A good read for undergraduate students in Pharmacy studying at the University of Mumbai. I will highly recommend Principles of Anatomy and Physiology by Tortora et al. All copyright to the original authors and publishers.
Fostering Friendships - Enhancing Social Bonds in the Classroom
Lymphatic system and immunity
1. Abhijeet Lokras
M. Pharm (Pharmacology) – University of Mumbai, India
MSc Drug Development – University of Copenhagen, Denmark
Chapter 22
The Lymphatic System and Immunity
Principles of Anatomy and Physiology
Thirteenth Edition
Gerard J. Tortora • Bryan H. Derrickson
2. COMPONENTS
• Lymph
• Lymphatic vessels
• Structures and organs containing lymphatic
tissues (thymus, lymph nodes)
• Red bone marrow
3. Lymphatic tissue is specialized type of reticular connective tissue
containing lymphocytes
4. FUNCTIONS OF LYMPHATIC
SYSTEM
1. Drain excess interstitial fluid
• Drain interstitial fluid from tissue spaces and return it to blood
• Maintain circulating blood volume
2. Transports dietary lipids
• Lipids and lipid soluble vitamins absorbed by gastrointestinal tract
3. Carrying out immune response
• Initiates highly specific responses against particular microbes or abnormal cells
5. (a) Anterior view of principal
components of lymphatic system
Palatine tonsil
Submandibular node
Cervical node
Right internal jugular vein
Right lymphatic duct
Right subclavian vein
Lymphatic vessel
Thoracic duct
Cisterna chyli
Intestinal node
Large intestine
Appendix
Red bone marrow
Lymphatic vessel
Left internal jugular vein
Left subclavian vein
Thoracic duct
Axillary node
Spleen
Aggregated lymphatic
follicle (Peyer’s patch)
Small intestine
Iliac node
Inguinal node
6. (b) Areas drained by right
lymphatic and thoracic ducts
Area drained by
right lymphatic duct
Area drained by
thoracic duct
7. (a) Relationship of lymphatic capillaries
to tissue cells and blood capillaries
Venule
Tissue cell
Lymph
Interstitial fluid
Blood
Blood capillary
Arteriole
Lymphatic capillary
Blood
LYMPHATIC VESSELS
8. LYMPHATIC VESSELS
• Vessels begin as capillaries
• Capillaries are closed at one end
• Capillaries converge to form vessels
• Lymph flows through Lymph Nodes. B Cells and T
cells
• In skin vessels lie in sub-cutaneous region.
In viscera, they follow arteries, forming network
around them
• NOT PRESENT IN: Cartilage, epidermis, cornea
of eye, CNS, portion of spleen and red bone marrow
9. (b) Details of a lymphatic capillary
Lymph
Endothelium of
lymphatic capillary
Tissue cell
Interstitial fluid
Anchoring filament
Opening
10. LYMPHATIC CAPILLARIES
• Greater permeability than blood capillaries (BC)
• Slightly larger diameter than BC
• One way structure – Interstitial fluid can pass only
in. Not Out
• Pressure increase cells adhere more closely
• Anchoring filaments. Attach endothelium to surrounding
tissues. When excess IF puts pressure, anchoring
filaments are pulled and thus opening is created
• LACTEALS
11. LYMPHATIC TRUNKS
• Lymph capillaries Lymph Vessels Lymph
Nodes Lymph Trunks
• Principal trunks:
1.Lumbar – drains lymph from lower limbs, wall of viscera and pelvis, kidney,
adrenal gland and abdominal wall.
