Organs of Immune System
Organs of Immune System
Organs of Immune System
• Primary Lymphoid Organs
– Bone Marrow
– Thymus
• Secondary Lymphoid Organs
– Lymph Nodes
– Mucosal-Associated Lymphoid Tissues (MALT)
• Gut-Associated Lymphoid Tissue (GALT)
• Cutaneous Associated Lymphoid Tissue
Primary Lymphoid Organs
• Immature lymphocytes generated in
hematopoiesis mature and become
committed to a particular antigenic specificity
within the primary lymphoid organs.
Bone Marrow
• Bone marrow is the site of B-cell origin and
development.
• Arising from lymphoid progenitors, immature
B cells proliferate and differentiate within the
bone marrow
• Stromal cells within the bone marrow interact
directly with the B cells and secrete various
cytokines that are required for development.
Bone Marrow
• Bone marrow is not the site of B-cell
development in all species.
• In birds, a lymphoid organ called the bursa of
Fabricius, a lymphoid tissue associated with
the gut, is the primary site of B-cell
maturation.
• In mammals such as primates and rodents,
there is no bursa and no single counterpart to
it as a primary lymphoid organ.
Bone Marrow
• In cattle and sheep, the primary lymphoid tissue
hosting the maturation, proliferation, and
diversification of B cells early in gestation is the fetal
spleen.
• Later in gestation, this function is assumed by a patch
of tissue embedded in the wall of the intestine called
the ileal Peyer’s patch, which contains a large number
(1010) B cells.
• The rabbit, too, uses gut-associated tissues such as the
appendix as primary lymphoid tissue for important
steps in the proliferation and diversification of B cells.
Thymus
• The thymus is the site of T-cell development and
maturation.
• It is a flat, bilobed organ situated above the heart.
• Each lobe is surrounded by a capsule and is divided
into lobules, which are separated from each other by
strands of connective tissue called trabeculae.
• Each lobule is organized into two compartments: the
outer compartment, or cortex, is densely packed with
immature T cells, called thymocytes, whereas the inner
compartment, or medulla, is sparsely populated with
thymocytes.
Thymus
• Both the cortex and medulla of the thymus are crisscrossed by
a three-dimensional stromal-cell network composed of
epithelial cells, dendritic cells, and macrophages, which make
up the framework of the organ and contribute to the growth
and maturation of thymocytes.
• Many of these stromal cells interact physically with the
developing thymocytes.
• Some thymic epithelial cells in the outer cortex, called nurse
cells, have long membrane extensions that surround as many
as 50 thymocytes, forming large multicellular complexes.
• Other cortical epithelial cells have long interconnecting
cytoplasmic extensions that form a network and have been
shown to interact with numerous thymocytes as they traverse
the cortex.
Thymus
• The function of the thymus is to generate and select a repertoire of T
cells that will protect the body from infection.
• As thymocytes develop, an enormous diversity of T-cell receptors is
generated by a random process that produces some T cells with
receptors capable of recognizing antigen-MHC complexes.
• However, most of the T-cell receptors produced by this random
process are incapable of recognizing antigen-MHC complexes.
• A small portion react with combinations of self antigen-MHC
complexes.
• The thymus induces the death of those T cells that cannot recognize
antigen- MHC complexes and those that react with self-antigen– MHC
and pose a danger of causing autoimmune disease.
• More than 95% of all thymocytes die by apoptosis in the thymus
without ever reaching maturity.
Thymus
• Aging is accompanied by a decline in thymic function.
• This decline may play some role in the decline in
immune function during aging in humans and mice.
• The thymus reaches its maximal size at puberty and
then atrophies, with a significant decrease in both
cortical and medullary cells and an increase in the total
fat content of the organ.
• Whereas the average weight of the thymus is 70 g in
infants, its age-dependent involution leaves an organ
with an average weight of only 3 g in the elderly.
Thymus
• A number of experiments have been designed to
look at the effect of age on the immune function
of the thymus.
• In one experiment, the thymus from a 1-day-old
or 33-month old mouse was grafted into
thymectomized adults.
• Mice receiving the newborn thymus graft showed
a significantly larger improvement in immune
function than mice receiving the 33- month-old
thymus.
Lymphatic System
• As blood circulates under pressure, its fluid
component (plasma) seeps through the thin wall
of the capillaries into the surrounding tissue.
