CONTENTS

1. INTRODUCTION 4. PHAGOCYTOSIS

2. BLOOD 5. CLINICAL CONNECTIONS

• COMPONENTS 6. SUMMARY

• FUNCTIONS 7. REFERENCES

3. RES - LYMPHATIC SYSTEM

• STRUCTURE AND FUNCTION

• DEVELOPMENT

• LYMPHATIC ORGANS AND TISSUE

 INTRODUCTION

• Also called as Mononuclear phagocyte system, macrophage system.

• Occur in widely separated parts of the human body and that have in common the property of

phagocytosis,

• whereby the cells engulf and destroy bacteria, viruses, and other foreign substances and ingest

worn-out or abnormal body cells.

• German pathologist Karl Albert Ludwig Aschoff in 1924.

• The later reclassification of phagocytic mononuclear cells, Aschoff’s term was

replaced in the latter part of the 20th century with the name mononuclear

phagocyte system.
 FUNCTIONS OF BLOOD

TRANSPORTATION REGULATION PROTECTION

• Respiration • Regulates pH • WBC protects against

• Nutrient carrier from GIT • Adjusts and maintains disease by phagocytosis

• Transportation of body temperature • Reservoir for substances

hormones from endocrine • Maintains water content like water, electrolyte etc.

glands of cells • Performs haemostasis

• Transports metabolic
wastes

Ref :Guyton A.C, Hall J.E. Textbook of Medical Physiology. Elsevier Saunders, Philadelphia, 11th edition, 2006.
Following is the classification of the formed elements in blood:

I. Red blood cells

II. White blood cells
A. Granular leukocytes
1. Neutrophils
2. Eosinophils
3. Basophils
B. Agranular leukocytes
1. T and B lymphocytes and natural killer (NK) cells
2. Monocytes
III. Platelets

Ref:Opie, LH. Heart Physiology. From Cell to Circulation. 4th Edition, 2014.
COMPONENTS OF BLOOD IN A NORMAL ADULT

APPEARANCE OF CENTRIFUGED BLOOD

 FUNCTIONS OF WHITE BLOOD CELLS

• Leukocytes - fighting forces.

• Eosinophils - parasitic infections.

• Basophils - allergic response .

• Neutrophils defend us from bacteria and fungus.

• Lymphocytes common in lymphatic system.

• They help in phagocytosis.

Katz, AM. Physiology of the Blood. Lippincott, Williams, and Wilkins, 12th edition, Philadelphia, 2010.
 ROLE OF NEUTROPHILS

• Form an essential part of innate immune system.

• Recruited to site of injury within minutes following trauma.

• Hallmark of acute inflammation.

• Undergo chemotaxis.

Have three strategies for directly attacking micro-organisms :

1.Phagocytosis (ingestion).

2.Release of soluble anti-microbials (including granule proteins)

3.Generation of neutrophil extracellular traps (NETs)

 ROLE OF EOSINOPHILS

Following activation, eosinophils effector functions include production of:

• Reactive oxygen species such as superoxide, peroxide, and hypobromite.

• Lipid mediators like the eicosanoids from the leukotriene and prostaglandin (e.g., PGE2)

families enzymes, such as elastase.

• Growth factors such as TGF beta, VEGF, and PDGF

• Cytokines such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-8, IL-13, and TNF alpha

Ref :Guyton A.C, Hall J.E. Textbook of Medical Physiology. Elsevier Saunders, Philadelphia, 11th edition, 2006.
 ROLE OF BASOPHILS

• Basophils appear in specific kinds of inflammatory reactions, particularly those that cause allergic

symptoms

• Basophils contain anticoagulant heparin, vasodilator histamine.

• Ectoparasite infection, e.g., ticks.

• Receptors on their cell surface that bind IgE, an immunoglobulin involved in macroparasite

defense and allergy.

Ref :Guyton A.C, Hall J.E. Textbook of Medical Physiology. Elsevier Saunders, Philadelphia, 11th edition, 2006.
 ROLE OF MONOCYTES
Monocytes have two main functions in the immune system:

1. Replenish resident macrophages and dendritic cells under normal states

2. In response to inflammation signals, monocytes can move quickly (approx. 8-12 hours) to sites of

infection.

Three important roles :

1.Phagocytosis.

2.Antigen presentation.

3.Muscle regeneration.

Ref :Guyton A.C, Hall J.E. Textbook of Medical Physiology. Elsevier Saunders, Philadelphia, 11th edition, 2006.
 LYMPHATIC SYSTEM STRUCTURE AND FUNCTION

• The lymphatic system consists - lymph, vessels called lymphatic vessels, organs
containing lymphatic tissue, and red bone marrow.