2.Intestinal – drains lymph from stomach, intestines, pancreas, spleen and part
of liver
3.Bronchomediastinal – drains lymph from thoracic wall, lung and heart
4.Subclavian – drains the upper limbs
5.Jugular – drain the head and neck
12. LYMPHATIC DUCTS
• Two channels – Thoracic duct and Right Lymphatic
Duct
• Thoracic duct 38-45 cm long. Originates as a
dilation called ‘cisterna chyli’ anterior to second
lumbar vertebra
• Major duct for return of lymph to blood
• Cisterna chyli receives lymph from right and left
lumbar trunks and from intestinal trunk
• RIGHT LYMPHATIC DUCT (See diagram)
13. (a) Overall anterior view
Right internal jugular vein
RIGHT JUGULAR TRUNK
RIGHT SUBCLAVIAN
TRUNK
Right subclavian vein
RIGHT LYMPHATIC
DUCT
Right brachiocephalic vein
RIGHT BRONCHO-
MEDIASTINAL TRUNK
Superior vena cava
Rib
Intercostal muscle
Azygos vein
CISTERNA CHYLI
RIGHT LUMBAR TRUNK
Inferior vena cava
Left internal jugular vein
LEFT JUGULAR TRUNK
THORACIC (LEFT
LYMPHATIC) DUCT
LEFT SUBCLAVIAN TRUNK
Left subclavian vein
First rib
Left brachiocephalic vein
Accessory hemiazygos vein
LEFT BRONCHO-
MEDIASTINAL TRUNK
THORACIC (LEFT
LYMPHATIC) DUCT
Hemiazygos vein
LEFT LUMBAR TRUNK
INTESTINAL TRUNK
14. (b) Detailed anterior view
Right jugular trunk
Right subclavian trunk
Right lymphatic duct
Right bronchomediastinal
trunk
Left jugular trunk
Left subclavian trunk
Thoracic (left lymphatic)
duct
Left bronchomediastinal
trunk
17. Right common
carotid artery
(a) Thymus of adolescent
Right lung
Thyroid gland
Trachea
Superior vena cava
Thymus
Left lung
Fibrous
pericardium
Diaphragm
Brachiocephalic veins
18. LYMPHATIC ORGANS AND
TISSUES
• Classified based on function
1.Primary Lymphatic Organs
• Sites where stem cells divide and become immunocompetent
• Red bone marrow and Thymus
• Stem cells give rise to mature, immunocompetent B cells and pre-T cells
• Pre-T cells migrate to thymus and become immunocompetent
2. Secondary Lymphatic Organs
• Sites where majority of immune reactions occur
• Lymph nodes, spleen, lymphatic nodules
Organs – Thymus, lymph nodes and spleen
Lymphatic nodules are NOT organs
19. THYMUS
• Location – Mediastinum (between sternum and
aorta)
• Lobes held by connective tissue
• Lobes separated by connective tissue CAPSULE
• Extensions of capsule (TRABECULAE) project
inward
• Trabeculae divide lobes into lobules
22. THYMUS
1. Cortex
• Outer part, deeply stained
• Composed of T-cells and scattered dendritic cells, epithelial cells and
macrophages
• Pre-T cells mature in thymus (Migrate from Red Bone Marrow)
• Dendritic cells are derived from monocytes. Assist maturation process
• Epithelial cells help the Pre-T cells in a process called POSITIVE SELECTION.
Also produce thymic hormones aiding in maturation process.