• Much of this fluid, called interstitial fluid, returns
to the blood through the capillary membranes.
• The remainder of the interstitial fluid, now called
lymph, flows from the spaces in connective tissue
into a network of tiny open lymphatic capillaries
and then into a series of progressively larger
collecting vessels called lymphatic vessels.
Lymphatic System
• The largest lymphatic vessel, the thoracic duct, empties
into the left subclavian vein near the heart.
• In this way, the lymphatic system captures fluid lost
from the blood and returns it to the blood, thus
ensuring steady-state levels of fluid within the
circulatory system.
• The heart does not pump the lymph through the
lymphatic system; instead the flow of lymph is
achieved as the lymph vessels are squeezed by
movements of the body’s muscles.
• A series of one-way valves along the lymphatic vessels
ensures that lymph flows only in one direction.
Lymphatic System
• When a foreign antigen gains entrance to the tissues, it
is picked up by the lymphatic system (which drains all
the tissues of the body) and is carried to various
organized lymphoid tissues such as lymph nodes,
which trap the foreign antigen.
• As lymph passes from the tissues to lymphatic vessels,
it becomes progressively enriched in lymphocytes.
• The lymphatic system serves as a means of
transporting lymphocytes and antigen from the
connective tissues to organized lymphoid tissues where
the lymphocytes may interact with the trapped antigen
and undergo activation.
Secondary Lymphoid Organs
• Various types of organized lymphoid tissues are
located along the vessels of the lymphatic
system.
• Some lymphoid tissue in the lung and lamina
propria of the intestinal wall consists of diffuse
collections of lymphocytes and macrophages.
• Other lymphoid tissue is organized into structures
called lymphoid follicles, which consist of
aggregates of lymphoid and nonlymphoid cells
surrounded by a network of draining lymphatic
capillaries.
Secondary Lymphoid Organs
• Until it is activated by antigen, a lymphoid follicle—
called a primary follicle—comprises a network of
follicular dendritic cells and small resting B cells.
• After an antigenic challenge, a primary follicle becomes
a larger secondary follicle—a ring of concentrically
packed B lymphocytes surrounding a center (the
germinal center) in which one finds a focus of
proliferating B lymphocytes and an area that contains
nondividing B cells, and some helper T cells
interspersed with macrophages and follicular dendritic
cells
Secondary Lymphoid Organs
• Lymph nodes and the spleen are the most
highly organized of the secondary lymphoid
organs; they comprise not only lymphoid
follicles, but additional distinct regions of T cell
and B-cell activity, and they are surrounded by
a fibrous capsule.
Secondary Lymphoid Organs
• Less-organized lymphoid tissue, collectively
called mucosal-associated lymphoid tissue
(MALT), is found in various body sites.
• MALT includes Peyer’s patches (in the small
intestine), the tonsils, and the appendix, as
well as numerous lymphoid follicles within the
lamina propria of the intestines and in the
mucous membranes lining the upper airways,
bronchi, and genital tract.
Lymph Node
• They are encapsulated bean shaped structures
containing a reticular network packed with
lymphocytes, macrophages, and dendritic
cells.
Lymph Node
• Can be divided into three roughly concentric
regions:
– Cortex
– Paracortex
– Medulla
Lymph Node
• Cortex – contains lymphocytes (mostly B cells),
macro-phages, and follicular dendritic cells
arranged in primary follicles.
• After antigenic challenge, the primary follicles
enlarge into secondary follicles, each containing a
germinal center.
• In children with B-cell deficiencies, the cortex
lacks primary follicles and germinal centers.
• Cortex is sometimes referred to as a thymus-
independent area.
Lymph Node
• Paracortex - is populated largely by T
lymphocytes and also contains interdigitating
dendritic cells thought to have migrated from
tissues to the node.
• These interdigitating dendritic cells express high
levels of class II MHC molecules, which are
necessary for presenting antigen to TH cells.
• Paracortex is sometimes referred to as a thymus-
dependent area.
Lymph Node
• Medulla - is more sparsely populated with
lymphoid-lineage cells; of those present, many
are plasma cells actively secreting antibody
molecules
Lymph Node
• As antigen is carried into a regional node by
the lymph, it is trapped, processed, and
presented together with class II MHC
molecules by interdigitating dendritic cells in
the paracortex, resulting in the activation of TH
cells.
