Anatomy of the Lymphatic and Immune Systems

LEARNING OBJECTIVES

By the end of this section, you will be able to:

• Describe the structure and function of the lymphatic tissue (lymph fluid,
vessels, ducts, and organs)
• Describe the structure and function of the primary and secondary
lymphatic organs
• Discuss the cells of the immune system, how they function, and their
relationship with the lymphatic system

The immune system is the complex collection of cells and organs that destroys or
neutralizes pathogens that would otherwise cause disease or death. The lymphatic
system, for most people, is associated with the immune system to such a degree that
the two systems are virtually indistinguishable. The lymphatic system is the system of
vessels, cells, and organs that carries excess fluids to the bloodstream and filters
pathogens from the blood. The swelling of lymph nodes during an infection and the
transport of lymphocytes via the lymphatic vessels are but two examples of the many
connections between these critical organ systems.

Functions of the Lymphatic System

A major function of the lymphatic system is to drain body fluids and return them to the
bloodstream. Blood pressure causes leakage of fluid from the capillaries, resulting in the
accumulation of fluid in the interstitial space—that is, spaces between individual cells in
the tissues. In humans, 20 liters of plasma is released into the interstitial space of the
tissues each day due to capillary filtration. Once this filtrate is out of the bloodstream
and in the tissue spaces, it is referred to as interstitial fluid. Of this, 17 liters is
reabsorbed directly by the blood vessels. But what happens to the remaining three
liters? This is where the lymphatic system comes into play. It drains the excess fluid and
empties it back into the bloodstream via a series of vessels, trunks, and
ducts. Lymph is the term used to describe interstitial fluid once it has entered the
lymphatic system. When the lymphatic system is damaged in some way, such as by
being blocked by cancer cells or destroyed by injury, protein-rich interstitial fluid
accumulates (sometimes “backs up” from the lymph vessels) in the tissue spaces. This
inappropriate accumulation of fluid referred to as lymphedema may lead to serious
medical consequences.

As the vertebrate immune system evolved, the network of lymphatic vessels became
convenient avenues for transporting the cells of the immune system. Additionally, the
transport of dietary lipids and fat-soluble vitamins absorbed in the gut uses this system.
Cells of the immune system not only use lymphatic vessels to make their way from
interstitial spaces back into the circulation, but they also use lymph nodes as major
staging areas for the development of critical immune responses. A lymph node is one
of the small, bean-shaped organs located throughout the lymphatic system.

Structure of the Lymphatic System

The lymphatic vessels begin as open-ended capillaries, which feed into larger and
larger lymphatic vessels, and eventually empty into the bloodstream by a series of
ducts. Along the way, the lymph travels through the lymph nodes, which are commonly
found near the groin, armpits, neck, chest, and abdomen. Humans have about 500–600
lymph nodes throughout the body.

Figure 1. Lymphatic vessels in the arms and legs convey lymph to the larger lymphatic vessels in the torso.

A major distinction between the lymphatic and cardiovascular systems in humans is that
lymph is not actively pumped by the heart, but is forced through the vessels by the
movements of the body, the contraction of skeletal muscles during body movements,
and breathing. One-way valves (semi-lunar valves) in lymphatic vessels keep the lymph
moving toward the heart. Lymph flows from the lymphatic capillaries, through lymphatic
vessels, and then is dumped into the circulatory system via the lymphatic ducts located
at the junction of the jugular and subclavian veins in the neck.

Lymphatic Capillaries

Lymphatic capillaries, also called the terminal lymphatics, are vessels where
interstitial fluid enters the lymphatic system to become lymph fluid. Located in almost
every tissue in the body, these vessels are interlaced among the arterioles and venules
of the circulatory system in the soft connective tissues of the body. Exceptions are the
central nervous system, bone marrow, bones, teeth, and the cornea of the eye, which
do not contain lymph vessels.