• Most components of blood plasma filter through blood capillary walls to form interstitial
fluid. After interstitial fluid passes into lymphatic vessels, it is called lymph.
 FUNCTIONS OF THE LYMPHATIC SYSTEM

The lymphatic system has three primary functions:

• Drains excess interstitial fluid.

• Transports dietary lipids

• Carries out immune responses.

DEVELOPMENT OF LYMPHATIC TISSUES
 Artery

Vein

Lymphatic
vessel
Vein

Artery

Lymphatic
vessel
Toward
Lymphatic venous
valve system

From lymphatic
capillaries
a A diagrammatic view of areolar connective tissue
containing small blood vessels and a lymphatic
vessel. The cross-sectional view emphasizes their
structural differences.
 THYMUS

• The thymus is a bilobed organ located in the mediastinum between the sternum and the aorta.

• A connective tissue capsule separates the two.

• The cortex is composed of large numbers of T cells and scattered dendritic cells, epithelial cells, and

macrophages.

• The medulla consists of widely scattered, more mature T cells, epithelial cells, dendritic cells, and

macrophages.

• These clusters are called thymic (Hassall’s) corpuscles.

• In infants, the thymus has a mass of about 70 g in old age the functional portion may weigh only 3 g
LYMPHATIC ORGANS

AND TISSUES
 LYMPH NODE

• Located along lymphatic vessels are about 600 bean-shaped lymph nodes.

• Large groups of lymph nodes are present near the mammary glands and in the axillae and groin.

• Lymph nodes are 1–25 mm (0.04–1 in.) long and, like the thymus, are covered by a capsule of dense

connective tissue that extends into the node.

• The newly formed T cells then migrate 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 migrated out of

the cortex into the medulla, and macrophages.

STRUCTURE OF
LYMPH NODE
 SPLEEN

• The oval in shape - largest single mass -12 cm (5 in.) in length.

• It is located in the left hypochondriac region.

• The parenchyma consists of two different kinds of tissue called white pulp and red pulp.

• White pulp is lymphatic tissue, consisting mostly of lymphocytes and macrophages. The red pulp

consists of blood filled venous sinuses and cords of splenic tissue called splenic (Billroth’s) cords.

• Splenic cords consist of red blood cells, macrophages, lymphocytes, plasma cells, and

granulocytes. Veins are closely associated with the red pulp.

STRUCTURE OF SPLEEN
 CLINICAL CONNECTION | Ruptured Spleen

• Prompt removal of the spleen, called a splenectomy, is needed to prevent death due to

bleeding. Other structures, particularly red bone marrow and the liver, can take over some

functions normally carried out by the spleen.

• Immune functions, however, decrease in the absence of a spleen. The spleen’s absence also

places the patient at higher risk for sepsis (a blood infection) due to loss of the filtering and

phagocytic functions of the spleen.

• To reduce the risk of sepsis, patients who have undergone a splenectomy take prophylactic

(preventive) antibiotics before any invasive procedures.

4. LYMPHATIC NODULES

• Lymphatic nodules (follicles) are egg-shaped masses of lymphatic tissue that are not

surrounded by a capsule.

• Because they are scattered throughout the lamina propria of mucous membranes lining the

gastrointestinal, urinary, and reproductive tracts and the respiratory airways, lymphatic nodules

in These areas are also referred to as mucosa-associated lymphatic tissue (MALT).

MALT is further divided into:

BALT (Bronchus associated Lymphoid tissue)

GALT (Gut associated lymphoid tissue)

NALT (nose-associated lymphoid tissue)

LALT (larynx-associated lymphoid tissue)

SALT (skin-associated lymphoid tissue)

CALT (conjunctiva-associated lymphoid tissue in the human eye)

VALT (vascular-associated lymphoid tissue. A newly recognized entity that exists inside arteries; its role in the immune

response is unknown.)
• Aggregated lymphatic follicles (Peyer’s patches) in the ileum of the small intestine.

• Waldeyer’s ring at the junction of the oral cavity and oropharynx and at the junction of the

nasal cavity and nasopharynx pharyngeal tonsil or adenoid, two palatine tonsils , paired

lingual tonsils.
WALDEYER’S RING
 CELL NAME LOCATION

Adipose tissue macrophages Adipose tissue

Monocyte Bone marrow and Blood

Kupffer cell Liver

Sinus histiocytes Lymph node

Alveolar macrophage (dust cell) Pulmonary alveolus of Lungs.