• The initial activation of B cells also take place
within the T-cell-rich paracortex.
Lymph Node
• Once activated, TH and B cells form small foci
consisting largely of proliferating B cells at the
edges of the paracortex.
• Some B cells within the foci differentiate into
plasma cells secreting IgM and IgG.
• These foci reach maximum size within 4–6 days of
antigen challenge.
• Within 4–7 days of antigen challenge, a few B
cells and TH cells migrate to the primary follicles
of the cortex.
Lymph Node
• Within a primary follicle, cellular interactions
between follicular dendritic cells, B cells, and
TH cells take place, leading to development of
a secondary follicle with a central germinal
center.
• Some of the plasma cells generated in the
germinal center move to the medullary areas
of the lymph node, and many migrate to bone
marrow.
Lymph Node
• Afferent lymphatic vessels pierce the capsule
of a lymph node at numerous sites and empty
lymph into the subcapsular sinus.
• Lymph coming from the tissues percolates
slowly inward through the cortex, paracortex,
and medulla, allowing phagocytic cells and
dendritic cells to trap any bacteria or
particulate material (e.g., antigen-antibody
complexes) carried by the lymph.
Lymph Node
• After infection or the introduction of other
antigens into the body, the lymph leaving a
node through its single efferent lymphatic
vessel is enriched with antibodies newly
secreted by medullary plasma cells and also
has a fifty fold higher concentration of
lymphocytes than the afferent lymph.
Lymph Node
• The increase in lymphocytes in lymph leaving a node is due
in part to lymphocyte proliferation within the node in
response to antigen.
• Most of the increase, however, represents blood-borne
lymphocytes that migrate into the node by passing
between specialized endothelial cells that line the
postcapillary venules of the node. These venules are lined
with usually plump endothelial cells that give them a
thickened appearance and they are called High Endothelial
Venules (HEV).
• Estimates are that 25% of the lymphocytes leaving a lymph
node have migrated across this endothelial layer and
entered the node from the blood.
Lymph Node
• Because antigenic stimulation within a node
can increase this migration tenfold, the
concentration of lymphocytes in a node that is
actively responding can increase greatly, and
the node swells visibly.
• Factors released in lymph nodes during
antigen stimulation are thought to facilitate
this increased migration.
Spleen
• The spleen plays a major role in mounting
immune responses to antigens in the blood
stream ---- Systemic Infection.
• It is a large, ovoid secondary lymphoid organ
situated high in the left abdominal cavity.
• Blood borne antigens and lymphocytes are
carried into the spleen through the splenic
artery.
Spleen
• The spleen is surrounded by a capsule that
extends a number of projections (trabeculae)
into the interior to form a compartmentalized
structure.
• The compartments are of two types, the red
pulp and white pulp, which are separated by a
diffuse marginal zone.
Spleen
• The splenic red pulp consists of a network of
sinusoids populated by macrophages and
numerous red blood cells (erythrocytes) and
few lymphocytes.
• It is the site where old and defective red blood
cells are destroyed and removed.
• Many of the macrophages within the red pulp
contain engulfed red blood cells or iron
pigments from degraded hemoglobin.
Spleen
• The splenic white pulp surrounds the
branches of the splenic artery, forming a
periarteriolar lymphoid sheath (PALS)
populated mainly by T lymphocytes.
• Primary follicles are attached to the PALS.
These follicles are rich in B cells.
• The marginal zone, located peripheral to the
PALS, is populated by lymphocytes and
macrophages.
Spleen
• Blood-borne antigens and lymphocytes enter
the spleen through the splenic artery, which
empties into the marginal zone.
• In the marginal zone, antigen is trapped by
interdigitating dendritic cells, which carry it to
the PALS.
• Lymphocytes in the blood also enter sinuses in
the marginal zone and migrate to the PALS.
Spleen
• The initial activation of B and T cells takes place in the Tcell-
rich PALS. Here interdigitating dendritic cells capture
antigen and present it combined with class II MHC
molecules to TH cells.
• Once activated, these TH cells can then activate B cells.
• The activated B cells, together with some TH cells, then
migrate to primary follicles in the marginal zone.