• Only 2 % of T-cells survive. Others under apoptosis (programmed cell death)
• Thymic MACROPHAGES help clear debris of dying and dead cells
23. (c) Details of the thymic medulla
385xLM
T cell
Thymic (Hassall’s)
corpuscle
Epithelial cell
24. THYMUS
2. Medulla
•Inner part, lightly stained
•Composed of widely scattered mature T cells, epithelial cells, dendritic cells and
macrophages
•Epithelial cells arrange into concentric layers of flat cells. Degenerate and get filled
with keratohyalin granules and keratin. Clusters are called Thymic corpuscles or
Hassall’s corpuscles
•May serve as a site for T cell death in medulla
Thymus
Reddish colour
Fatty – yellowish appearance
Size
25. LYMPH NODES
• Located along lymphatic vessels
• Scattered throughout – both superficially and deep
• 1-25 mm long, covered by a capsule of dense connective tissue
• Extensions of capsule called Trabeculae:
- Divide the node into compartments
- Provide the route for blood vessels interior to the nodes
• Stroma = Capsule + Trabeculae + Reticular Fibers + Fibroblasts
• Stroma is supporting framework of a connective tissue of lymph node
26. LYMPH NODES
FUNCTIONING PART OF LYMPH NODES – Parenchyma. Divided into Cortex and
Medulla
1.Cortex
•Outer and inner part
•Primary Lymphatic Nodule – Lymphatic nodule consisting chiefly of B cells
•Outer – contain B cells. Lymphatic nodules are Secondary Lymphatic Nodules. Sites
of Plasma and memory B cell formation
•Primary LN Secondary LN (when B cells in Primary LN recognize antigen)
•Germinal centre – Centre of Secondary LN containing a region of light-staining cells
•Follicular dendritic cells bring ‘antigen’ to B cells and they replicate, developing into
‘antibody’ producing cells. Memory B cells remembers this antigen
•INNER CORTEX – NO lymphatic nodules
•T cells and dendritic cells entering from other tissues
•Dendritic cells bring ‘antigen’ to T cells. They proliferate, migrating from lymph node
to areas of antigenic activity
27. LYMPH NODES
2. Medulla
•B cells which have migrated out of cortex and macrophages
•FLOW OF LYMPH
•Filter mechanisms Larger afferent inputs More intake of lymph Lesser efferent output More time
to filter and combat foreign particles
28. (a) Partially sectioned lymph node
Valve
Afferent lymphatic
vessel
Afferent
lymphatic
vessels
Subcapsular sinus
Reticular fiber
Trabecula
Trabecular sinus
Outer cortex:
Germinal center in secondary
lymphatic nodule
Cells around germinal center
Inner cortex
Medulla
Medullary sinus
Reticular fiber
Efferent lymphatic vessels
Valve
Hilum
Capsule
Cells in germinal center of
outer cortex
B cells
Follicular dendritic cells
Macrophages
Cells around
germinal center of
outer cortex
B cells
Cells of inner
cortex
T cells
Dendritic cells
Cells of medulla
B cells
Plasma cells
Macrophages
Route of lymph flow
through a lymph node:
Afferent lymphatic vessel
Subcapsular sinus
Trabecular sinus
Efferent lymphatic vessel
Medullary sinus
29. Capsule
(b) Portion of a lymph node
40xLM
Subcapsular sinus
Outer cortex
Trabecular sinus
Germinal center in secondary
lymphatic nodule
Trabecula
Inner cortex
Medullary sinus
Medulla
32. (b) Internal structure
Splenic artery
Splenic vein
White pulp
Red pulp:
Venous sinus
Splenic cord
Central artery
Trabecula
Capsule
33. SPLEEN
• Largest single mass of lymphatic tissue
• Located in left hypochondriac region between stomach and diaphragm
• Superior part of spleen is convex, complementary to the concave diaphragm
• Indentations in the spleen due to various organs:
- Gastric impression (stomach)
- Renal impression (Left kidney)
- Colic impression (Left colic flexure of large intestine)
• Splenic artery and vein, efferent lymphatic vessels pass through hilum
• Parenchyma consists of two kinds of tissue:
- White pulp
- Red pulp
34. SPLEEN
1. White pulp
• Lymphatic tissue
• Lymphocytes and macrophages arranged around central arteries
• B cells and T cells carry out immune responses similar to lymph nodes.
• Spleen macrophages destroy blood-borne pathogens
2. Red pulp
• Blood filled venous sinuses and splenic cords
• Splenic cords consists of RBCs, macrophages, lymphocytes, plasma cells,
granulocytes
• Three functions related to red blood cells:
- Removal of ruptured, worn out or defective blood cells and platelets by
macrophages
- Storage of platelets
- Production of blood cells during fetal life
35. (c) Portion of the spleen
25xLM
Capsule
Red pulp
Trabecula
Central artery
White pulp
36. INNATE IMMUNITY
• External physical and chemical barrier provided by skin and mucous membrane
• Antimicrobial substances, NK Cells, phagocytes, inflammation and fever
• FIRST LINE OF DEFENCE – SKIN AND MUCOUS MEMBRANES
Epidermis of skin – keratinized cells. First barrier
Epithelial layer of Mucous Membrane secretes mucus – lubricates and moistens cavity
surface
Mucus membrane of nose
URT – cilia (microscopic hair-like projections on surface of epithelial cells)
Coughing, sneezing throws microbes out
Lacrimal apparatus – produces and drains tears in response to irritants. Blinking covers
the tears over the eye and prevents settling of microbes
Lysozyme – Present in tears, saliva, perspiration, nasal secretions and tissue fluids.
