Interleukn-10 (IL-10) Inhibits the secretion of interferon gamma

and interleukins; secreted by regulatory T
cells

Interleukin-15 (IL-15) Promotes inflammation and activates

memory T cells and natural killer cells

Lymphotoxin Kills target cells; secreted by cytotoxic T

cells

Perforin Makes a hole in the membrane of target

cells, resulting in lysis of the cell; secreted
by cytotoxic T cells

Tumor necrosis factor α (TNFα) Activates macrophages and promotes

fever (pyrogen); secreted by
macrophages

LYMPHOCYTE PROLIFERATION

Before exposure to an antigen, the number of lymphocytes in a clone is too small to

produce an effective response against the antigen. Exposure to an antigen results in an
increase in lymphocyte number. The first lymphocytes to increase in number are the
helper T cells. This is important because the increased number of helper T cells
responding to the antigen can find and stimulate B cells or cytotoxic T cells.
Subsequently, the number of B cells or cytotoxic T cells increases. This is important
because these cells are responsible for the immune response that destroys the antigen.
Proliferation of Helper T cells

An antigen-presenting cell (macrophage) stimulates helper T cells to divide.

1. An antigen-presenting cell, such as a macrophage, phagocytizes, processes, and

displays an antigen on its cell membrane on a MHC class II molecule.
2. A helper T cell interacts with the macrophage through its T-cell receptor.
3. Costimulation (described in more detail below) occurs through other chemical
signaling, such as interleukins secreted by the macrophage and CD4
glycoproteins of the helper T cell.
4. The helper T cell is activated and stimulated to divide through the actions of
interleukin-2 (described below), producing daughter cells.
5. The newly formed “daughter” helper T cells can be stimulated to divide as well.
These helper T cells can also stimulate B cells and cytotoxic T cells.
6. Some daughter cells will become memory T cells. Memory helper T cells
become active in future encounters with the same antigen.
Proliferation of B cells

A helper T cell stimulates a B cell to divide and differentiate into plasma cells,
which produce antibodies.

1. B-cell proliferation begins when a B cell takes in the same kind of antigen that
stimulated the helper T cell.
2. The antigen is processed by the B cell and presented on the B-cell surface by an
MHC class II molecule.
3. A helper T cell is stimulated when it binds to the MHC class II/antigen complex.
There is also costimulation involving CD4 and interleukins.
4. As a result, the B cell divides into two “daughter” cells.
5. One of these daughter cells differentiates into a plasma cell, which produces
antibodies.
6. The division process continues, increasing the number of cells capable of
producing antibodies and resulting in sufficient antibodies to destroy all the
antigens.
7. Daughter cells that do not become plasma cells, reduce in size and become
memory B cells. Memory B cells become active in future encounters with the
same antigen
TYPES OF ADAPTIVE IMMUNITY

1. Antibody-Mediated or Humoral Immunity

● Exposure of the body to an antigen can lead to the activation of B cells

and the production of antibodies.
● The antibodies bind to the antigens, which can be destroyed through
several different mechanisms. Because antibodies are in body fluids,
antibody-mediated immunity is effective against extracellular antigens,
such as bacteria, viruses (when they are outside cells), and toxins.
Antibody-mediated immunity is also involved in certain allergic reactions.

STRUCTURE OF ANTIBODIES

This structure is a Y-shaped protein consisting of four polypeptide chains: two

identical heavy chains and two identical light chains. Each light chain is attached
to a heavy chain.

Variable Region

The end of each "arm" of the antibody. This region is the part of the antibody that
combines with the antigen. The variable region of a particular antibody can join only with
a particular antigen.
Constant region

The rest of the antibody. The constant region is responsible for the activities of
antibodies, such as the ability to activate complement or to attach the antibody to cells
such as macrophages, basophils, mast cells, and eosinophils. The constant region is
nearly the same for all the antibodies of a particular class.

Antibodies make up a large portion of the proteins in plasma. Most plasma proteins
can be separated into albumin and alpha, beta, and gamma globulin portions.

Antibodies are sometimes called gamma globulins because they are found mostly in
the gamma globulin part of plasma. Antibodies are also called immunoglobulins (Ig)
because they are globulin proteins involved in immunity. The five general classes of
antibodies are denoted IgG, IgM, IgA, IgE, and IgD.