• Upon antigenic challenge, these primary follicles develop
into characteristic secondary follicles containing germinal
centers (like those in the lymph nodes), where rapidly
dividing B cells (centroblasts) and plasma cells are
surrounded by dense clusters of concentrically arranged
lymphocytes.
Spleen
• The effects of splenectomy on the immune
response depends on the age at which the spleen
is removed.
• In children, splenectomy often leads to an
increased incidence of bacterial sepsis caused
primarily by Streptococcus pneumoniae, Neisseria
meningitidis, and Haemophilus influenzae.
• Splenectomy in adults has less adverse effects,
although it leads to some increase in blood-borne
bacterial infections (bacteremia).
Mucosal Associated Lymphoid Tissue
• Structurally, these tissues range from loose, barely
organized clusters of lymphoid cells in the lamina
propria of intestinal villi to well-organized structures
such as the familiar tonsils and appendix, as well as
Peyer’s patches, which are found within the
submucosal layer of the intestinal lining.
• The functional importance of MALT in the body’s
defense is attested to by its large population of
antibody-producing plasma cells, whose number far
exceeds that of plasma cells in the spleen, lymph
nodes, and bone marrow combined.
GALT
• Has the capacity to endocytose antigen from
the lumen. Immune reactions are initiated
against pathogens and antibody can be
generated and exported to the lumen to
combat the invading organisms.
• Lymphoid cells are found in various regions
within this tissue.
GALT
• The lamina propria, which lies under the epithelial
layer, contains large numbers of B cells, plasma cells,
activated TH cells, and macrophages in loose clusters.
• Histologic sections have revealed more than 15,000
lymphoid follicles within the intestinal lamina propria
of a healthy child.
• The submucosal layer beneath the lamina propria
contains Peyer’s patches, nodules of 30–40 lymphoid
follicles.
• Like lymphoid follicles in other sites, those that
compose Peyer’s patches can develop into secondary
follicles with germinal centers.
M cells
• The epithelial cells of mucous membranes play an
important role in promoting the immune
response by delivering small samples of foreign
antigen from the lumina of the respiratory,
digestive, and urogenital tracts to the underlying
mucosal-associated lymphoid tissue.
• This antigen transport is carried out by
specialized M cells. The structure of the M cell is
striking: these are flattened epithelial cells lacking
the microvilli that characterize the rest of the
mucous epithelium.
M cells
• M cells have a deep invagination, or pocket, in
the basolateral plasma membrane; this pocket is
filled with a cluster of B cells, T cells, and
macrophages.
• Luminal antigens are endocytosed into vesicles
that are transported from the luminal membrane
to the underlying pocket membrane.
• The vesicles then fuse with the pocket
membrane, delivering the potentially response-
activating antigens to the clusters of lymphocytes
contained within the pocket.
M cells
• Antigens transported across the mucous
membrane by M cells can activate B cells within
these lymphoid follicles.
• The activated B cells differentiate into plasma
cells, which leave the follicles and secrete the IgA
class of antibodies.
• These antibodies then are transported across the
epithelial cells and released as secretory IgA into
the lumen, where they can interact with antigens.
CALT
• The skin is an important anatomic barrier to the external environment,
and its large surface area makes this tissue important in nonspecific
(innate) defenses.
• The epidermal (outer) layer of the skin is composed largely of
specialized epithelial cells called keratinocytes. These cells secrete a
number of cytokines that may function to induce a local inflammatory
reaction.
• In addition, keratinocytes can be induced to express class II MHC
molecules and may function as antigen-presenting cells.
• Scattered among the epithelial-cell matrix of the epidermis are
Langerhans cells, a type of dendritic cell, which internalize antigen by
phagocytosis or endocytosis.
• The Langerhans cells then migrate from the epidermis to regional
lymph nodes, where they differentiate into interdigitating dendritic
cells.
• These cells express high levels of class II MHC molecules and function as
potent activators of naive TH cells.
CALT
• The epidermis also contains so-called
intraepidermal lymphocytes. These are similar to
the intraepithelial lymphocytes of MALT in that
most of them are CD8 T cells.
• These intraepidermal T cells are well situated to
encounter antigens that enter through the skin.
• The underlying dermal layer of the skin contains
scattered CD4 and CD8 T cells and macrophages.
• Most of these dermal T cells were either
previously activated cells or are memory cells.