Figure 2. Lymphatic capillaries are interlaced with the arterioles and venules of the cardiovascular system.
Collagen fibers anchor a lymphatic capillary in the tissue (inset). Interstitial fluid slips through spaces between
the overlapping endothelial cells that compose the lymphatic capillary.

Lymphatic capillaries are formed by a one cell-thick layer of endothelial cells and
represent the open end of the system, allowing interstitial fluid to flow into them via
overlapping cells. When interstitial pressure is low, the endothelial flaps close to prevent
“backflow.” As interstitial pressure increases, the spaces between the cells open up,
allowing the fluid to enter. Entry of fluid into lymphatic capillaries is also enabled by the
collagen filaments that anchor the capillaries to surrounding structures. As interstitial
pressure increases, the filaments pull on the endothelial cell flaps, opening up them
even further to allow easy entry of fluid.
In the small intestine, lymphatic capillaries called lacteals are critical for the transport of
dietary lipids and lipid-soluble vitamins to the bloodstream. In the small intestine, dietary
triglycerides combine with other lipids and proteins, and enter the lacteals to form a
milky fluid called chyle. The chyle then travels through the lymphatic system, eventually
entering the liver and then the bloodstream.

Larger Lymphatic Vessels, Trunks, and Ducts

The lymphatic capillaries empty into larger lymphatic vessels, which are similar to veins
in terms of their three-tunic structure and the presence of valves. These one-way valves
are located fairly close to one another, and each one causes a bulge in the lymphatic
vessel, giving the vessels a beaded appearance.

The superficial and deep lymphatics eventually merge to form larger lymphatic vessels
known as lymphatic trunks. On the right side of the body, the right sides of the head,
thorax, and right upper limb drain lymph fluid into the right subclavian vein via the right
lymphatic duct. On the left side of the body, the remaining portions of the body drain into
the larger thoracic duct, which drains into the left subclavian vein. The thoracic duct
itself begins just beneath the diaphragm in the cisterna chyli, a sac-like chamber that
receives lymph from the lower abdomen, pelvis, and lower limbs by way of the left and
right lumbar trunks and the intestinal trunk.

Figure 3. The thoracic duct drains a much larger portion of the body than does the right lymphatic duct.

The overall drainage system of the body is asymmetrical. The right lymphatic
duct receives lymph from only the upper right side of the body. The lymph from the rest
of the body enters the bloodstream through the thoracic duct via all the remaining
lymphatic trunks. In general, lymphatic vessels of the subcutaneous tissues of the skin,
that is, the superficial lymphatics, follow the same routes as veins, whereas the deep
lymphatic vessels of the viscera generally follow the paths of arteries.

The Organization of Immune Function

The immune system is a collection of barriers, cells, and soluble proteins that interact
and communicate with each other in extraordinarily complex ways. The modern model
of immune function is organized into three phases based on the timing of their effects.
The three temporal phases consist of the following:

• Barrier defenses such as the skin and mucous membranes, which act
instantaneously to prevent pathogenic invasion into the body tissues
• The rapid but nonspecific innate immune response, which consists of a
variety of specialized cells and soluble factors
• The slower but more specific and effective adaptive immune response,
which involves many cell types and soluble factors, but is primarily
controlled by white blood cells (leukocytes) known as lymphocytes, which
help control immune responses

The cells of the blood, including all those involved in the immune response, arise in the
bone marrow via various differentiation pathways from hematopoietic stem cells. In
contrast with embryonic stem cells, hematopoietic stem cells are present throughout
adulthood and allow for the continuous differentiation of blood cells to replace those lost
to age or function. These cells can be divided into three classes based on function:

• Phagocytic cells, which ingest pathogens to destroy them

• Lymphocytes, which specifically coordinate the activities of adaptive
immunity
• Cells containing cytoplasmic granules, which help mediate immune
responses against parasites and intracellular pathogens such as viruses
Figure 4. All the cells of the immune response as well as of the blood arise by differentiation from hematopoietic
stem cells. Platelets are cell fragments involved in the clotting of blood.