Tissue macrophages (Histiocyte) leading Connective Tissues
to Giant cells

Langerhans cell Skin and Mucosa

Microglia Central Nervous System

Hofbauer cell Placenta

Intraglomerular mesangial cell Kidney

Osteoclasts Bone
Epithelioid cells Granulomas

Red Pulp Macrophage (Sinusoidal lining Red pulp of Spleen

cells)

Peritoneal macrophages Peritoneal cavity

Components of the lymphatic system.
LYMPHATIC CAPPILARIES
 PHAGOCYTOSIS
• Russian zoologist, Elie Metchnikoff (1845 – 1916)

Phagocytosis is defined as the receptor-mediated

engulfment of large (≥0.5 mm) particles into plasma

membrane-derived vacuoles called phagosomes.

 PHAGOCYTOSIS IN INNATE IMMUNITY

• Innate (nonspecific) immunity includes the external physical and chemical barriers provided

by the skin and mucous membranes.

• It also includes various internal defenses, such as antimicrobial substances, natural killer cells,

phagocytes, inflammation, and fever.

• Phagocytosis occurs in five phases: chemotaxis, adherence, ingestion, digestion, and killing
 EMIGRATION OF PHAGOCYTES

Within an hour after the inflammatory process starts, phagocytes appear on the scene. As large

amounts of blood accumulate, neutrophils begin to stick to the inner surface of the endothelium

(lining) of blood vessels.

Then the neutrophils begin to squeeze through the wall of the blood vessel to reach the damaged

area. This process, called emigration.

• Neutrophils attempt to destroy the invading microbes by phagocytosis. Although

neutrophils predominate in the early stages of infection, they die off rapidly.

• As the inflammatory response continues, monocytes follow the neutrophils into the

infected area. Once in the tissue, monocytes transform into wandering macrophages that

add to the phagocytic activity of the fixed macrophages already present.

• True to their name, macrophages are much more potent phagocytes than neutrophils
 ADAPTIVE IMMUNITY

The ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses,

and foreign tissues is called adaptive (specific) immunity.

Substances that are recognized as foreign and provoke immune responses are called antigens (Ags)

Two properties distinguish adaptive immunity from innate immunity:

• specificity for particular foreign molecules (antigens), which also involves distinguishing self from

nonself molecules, and

• memory for most previously encountered antigens so that a second encounter prompts an even

more rapid and vigorous response.

 Types of Adaptive Immunity

There are two types of adaptive immunity:

• cell-mediated immunity and

• antibody-mediated immunity.

• In cell-mediated immunity, cytotoxic T cells directly attack invading antigens.

• In antibody-mediated immunity, B cells transform into plasma cells, which synthesize and secrete

specific proteins called antibodies (Abs) or immunoglobulins (Igs)

Cell-mediated immunity is particularly effective against

1. Intracellular pathogens, which include any viruses, bacteria, or fungi that are inside cells.

2. some cancer cells; and

3. Foreign tissue transplants.

Thus, cell-mediated immunity always involves cells attacking cells. Antibody mediated immunity

works mainly against extracellular pathogens, which include any viruses, bacteria, or fungi that are

in body fluids outside cells. Since antibody mediated immunity involves antibodies that bind to

antigens in body humors or fluids (such as blood and lymph), it is also referred to as humoral

immunity.
 CLINICAL CONNECTION | Graft Rejection and Tissue
Typing

• Organ transplantation involves the replacement of an injured or diseased organ, such as the heart, liver,

kidney, lungs, or pancreas, with an organ donated by another individual.

• Usually, the immune system recognizes the proteins in the transplanted organ as foreign and mounts both cell-

mediated and antibody-mediated immune responses against them. This phenomenon is known as graft

rejection.
• The success of an organ or tissue transplant depends on histocompatibility that is, the tissue compatibility
between the donor and the recipient.

• The more similar the MHC antigens, the greater the histocompatibility, and thus the greater the probability that
the transplant will not be rejected.

• Tissue typing (histocompatibility testing) is done before any organ transplant.

• The closer the match between the major histocompatibility complex proteins of the donor and recipient, the
weaker is the graft rejection response.
 • To reduce the risk of graft rejection, organ transplant recipients receive immunosuppressive drugs. One

such drug is cyclosporine, derived from a fungus, which inhibits secretion of interleukin-2 by helper T

cells but has only a minimal effect on B cells. Thus, the risk of rejection is diminished while resistance to

some diseases is maintained.