Lyses bacterial cell wall.
Sebum – Oily secretions of skin forms a protective layer over the skin. Skin is acidic –
fatty acids and lactic acid secretions
Gastric acid – Mixture of enzymes, hydrochloric acid and mucus
37. INNATE IMMUNITY
• SECOND LINE OF DEFENCE – INTERNAL DEFENCES
Internal antimicrobial substances, phagocytes, NK cells, inflammation and fever
Antimicrobial agents:
1. Interferons (IFNs) – IFN alpha, beta and gamma
2. Complement system – cytolysis of microbes, promotion of phagocytosis,
contribution to inflammation
3. Iron-binding proteins – transferrin, lactoferrin, ferritin, hemoglobin
4. Antimicrobial proteins – dermicidin, defensins and cathelicidins, thrombicidins
38. INNATE IMMUNITY
• Natural Killer Cells and phagocytes
• Lack specificity
• Binding of NK cell to infected human cell Release of granules containing toxic
substances
• Perforin – Protein inserted in plasma membrane, creating perforations ECF flows
into target cell Cell bursts (cytolysis)
• Granzymes – Protein digesting enzymes that induce target cell to undergo apoptosis.
Cells are killed, but microbes remain alive. They are killed by macrophages
PHAGOCYTES
• Neutrophils and macrophages
• Migrate to infected area
• Monocytes enlarge develop into actively phagocytic macrophages called
WANDERING MACROPHAGES
• FIXED MACROPHAGES Stand guard in tissues
• Examples – Kupffer cells in liver, tissue macrophages in spleen, kidneys, alveolar
macrophages in liver
43. Primary lymphatic
organs Red bone marrow
Thymus
Pre-
T cells
Mature T cells Mature B cells
Cytotoxic
T cell
Helper
T cell B cell B cell
Antigen
receptors
CD4
protein
Activation of
helper T cell
Formation of helper T cell clone:
Memory
helper
T cells HelpHelp
Active helper
T cells
Activation of
cytotoxic T cell
Activation of
B cell
Formation of B cell
clone:
Formation of cytotoxic T cell clone:
Active cytotoxic
T cells
Memory
cytotoxic
T cells
Antibodies
Plasma
cells
Memory
B cells
Antibodies bind to and
inactivate antigens in
body fluids
Active cytotoxic T cells
leave lymphatic tissue to
attack invading antigens
Secondary lymphatic
organs and tissues
CD8
protein
CELL-MEDIATED IMMUNITY
Directed against intracellular pathogens,
some cancer cells, and tissue transplants
ANTIBODY-MEDIATED IMMUNITY
Directed against extracellular pathogens
44. ADAPTIVE IMMUNE SYSTEM
• Ability of the body to defend itself against SPECIFIC invading agents such as
bacteria, toxins, viruses and foreign tissues
• Antigens – substances that are recognized as foreign and provoke immune response
• Two distinguishing points from Innate immunity:
-Specificity for particular foreign molecules
- Memory for previously encountered antigens
• Two types of adaptive immunity:
1. Cell-mediated
2. Antibody-mediated
• Cell mediated – Cytotoxic T cell directly attack invading pathogens
• Antibody mediated – B cells transform into plasma cells which synthesize and
secrete specific proteins called antibodies or immunoglobulins
• CMI effective against intracellular pathogens, any viruses, bacteria fungi INSIDE
the cells. It always involves CELLS ATTACKING CELLS
45. • Antibody-mediated works against extracellular pathogens, any viruses fungi outside
cells.