CLASSES OF ANTIBODIES AND THEIR FUNCTIONS

IgG

● 80 to 85% in serum
● activates complement and increases phagocytosis
● can cross the placenta and provide protection to the fetus
● responsible for Rh reactions, such as hemolytic disease of the newborn
IgM

● 5 to 10% in serum
● activates complement
● acts as an antigen binding receptor on the surface of B cells
● Responsible for transfusion reactions in the ABO blood system
● often the first antibody produced in response to an antigen

IgA

● 15% in serum
● secreted into saliva, into tears, and onto mucous membranes
● protects body surfaces
● found in colostrum and milk to provide immune protection to the newborn

IgE

● 0.002% in serum
● binds to mast cells and basophils and stimulates the inflammatory response

IgD

● 0.2% in serum
● functions as an antigen-binding receptor on B cells

EFFECTS OF ANTIBODIES

Antibodies can directly affect antigens in two ways:

1. The antibody can bind to the antigenic determinant and interfere with the
antigen’s ability to function.
2. The antibody can combine with an antigenic determinant on two different
antigens, rendering the antigens ineffective

The ability of antibodies to join antigens together is the basis for many clinical tests,
such as blood typing, because, when enough antigens are bound together, they
become visible as a clump or a precipitate.
 A. Antibody binding inactivates the antigen
B. Antibodies bind several antigens together
C. Activate the complement cascade
D. Initiate the release of inflammatory chemicals
E. Facilitate phagocytosis

Antibodies indirectly affect antigens by activating other mechanisms through the

constant region of the antibody. Indirect mechanisms include activation of complement,
increased inflammation resulting from the release of inflammatory chemicals from mast
cells or basophils, and increased phagocytosis resulting from antibody attachment to
macrophages.
Most of the effectiveness of antibodies results from indirect effects. After an antibody
has been attached by its variable region to an antigen, the constant region of the
antibody can activate other mechanisms that destroy the antigen.

ANTIBODY PRODUCTION

● The production of antibodies after the first exposure to an antigen is different

from that following a second or subsequent exposure.
● Antibody production in a primary response has a longer response time and
produces lower numbers of antibodies compared to a secondary response.

The primary response results from the first exposure of a B cell to an antigen. When
the antigen binds to the antigen-binding receptor on the B cell and the B cell has been
activated by a helper T cell, the B cell undergoes several divisions to form plasma cells
and memory B cells.

Plasma cells produce antibodies. The primary response normally takes 3– 14 days to
produce enough antibodies to be effective against the antigen. In the meantime, the
individual usually develops disease symptoms because the antigen has had time to
cause tissue damage.

The secondary response or memory response occurs when the immune system is
exposed to an antigen against which it has already produced a primary response. When
exposed to the antigen, the memory B cells quickly divide to form plasma cells, which
rapidly produce antibodies.
Two reasons it provides better protection:

1. The time required to start producing antibodies is less (hours to a few days).
2. More plasma cells and antibodies are produced. As a consequence, the antigen
is quickly destroyed, no disease symptoms develop, and the person is immune.

The secondary response also includes the formation of new memory cells, which
provide protection against additional exposures to a specific antigen.

Memory cells are the basis of adaptive immunity. After the destruction of the antigen,
plasma cells die, the antibodies they release are degraded, and antibody levels decline
to the point where they can no longer provide adequate protection. However, memory
cells persist for many years—for life, in some cases.

2. Cell-Mediated Immunity

● Cell-mediated immunity is a function of cytotoxic T cells and is most effective

against microorganisms that live inside body cells. Viruses and some bacteria are
examples of intracellular microorganisms.
● Cell-mediated immunity is also involved with some allergic reactions, the control
of tumors, and graft rejection.
● Cell-mediated immunity is essential for fighting viral infections. When viruses
infect cells, they direct the cells to make new viruses, which are then released to
infect other cells. Thus, cells are turned into “virus factories.” While inside the
cell, viruses have a safe haven from antibody-mediated immunity because
antibodies cannot cross the cell membrane.
● Cell-mediated immunity fights viral infections by destroying virally infected cells.

Types of T cells for Cell-Mediated Immunity

Helper T cells:

● activate macrophages
● help form B cells
● promote the production of cytotoxic T cells

Cytotoxic T cells

● precursor to cytotoxic T lymphocytes (CTL)

Cytotoxic T lymphocytes (CTL):

● destroys antigen on contact

Regulatory T cells (Tr):

● turn off immune system response when antigen is gone

Proliferation of Cytotoxic T Cells

Cytotoxic T cells increase in number in response to an abnormal MHC class I

molecule.