Lymphocytes

As stated above, lymphocytes are the primary cells of adaptive immune responses (see
Table 1 for more details). The two basic types of lymphocytes, B cells and T cells, are
identical morphologically with a large central nucleus surrounded by a thin layer of
cytoplasm. They are distinguished from each other by their surface protein markers as
well as by the molecules they secrete. While B cells mature in red bone marrow and T
cells mature in the thymus, they both initially develop from bone marrow. T cells migrate
from bone marrow to the thymus gland where they further mature. B cells and T cells
are found in many parts of the body, circulating in the bloodstream and lymph, and
residing in secondary lymphoid organs, including the spleen and lymph nodes, which
will be described later in this section. The human body contains approximately
1012 lymphocytes.

B Cells

B cells are immune cells that function primarily by producing antibodies. An antibody is
any of the group of proteins that binds specifically to pathogen-associated molecules
known as antigens. An antigen is a chemical structure on the surface of a pathogen
that binds to T or B lymphocyte antigen receptors. Once activated by binding to antigen,
B cells differentiate into cells that secrete a soluble form of their surface antibodies.
These activated B cells are known as plasma cells.

T Cells

The T cell, on the other hand, does not secrete antibody but performs a variety of
functions in the adaptive immune response. Different T cell types have the ability to
either secrete soluble factors that communicate with other cells of the adaptive immune
response or destroy cells infected with intracellular pathogens. The roles of T and B
lymphocytes in the adaptive immune response will be discussed further in this chapter.

Plasma Cells

Another type of lymphocyte of importance is the plasma cell. A plasma cell is a B cell
that has differentiated in response to antigen binding, and has thereby gained the ability
to secrete soluble antibodies. These cells differ in morphology from standard B and T
cells in that they contain a large amount of cytoplasm packed with the protein-
synthesizing machinery known as rough endoplasmic reticulum.

Natural Killer Cells

A fourth important lymphocyte is the natural killer cell, a participant in the innate immune
response. A natural killer cell (NK) is a circulating blood cell that contains cytotoxic
(cell-killing) granules in its extensive cytoplasm. It shares this mechanism with the
cytotoxic T cells of the adaptive immune response. NK cells are among the body’s first
lines of defense against viruses and certain types of cancer.

Table 1. Lymphocytes

Type of lymphocyte Primary function

B lymphocyte Generates diverse antibodies

T lymphocyte Secretes chemical messengers

 Table 1. Lymphocytes

Type of lymphocyte Primary function

Plasma cell Secretes antibodies

NK cell Destroys virally infected cells

Primary Lymphoid Organs and Lymphocyte Development

Understanding the differentiation and development of B and T cells is critical to the

understanding of the adaptive immune response. It is through this process that the body
(ideally) learns to destroy only pathogens and leaves the body’s own cells relatively
intact. The primary lymphoid organs are the bone marrow, spleen, and thymus gland.
The lymphoid organs are where lymphocytes mature, proliferate, and are selected,
which enables them to attack pathogens without harming the cells of the body.

Bone Marrow

Figure 5. Red bone marrow fills the head of the femur, and a spot of yellow bone marrow is visible in the center.
The white reference bar is 1 cm.

In the embryo, blood cells are made in the yolk sac. As development proceeds, this
function is taken over by the spleen, lymph nodes, and liver. Later, the bone marrow
takes over most hematopoietic functions, although the final stages of the differentiation
of some cells may take place in other organs. The red bone marrow is a loose
collection of cells where hematopoiesis occurs, and the yellow bone marrow is a site of
energy storage, which consists largely of fat cells. The B cell undergoes nearly all of its
development in the red bone marrow, whereas the immature T cell, called a thymocyte,
leaves the bone marrow and matures largely in the thymus gland.
Thymus

The thymus gland is a bilobed organ found in the space between the sternum and the
aorta of the heart. Connective tissue holds the lobes closely together but also separates
them and forms a capsule.