• Antibodies bind to antigens in body humors or fluids. Hence also termed as humoral
immunity
CLONAL SELECTION: THE PRINCIPLE
• Specific antigen has many copies throughout body fluids and tissues
• Antigen outnumbers the small group of helper and cytotoxic T cells and B cells with
correct antigen receptors to respond
• Each lymphocyte encounters a copy of antigen, it undergoes CLONAL
SELECTION
• Process by which a lymphocyte proliferates (divides) and differentiates (forming
more highly specialized cells) in response to a specific antigen
• Formation of clones
• Before exposure, few lymphocytes can identify antigen. But later, thousands can
identify at once.
• Clonal selection occurs in secondary lymphatic tissues and organs
ADAPTIVE IMMUNE SYSTEM
46. ADAPTIVE IMMUNE SYSTEM
• Clonal selection produces two types of cells:
- Effector (examples: Active helper T, active cytotoxic T, B cells)
- Memory (examples: Memory helper T, memory cytotoxic T, memory B cells)
• Memory cells do not participate in immune reaction. If same antigen enters, far
more lymphocytes are available for attack
• Response is fast. No visible effects of inflammation
47. ADAPTIVE IMMUNE SYSTEM
ANTIGENS AND ANTIGEN RECEPTORS
Two important characteristics:
1.Immunogenicity – Ability to provoke an immune response by stimulating the
production of specific antibodies, proliferation of specific T cells, or both
2. Reactivity - ability of the antigen to react specifically with the antibodies or
cells it provoked
•Certain parts of a large antigen are responsible for initiating an immune
response. These parts are called epitopes or antigenic determinants
•Entry of antigens that skip innate defenses:
1.Get trapped into spleen moving through blood
2.Antigens that penetrate the skin enter lymphatic vessels and then trapped in lymph
nodes
3.Antigens that penetrate mucous membrane are trapped by MALT
49. ADAPTIVE IMMUNE SYSTEM
• CHEMICAL NATURE OF ANTIGENS
• Large, complex molecules
• Most often proteins
• Nuclei acids, lipoproteins, glycoproteins and polysaccharides can also act as antigen
• Large molecules with repeating units (such as plastics) are non antigenic
• HAPTEN : A smaller substance that has reactivity but lacks immunogenicity
50. Exogenous
antigen
1
2
3
4
5
Phagosome
or endosome
Digestion of
antigen into
peptide fragmentsAntigen-presenting
cell (APC)
Packaging of MHC-II
molecules into a vesicle
Synthesis of MHC-II molecules
Vesicles containing antigen
peptide fragments and MHC-II
molecules fuse Antigen peptide
fragments bind to
MHC-II molecules
Vesicle undergoes
exocytosis and antigen–
MHC-II complexes are
inserted into plasma
membrane
Endoplasmic
reticulum
Key:
Antigen
peptide
fragments
MHC-II
self-antigen
Phagocytosis or
endocytosis of
antigen
6
7
APCs present exogenous antigens in association with MHC-II molecules
51. 1
2
3
4
Endogenous
antigen
Digestion of antigen
into peptide fragments
Antigen peptide fragments
bind to MHC-I molecules
Synthesis of MHC-I molecules
Endoplasmic
reticulum
Packaging of
antigen–MHC-I
molecules into a vesicle
Vesicle undergoes exocytosis and
antigen–MHC-I complexes are
inserted into plasma membrane
Infected body
cell
Key:
Antigen
peptide
fragments
MHC-I
self-antigen
5
Infected body cells present endogenous antigens in association with MHC-I molecules
52. Antigen-presenting
cell (APC)
Costimulation
Antigen recognition
Inactive
helper
T cell
Activated
helper
T cell
Formation of helper T cell clone:
Clonal selection
(proliferation and
differentiation)
Active helper T cells (secrete
IL-2 and other cytokines)
Memory helper T cells
(long-lived)
Inactive helper
T cell
MHC-II
Antigen
TCR
CD4
protein
53. Infected
body cell Helper T
cell