Ref:Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–91.
 ANTIGEN-PRESENTING CELLS

Antigen-presenting cells are the special type of cells in the body, which induce the release of

antigenic materials from invading organisms and later present these materials to the helper T cells.

Types of Antigen-Presenting Cells

Antigen-presenting cells are of three types:

1. Macrophages

2. Dendritic cells

3. B lymphocytes.

Among these cells, macrophages are the major antigen- presenting cells.
 EXOGENOUS AND ENDOGENOUS ANTIGENS

• Exogenous antigens – present in fluid outside body cells

• Antigen-presenting cells (APCs) include dendritic cells, macrophages and B cells

• Ingest antigen, process, place next to MHC-II molecule in plasma membrane, and

present to T cells

• Endogenous antigens – antigens inside body cells

• Infected cell displays antigen next to MHC-I

 Key:

5 Vesicles containing antigen Antigen

peptide fragments and peptide
1 Phagocytosis or MHC-II molecules fuse fragments
Exogenous endocytosis of 6 Antigen peptide
antigen antigen fragments bind to MHC-II
MHC-II molecules self-antigen

Phagosome
or endosome
7 Vesicle undergoes
2 Digestion of exocytosis and
antigen into antigen–MHC-II
peptide fragments complexes are inserted
Antigen- 4 Packaging of MHC-II into plasma membrane
presenting molecules into a vesicle
cell (APC)

Endoplasmic
reticulum

3 Synthesis of MHC-II molecules

APCs present exogenous antigens in association with MHC-II molecules

 ROLE OF ANTIGEN-PRESENTING CELLS

• Invading foreign organisms are either engulfed by macrophages through phagocytosis or trapped by

dendritic cells. Later, the antigen from these organisms is digested into small peptide products.

• These antigenic peptide products move towards the surface of the antigen-presenting cells and bind with

human leukocyte antigen (HLA).

• HLA is a genetic matter present in the molecule of class II major histocompatiblility complex (MHC), which is

situated on the surface of the antigen presenting cells. B-cells ingest the foreign bodies by means of

pinocytosis.
 MHC AND HLA

• Major histocompatibility complex (MHC) is a large molecule present in the short arm of

chromosome 6.

MHC molecules in human beings are divided into two types:

1. Class I MHC molecule: It is found on every cell in human body. It is specifically responsible for presentation of

endogenous antigens (antigens produced intracellularly such as viral proteins and tumor antigens) to

cytotoxic T cells.

2. Class II MHC molecule: It is found on B cells, macrophages and other antigen-presenting cells. It is

responsible for presenting the exogenous antigens (antigens of bacteria or viruses which are engulfed by

antigen-presenting cells) to helper T cells.

 CLINICAL CONNECTION | Monoclonal
Antibodies
• The antibodies produced against a given antigen by plasma cells can be harvested from an individual’s blood.

• However, because an antigen typically has many epitopes, several different clones of plasma cells produce

different antibodies against the antigen.

• If a single plasma cell could be isolated and induced to proliferate into a clone of identical plasma cells, then a

large quantity of identical antibodies could be produced. Unfortunately, lymphocytes and plasma cells are

difficult to grow in culture, so scientists sidestepped this difficulty by fusing B cells with tumor cells that grow easily

and proliferate endlessly.

• The resulting hybrid cell is called a hybridoma Hybridomas are longterm sources of large quantities of pure, identical

antibodies, called monoclonal antibodies (MAbs) because they come from a single clone of identical cells.

• One clinical use of monoclonal antibodies is for measuring levels of a drug in a patient’s blood. Other uses include

the diagnosis of strep throat, pregnancy, allergies, and diseases such as hepatitis, rabies, and some sexually

transmitted diseases. MAbs have also been used to detect cancer at an early stage and to ascertain the extent of

metastasis. They may also be useful in preparing vaccines to counteract the rejection associated with transplants, to

treat autoimmune diseases, and perhaps to treat AIDS

Ref : Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial pathogens. Annual review of immunology. 2008;26:421–
452.
 PRESENTATION OF ANTIGEN

Antigen-presenting cells present their class II MHC molecules together with antigen-bound HLA

to the helper T cells. This activates the helper T cells through series of Events

Sequence of Events during Activation of Helper T cells

• Helper T cell recognizes the antigen displayed on the surface of the antigen-presenting cell

with the help of its own surface receptor protein called T cell receptor.
 • At the same time, macrophages (the antigen-presenting cells) release interleukin-1,

which facilitates the activation and proliferation of helper T cells.