Fiugre 6. The thymus lies above the heart. The trabeculae and lobules, including the darkly staining cortex and
the lighter staining medulla of each lobule, are clearly visible in the light micrograph of the thymus of a newborn.
LM × 100. (Micrograph provided by the Regents of the University of Michigan Medical School © 2012)

The connective tissue capsule further divides the thymus into lobules via extensions
called trabeculae. The outer region of the organ is known as the cortex and contains
large numbers of thymocytes with some epithelial cells, macrophages, and dendritic
cells (two types of phagocytic cells that are derived from monocytes). The cortex is
densely packed so it stains more intensely than the rest of the thymus. The medulla,
where thymocytes migrate before leaving the thymus, contains a less dense collection
of thymocytes, epithelial cells, and dendritic cells.

Secondary Lymphoid Organs and their Roles in Active Immune

Responses
Lymphocytes develop and mature in the primary lymphoid organs, but they mount
immune responses from the secondary lymphoid organs. A naïve lymphocyte is one
that has left the primary organ and entered a secondary lymphoid organ. Naïve
lymphocytes are fully functional immunologically, but have yet to encounter an antigen
to respond to. In addition to circulating in the blood and lymph, lymphocytes concentrate
in secondary lymphoid organs, which include the lymph nodes, spleen, and lymphoid
nodules. All of these tissues have many features in common, including the following:

• The presence of lymphoid follicles, the sites of the formation of

lymphocytes, with specific B cell-rich and T cell-rich areas
• An internal structure of reticular fibers with associated fixed macrophages
• Germinal centers, which are the sites of rapidly dividing B lymphocytes
and plasma cells, with the exception of the spleen
• Specialized post-capillary vessels known as high endothelial venules; the
cells lining these venules are thicker and more columnar than normal
endothelial cells, which allow cells from the blood to directly enter these
tissues

Lymph Nodes

Lymph nodes function to remove debris and pathogens from the lymph, and are thus
sometimes referred to as the “filters of the lymph”. Any bacteria that infect the interstitial
fluid are taken up by the lymphatic capillaries and transported to a regional lymph node.
Dendritic cells and macrophages within this organ internalize and kill many of the
pathogens that pass through, thereby removing them from the body. The lymph node is
also the site of adaptive immune responses mediated by T cells, B cells, and accessory
cells of the adaptive immune system. Like the thymus, the bean-shaped lymph nodes
are surrounded by a tough capsule of connective tissue and are separated into
compartments by trabeculae, the extensions of the capsule. In addition to the structure
provided by the capsule and trabeculae, the structural support of the lymph node is
provided by a series of reticular fibers laid down by fibroblasts.
Figure 7. Lymph nodes are masses of lymphatic tissue located along the larger lymph vessels. The micrograph
of the lymph nodes shows a germinal center, which consists of rapidly dividing B cells surrounded by a layer of
T cells and other accessory cells. LM × 128.

The major routes into the lymph node are via afferent lymphatic vessels. Cells and
lymph fluid that leave the lymph node may do so by another set of vessels known as
the efferent lymphatic vessels. Lymph enters the lymph node via the subcapsular
sinus, which is occupied by dendritic cells, macrophages, and reticular fibers. Within the
cortex of the lymph node are lymphoid follicles, which consist of germinal centers of
rapidly dividing B cells surrounded by a layer of T cells and other accessory cells. As
the lymph continues to flow through the node, it enters the medulla, which consists of
medullary cords of B cells and plasma cells, and the medullary sinuses where the lymph
collects before leaving the node via the efferent lymphatic vessels.