1. When viruses infect cells, some viral proteins are broken down and become
processed antigens that are combined with MHC class I molecules and displayed
on the surface of the infected cell. Cytotoxic T cells can distinguish between
virally infected cells and noninfected cells because the T-cell receptor can bind to
the MHC class I/viral antigen complex, which is not present in uninfected cells.
2. The cytotoxic T cell is activated when the T-cell receptor binds with the MHC
class I/antigen complex.
3. Costimulation by other surface molecules, such as CD8, also occurs.
4. Helper T cells provide costimulation as well by releasing cytokines, such as
interleukin-2, which stimulate activation and cell division of cytotoxic T cells.
5. Increasing the number of “daughter” helper T cells results in greater stimulation
of cytotoxic T cells. In cell-mediated responses, helper T cells are activated and
stimulated to divide in the same fashion as in antibody-mediated responses.
After cytotoxic T cells are activated by an antigen on the surface of a target cell, they
undergo a series of divisions to produce additional cytotoxic T cells and memory T cells
The cytotoxic T cells are responsible for the immediate cell-mediated immune response,
and the memory T cells provide a secondary response and long-lasting immunity in the
same fashion as memory B cells.

ACQUIRED ADAPTIVE IMMUNITY

Active immunity results when an individual is exposed to an antigen and the response
of the individual's immune system is the cause of the immunity.

Passive immunity occurs when another person or an animal develops immunity and
the immunity is transferred to a nonimmune individual.

Natural and artificial refer to the method of exposure/antibody transfer.

● Natural implies that contact with the antigen or transfer of antibodies occurs as
part of everyday living and is not deliberate.
● Artificial implies that the deliberate introduction of an antigen or antibody into the
body has occurred.

1. Active Natural Immunity

Results from natural exposure to an antigen, such as a disease-causing

microorganism, that stimulates the immune system to respond against the
antigen. Because the individual is not immune during the first exposure, he or
she usually develops the symptoms of the disease.

2. Active Artificial Immunity

In active artificial immunity, an antigen is deliberately introduced into an individual

to stimulate the immune system. This process is called vaccination, and the
introduced antigen is a vaccine. The vaccine usually consists of part of a
pathogen, either a dead microorganism or a live, altered one.

The antigen has been changed so that it will stimulate an immune response but
will not cause the disease symptoms. Because active artificial immunity produces
long-lasting immunity without disease symptoms, it is the preferred method of
acquiring adaptive immunity.
3. Passive Natural Immunity

Results when antibodies are transferred from a mother to her child across the
placenta before birth. During her life, the mother has been exposed to many
antigens, either naturally or artificially, and she has antibodies against many of
these antigens, which protect her and the developing fetus against disease.

Some of the antibodies (IgG) can cross the placenta and enter the fetal blood.
Following birth, the antibodies protect the baby for the first few months.
Eventually, the antibodies break down, and the baby must rely on its own
immune system. If the mother breastfeeds her baby, antibodies (IgA) in the
mother’s milk also provide protection for the baby.

4. Passive Artificial Immunity

Usually begins with vaccinating an animal, such as a horse. After the animal’s
immune system responds to the antigen, antibodies (and sometimes T cells) are
removed from the animal and injected into the human requiring immunity. In
some cases, a human who has developed immunity through natural exposure or
vaccination can serve as a source of antibodies.

Passive artificial immunity provides immediate protection for the individual

receiving the antibodies and is therefore preferred when time might not be
available for the individual to develop his or her own immunity. However, this
technique provides only temporary immunity because the antibodies are used or
eliminated by the recipient.

Antiserum is the general term for the injection that contains antibodies
responsible for passive artificial immunity. Antiserum is essentially blood serum,
which is plasma minus the clotting factors. Antisera are available against
microorganisms that cause diseases, such as rabies, hepatitis, and measles;
bacterial toxins, such as those that cause tetanus, diphtheria, and botulism; and
venoms from poisonous snakes and black widow spiders.
REFERENCES USED:

Seeley, R., VanPutte, C., Russo, A., & Regan, J. (2016, January 4). Seeley’s Anatomy &
Physiology. McGraw-Hill Education.

Tortora, G. J., & Derrickson, B. H. (2018, May 15). Principles of Anatomy and
Physiology. John Wiley & Sons.