• Activated helper T cells proliferate and the proliferated cells enter the circulation for

further actions.

• Simultaneously, the antigen which is bound to class II MHC molecules activates the B

cells also, resulting in the development of humoral immunity

Ref:Samstein M, Schreiber HA, Leiner IM, Susac B, Glickman MS, Pamer EG. Essential yet limited role for CCR2+ inflammatory monocytes during
Mycobacterium tuberculosis-specific T cell priming. eLife. 2013;2:e01086
 ROLE OF HELPER T CELLS

Helper T cells (CD4 cells) which enter the circulation activate all the other T cells and B cells. Normal,

CD4

count in healthy adults varies between 500 and 1500 per cubic millimeter of blood.

Helper T cells are of two types:

1. Helper-1 (TH1) cells

2. Helper-2 (TH2) cells.

ref: Imai T, et al. Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and
adhesion. Cell. 1997;91:521–530.
 ROLE OF CYTOTOXIC T CELLS

Cytotoxic T cells that are activated by helper T cells, circulate through blood, lymph and

lymphatic tissues and destroy the invading organisms by attacking them directly.

Mechanism of Action of Cytotoxic T Cells

1. Receptors situated on the outer membrane of cytotoxic T cells bind the antigens or

organisms tightly with cytotoxic T cells.

2. Then, the cytotoxic T cells enlarge and release cytotoxic substances like the lysosomal

enzymes.

3. These substances destroy the invading organisms.

4. Like this, each cytotoxic T cell can destroy a large number of microorganisms one after

another.
a) Some pathogens bind directly to b) Bacteria with capsules must be coated with
phagocyte receptors. antibody before phagocytes can recognize and
ingest them.
 CLINICAL CONNECTION | Cytokine Therapy

• Cytokine therapy is the use of cytokines to treat medical conditions.

• Interferons were the first cytokines shown to have limited effects against some human cancers.

• Alpha-interferon (Intron A¨) is approved in the United States for treating Kaposi sarcoma, a cancer

that often occurs in patients infected with HIV, the virus that causes AIDS.

• Other approved uses for alpha-interferon include treating genital herpes caused by the herpes virus;

treating hepatitis B and C, and treating hairy cell leukemia.

• A form of beta-interferon (Betaseron¨) slows the progression of multiple sclerosis (MS) and lessens the

frequency and severity of MS attacks.

• Of the interleukins, the one most widely used to fight cancer is interleukin-2.

• Although this treatment is effective in causing tumor regression in some patients, it also can be very

toxic.

• Among the adverse effects are high fever, severe weakness, difficulty breathing due to pulmonary edema,

and hypotension leading to shock

 REFERENCES

1. Guyton A.C, Hall J.E. Textbook of Medical Physiology. Elsevier Saunders, Philadelphia, 11th edition,

2006.

2. Opie, LH. Heart Physiology. From Cell to Circulation. 4th Edition, 2014.

3. Edwards C.R.W, Bouchier I.A.D , Haslett C, Chilvers E. R, Davidson’s Principles and Practices of

Medicine . 17th Edition , Edinburgh New York : Churchill Livingstone, 1995.

4. Katz, AM. Physiology of the blood. Lippincott, Williams, and Wilkins, 12th edition, Philadelphia, 2010.
5. Bers DM. Reticuloendothelial system – A review . 2nd edition. Kluwer Academic Publishers,

Dordrecht/Boston/London, 2001.

6. Yona S, et al. Fate mapping reveals origins and dynamics of monocytes and tissue

macrophages under homeostasis. Immunity. 2013;38:79–91.

7. Serbina NV, Jia T, Hohl TM, Pamer EG. Monocyte-mediated defense against microbial

pathogens. Annual review of immunology. 2008;26:421–452.

8. Imai T, et al. Identification and molecular characterization of fractalkine receptor CX3CR1,

which mediates both leukocyte migration and adhesion. Cell. 1997;91:521–530.

9. Samstein M, Schreiber HA, Leiner IM, Susac B, Glickman MS, Pamer EG. Essential yet limited

role for CCR2+ inflammatory monocytes during Mycobacterium tuberculosis-specific T cell

priming. eLife. 2013;2:e01086.

10. Lee PY, et al. Type I interferon modulates monocyte recruitment and maturation in chronic

inflammation. The American journal of pathology. 2009;175:2023–2033.

11. Fabri M, et al. Vitamin D is required for IFN-gamma-mediated antimicrobial activity of

human macrophages. Science translational medicine. 2011;3:104ra102.