Spleen

In addition to the lymph nodes, the spleen is a major secondary lymphoid organ. It is
about 12 cm (5 in) long and is attached to the lateral border of the stomach via the
gastrosplenic ligament. The spleen is a fragile organ without a strong capsule, and is
dark red due to its extensive vascularization. The spleen is sometimes called the “filter
of the blood” because of its extensive vascularization and the presence of macrophages
and dendritic cells that remove microbes and other materials from the blood, including
dying red blood cells. The spleen also functions as the location of immune responses to
blood-borne pathogens.
Figure 8. (a) The spleen is attached to the stomach. (b) A micrograph of spleen tissue shows the germinal center.
The marginal zone is the region between the red pulp and white pulp, which sequesters particulate antigens from
the circulation and presents these antigens to lymphocytes in the white pulp. EM × 660.

The spleen is also divided by trabeculae of connective tissue, and within each splenic
nodule is an area of red pulp, consisting of mostly red blood cells, and white pulp, which
resembles the lymphoid follicles of the lymph nodes. Upon entering the spleen, the
splenic artery splits into several arterioles (surrounded by white pulp) and eventually
into sinusoids. Blood from the capillaries subsequently collects in the venous sinuses
and leaves via the splenic vein. The red pulp consists of reticular fibers with fixed
macrophages attached, free macrophages, and all of the other cells typical of the blood,
including some lymphocytes. The white pulp surrounds a central arteriole and consists
of germinal centers of dividing B cells surrounded by T cells and accessory cells,
including macrophages and dendritic cells. Thus, the red pulp primarily functions as a
filtration system of the blood, using cells of the relatively nonspecific immune response,
and white pulp is where adaptive T and B cell responses are mounted.
Lymphoid Nodules

The other lymphoid tissues, the lymphoid nodules, have a simpler architecture than
the spleen and lymph nodes in that they consist of a dense cluster of lymphocytes
without a surrounding fibrous capsule. These nodules are located in the respiratory and
digestive tracts, areas routinely exposed to environmental pathogens.

Tonsils are lymphoid nodules located along the inner surface of the pharynx and are
important in developing immunity to oral pathogens. The tonsil located at the back of the
throat, the pharyngeal tonsil, is sometimes referred to as the adenoid when swollen.
Such swelling is an indication of an active immune response to infection. Histologically,
tonsils do not contain a complete capsule, and the epithelial layer invaginates deeply
into the interior of the tonsil to form tonsillar crypts. These structures, which accumulate
all sorts of materials taken into the body through eating and breathing, actually
“encourage” pathogens to penetrate deep into the tonsillar tissues where they are acted
upon by numerous lymphoid follicles and eliminated. This seems to be the major
function of tonsils—to help children’s bodies recognize, destroy, and develop immunity
to common environmental pathogens so that they will be protected in their later lives.
Tonsils are often removed in those children who have recurring throat infections,
especially those involving the palatine tonsils on either side of the throat, whose
swelling may interfere with their breathing and/or swallowing.
Figure 9. (a) The pharyngeal tonsil is located on the roof of the posterior superior wall of the nasopharynx. The
palatine tonsils lay on each side of the pharynx. (b) A micrograph shows the palatine tonsil tissue. LM × 40.

Mucosa-associated lymphoid tissue (MALT) consists of an aggregate of lymphoid

follicles directly associated with the mucous membrane epithelia. MALT makes up
dome-shaped structures found underlying the mucosa of the gastrointestinal tract,
breast tissue, lungs, and eyes. Peyer’s patches, a type of MALT in the small intestine,
are especially important for immune responses against ingested substances. Peyer’s
patches contain specialized endothelial cells called M (or microfold) cells that sample
material from the intestinal lumen and transport it to nearby follicles so that adaptive
immune responses to potential pathogens can be mounted.

Figure 10. LM × 40.

Bronchus-associated lymphoid tissue (BALT) consists of lymphoid follicular

structures with an overlying epithelial layer found along the bifurcations of the bronchi,
and between bronchi and arteries. They also have the typically less-organized structure
of other lymphoid nodules. These tissues, in addition to the tonsils, are effective against
inhaled pathogens.