Costimulation
by IL-2
Antigen
recognition
Inactive
cytotoxic
T cell
Activated
cytotoxic
T cell
Clonal selection
(proliferation and
differentiation)
Formation of cytotoxic T cell clone:
Inactive helper
T cell
MHC-II
Antigen
TCR
CD8
protein
Active cytotoxic
T cells (attack
infected body cells)
Memory cytotoxic
T cells (long-lived)
54. Activated
cytotoxic
T cell
Activated
cytotoxic
T cell
Recognition
and attachment
Microbe
Infected
body cell
Infected body cell
undergoing apoptosis
Microbe
Phagocyte
Granzymes
Recognition
and attachment
Infected
body cell
Infected body cell
undergoing cytolysis
(b) Cytotoxic T cell destruction of infected cell by
release of perforins that cause cytolysis; microbes
are destroyed by granulysin
Granulysin
Perforin
Channel
Key:
CD8
protein
Antigen-MHC-I
complex
TCR
(a) Cytotoxic T cell destruction of infected cell by
release of granzymes that cause apoptosis;
released microbes are destroyed by phagocyte
55. B-cell
receptor
Inactive
B cell
Microbe
Microbe
Microbe
Activated
B cell
Activated
B cell
Helper
T cell
B cell
recognizing
unprocessed
antigen
Costimulation
by several interleukins
B cell displaying processed
antigen is recognized
by helper T cell, which
releases costimulators
Clonal selection
(proliferation and
differentiation)
Formation of B cell clone:
Antibodies
Plasma cells
(secrete antibodies)
Memory B cells
(long-lived)
57. Heavy (H) chain
Hinge region
Carbohydrate
chain
Light (L) chain
Antigen
binding
sites
Stem
region
(b) Diagram of IgG heavy and light chains
VH
CH
CL
VL
VH
CH
CH
CHCH
CH
CL
VL
59. PHAGOCYTOSIS:
Enhancement of phagocytosis
by coating with C3b
M
icrobe
Microbe
C3
C3b C3a
C5
C5b C5a
C6
C7
C8
C9
C6 C5b Channel
Membrane attack
complex forms channel
CYTOLYSIS:
Bursting of microbe due to inflow of extracellular fluid through
channel formed by membrane attack complex C5–C9
Microbial
plasma
membrane
Microbe
INFLAMMATION:
Increase of blood vessel
permeability and chemotactic
attraction of phagocytes
Mast cell
Histamine
C7
C8 C9
1
2
3
4
60. Primary response Secondary response
1000
100
10
1
0.1
Antibodytiter(arbitraryunits)
IgG
IgM
0 14 28 42 56
First exposure Second exposure
Days
61. Death of cells that cannot
recognize self-MHC molecules
No
Yes
Does immature T cell
recognize self-MHC
proteins?
(b) Selection of T cells after they emerge from the thymus
Mature T cell in
lymphatic tissue
Deletion (death) of B cell
in bone marrow
Does immature B cell in
bone marrow recognize
self- MHC molecule or
other selfantigens?
(c) Selection of B cells
Cell survival or activation
Cell death or anergy (inactivation)
Key:
Yes
No Mature B cell
recognizes antigen
(first signal)
Costimulation
(second signal)
Nocostimulation
Anergy (inactivation) of B
cell in secondary lymphatic
tissues and blood
Activation of B cell, which
proliferates and differentiates
into clone of plasma cells
Activation of T cell, which
proliferates and differentiates
Survival of T cells that can
recognize self-MHC proteins
but not self-peptides
Deletion (death) of T cell
Anergy (inactivation) of T cell
Anergy (inactivation) of T cell
Death of T cell
Positive
selection
Is TCR capable of binding
to and recognizing self-
peptides?
Negative
selection
Antigen recognition with costimulation
Antigen recognition without costimulation
Deletion signal (?)
No
Yes
Yes
(a) Positive and negative selection of T cells in the thymus
Negative
selection
Blood filtered to form interstitial fluid. When IF enters lymphatic vessel it is called lymph (limf=clear).
IF found between cells
Lymph is within lymphatic vessel and lymphatic tissue
Vessels begin as capillaries. CONVERGE TO FORM LYMPHATIC VESSELS
Permeability – Proteins and lipids can pass into it