Chapter Review

The lymphatic system is a series of vessels, ducts, and trunks that remove interstitial
fluid from the tissues and return it the blood. The lymphatics are also used to transport
dietary lipids and cells of the immune system. Cells of the immune system all come from
the hematopoietic system of the bone marrow. Primary lymphoid organs, the bone
marrow and thymus gland, are the locations where lymphocytes of the adaptive immune
system proliferate and mature. Secondary lymphoid organs are site in which mature
lymphocytes congregate to mount immune responses. Many immune system cells use
the lymphatic and circulatory systems for transport throughout the body to search for
and then protect against pathogens.
 CRITICAL THINKING QUESTION

Describe the flow of lymph from its origins in interstitial fluid to its emptying into the venous
bloodstream.
Show Answer
The lymph enters through lymphatic capillaries, and then into larger lymphatic vessels. The
lymph can only go in one direction due to valves in the vessels. The larger lymphatics merge to
form trunks that enter into the blood via lymphatic ducts.

Glossary

adaptive immune response: relatively slow but very specific and effective immune
response controlled by lymphocytes

afferent lymphatic vessels: lead into a lymph node

antibody: antigen-specific protein secreted by plasma cells; immunoglobulin

antigen: molecule recognized by the receptors of B and T lymphocytes

barrier defenses: antipathogen defenses deriving from a barrier that physically

prevents pathogens from entering the body to establish an infection

B cells: lymphocytes that act by differentiating into an antibody-secreting plasma cell

bone marrow: tissue found inside bones; the site of all blood cell differentiation and
maturation of B lymphocytes

bronchus-associated lymphoid tissue (BALT): lymphoid nodule associated with the

respiratory tract

chyle: lipid-rich lymph inside the lymphatic capillaries of the small intestine

cisterna chyli: bag-like vessel that forms the beginning of the thoracic duct

efferent lymphatic vessels: lead out of a lymph node

germinal centers: clusters of rapidly proliferating B cells found in secondary lymphoid

tissues

high endothelial venules: vessels containing unique endothelial cells specialized to

allow migration of lymphocytes from the blood to the lymph node

immune system: series of barriers, cells, and soluble mediators that combine to
response to infections of the body with pathogenic organisms
innate immune response: rapid but relatively nonspecific immune response

lymph: fluid contained within the lymphatic system

lymph node: one of the bean-shaped organs found associated with the lymphatic
vessels

lymphatic capillaries: smallest of the lymphatic vessels and the origin of lymph flow

lymphatic system: network of lymphatic vessels, lymph nodes, and ducts that carries
lymph from the tissues and back to the bloodstream.

lymphatic trunks: large lymphatics that collect lymph from smaller lymphatic vessels
and empties into the blood via lymphatic ducts

lymphocytes: white blood cells characterized by a large nucleus and small rim of
cytoplasm

lymphoid nodules: unencapsulated patches of lymphoid tissue found throughout the

body

mucosa-associated lymphoid tissue (MALT): lymphoid nodule associated with the

mucosa

naïve lymphocyte: mature B or T cell that has not yet encountered antigen for the first
time

natural killer cell (NK): cytotoxic lymphocyte of innate immune response

plasma cell: differentiated B cell that is actively secreting antibody

primary lymphoid organ: site where lymphocytes mature and proliferate; red bone
marrow and thymus gland

right lymphatic duct: drains lymph fluid from the upper right side of body into the right
subclavian vein

secondary lymphoid organs: sites where lymphocytes mount adaptive immune

responses; examples include lymph nodes and spleen

spleen: secondary lymphoid organ that filters pathogens from the blood (white pulp)
and removes degenerating or damaged blood cells (red pulp)

T cell: lymphocyte that acts by secreting molecules that regulate the immune system or
by causing the destruction of foreign cells, viruses, and cancer cells
thoracic duct: large duct that drains lymph from the lower limbs, left thorax, left upper
limb, and the left side of the head

thymocyte: immature T cell found in the thymus

thymus: primary lymphoid organ; where T lymphocytes proliferate and mature

tonsils: lymphoid nodules associated with the nasopharynx