Chapter 22

Lymphatic System and Immunity

THE LYMPHATIC SYSTEM AND IMMUNITY

A human body recognizes anything other than its own as an invader.

When these foreign bodies are capable of living in the human body and are harmful, they are called pathogens.

The lymph and plasma contains antibodies and special cells which fight against cells other than its own. These antibodies are formed when the infants are about three month old. Recall the timing when the blood types were formed.

When the reaction is against each specific foreign body, it is called immune response or immunity.

The lymphatic system in the body identifies and destroys foreign bodies by their antibodies.

But, how do we distinguish our own from the others?

1. Organization and functions of the lymphatic system

In the lymphatic system there are:

(1) Lymphatic fluid (lymph) that contains lymphocytes,

(2) Vessels that transport lymph

(3) And the sites where large amounts of lymphocytes are held: Lymph nodes,

spleen and thymus.

(4) Where are the lymphocytes made?

Lymphatic System

• Lymph• Lymphatic vessels• Lymphatic tissue• Lymphatic nodules• Lymph nodes• Tonsils• Spleen• Thymus

Functions of the Lymphatic System

• Fluid balance– Excess interstitial fluid enters lymphatic

capillaries and becomes lymph

• Fat absorption– Absorption of fat and other substances from

digestive tract

• Defense– Microorganisms and other foreign substances

are filtered from lymph by lymph nodes and from blood by spleen

Fluid balance. Circulating blood release about 30 L of fluid into the interstitial space each day. Of which 27 L are returned to the circulation. Remaining 3 L will enters the lymphatic system as lymph. The lymph passes through the lymphatic system and returns to the blood vessels.

In addition to water, lymph contains substances in plasma and substances extracted from cells.

Lymphatics spread out throughout the body except the region of central nervous system. (Fig. 22-1).

They start from lymphocyte producing organs.

There is a major thoracic duct.

Many lymph nodes in which nodules are found.

Lymphatic Vessels

• Lymphatic capillaries join to form

• Lymphatic vessels

– Have valves that ensure one-way flow

• Lymph nodes: Distributed along vessels and filter lymph

• Lymphatic trunks: Jugular, subclavian, bronchomediastinal, intestinal, lumbar

• Lymphatic ducts: Right and thoracic which connect to large veins, brachiocephalic veins.

Like blood vessels, they have small vessels called lymphatic capillaries, which become close to the blood capillaries. (Fig. 22-2a,b)

Lymph soluble fluid will be picked up through the lymph capillaries and pushed back to a larger trunk. (Fig. 22-4b) Thelymphatic system drains into the blood at brachiocephalic veins.

Lymph Drainage Into Veins

They even have valves to control the flow of lymph through very low pressure of fluid. (Fig. 22-3)

c. Lymphocytes

They compose the 25% of circulating white cells and could be up to one Kg in total, but the majority of lymphocytes remain in peripheral tissues.

i. Types of lymphocytesThere are three types of lymphocytes: (Fig. 22-5) They originate in red bone marrow, but T-cells mature in thymus.

(a) T cells: 80% of circulating lymphocytes

Lymphoid stem cells in the red bone marrow migrate to thymus and become mature T-cells.

Cytotoxic T cells attack foreign cells or cells infected with viruses.

Provides cell-mediated immunity.

Helper T cells stimulate the activities of T cell and B cells.

Suppresser T cells inhibit T cells and B cells.

(a) B cells: 10 - 15 %.

Plasma cells produce antibodies (immunoglobulins) and react antigenic pathogens.

Reside in lymph nodes, the spleen, and other lymphoid tissues

Antibody-mediated immunity.

(b) NK cells: The remainder.

Attack foreign cells, normal cell infected with viruses and cancer cells.

They immunological survey peripheral tissues.

ii.Origin and development of lymphocytes

Lymphocytes travel around the entire body and have significantly long life span.

80% survive up to 4 years and some to 20 years!

As we have already seen, lymphocytes are made in the red bone marrow and some continue to develop in the thymus. (Fig. 22-5)

Pre-B cells and pre-T cells are in the red bone marrow. Pre-B cell mature in the red bone marrow and become B cell.

Pre T-cells move into the thymus and become T-cells. Recall there are suppressor T-cells and helper T-cell.

A positive selection process keep cells capable of immune response. Those which are incapable will die.

“A group of B or T cells capable of responding to a specific antigen is a clone.“

Each clone is capable of responding to a particular antigen and there are many clones.

When the clones respond to self-antigens, negative selection eliminates such clones.

If this is done successfully, there will be no auto-immune response.

These processed will start during the prenatal development, but may continue throughout life.

d. Lymphatic organs

i. Diffuse lymphatic tissue.

Dispersed lymphocytes, macrophages and others. No clear boundaries (Fig. 22-6a)

• Lymphatic tissue– Consists mainly of

lymphocytes

– Encapsulated or not

• Lymphatic nodules– Numerous in loose

connective tissue of digestive (Peyer’s patches), respiratory, urinary, reproductive systems

Lymphoid nodules (Fig.

22-6a)

Lymphoid nodules

Packed with lymphocytes.

Flexible in size depending upon the number of lymphocytes.

Found in the digestive, respiratory and urinary systems.

Peyer’s Patches on the intestine are large number of aggregated lymph nodules.

There is a germinal center, where lymphocytes divide.

Though filled with lymphocytes, lymphoid nodules could be infected: tonsillitis, appendicitis.

i. Tonsils

Large groups of lymphnodules and diffuse lymphatic tissue located in the oral cavity. (Fig. 22-6b)

Protection against bacteria, etc. in the nose and mouth.

Three types of tonsils.

Enlarged pharyngeal tonsil is called adenoid.

i. Lymph nodes (Fig. 22-1 and Fig. 22-7)

Lymph nodes

An encapsulation of lymphocytes, macrophages and reticular cells with blood vessels.

Found through out the body except the CNS.

1 - 25 mm in diameter and has medulla and cortex.

Act as a sieve and remove 99% of the antigens while reactivating T cells and B cells.

Lymphocytes division takes place in the nodules of the lymph nodes

The spleen Fig. 22-9

The spleen

Largest as the lymphatic tissue. 160g.

Found in the upper-left and posterial part of the abdominal cavity.

Pulps of the spleen.

The red pulp - Red blood cells.

The white pulp - lymphoid nodules.

Removes antigens and damaged blood cells.

Immune response, irons for recycling

The thymus gland (Fig. 22-8)

The thymus gland

Found on top of the heart. (Fig. 22-8)

Lobules consist of cortex and medulla.

T cells are made and mature here.

Becomes large in size during the first or second year.

Intrinsic size is the largest at puberty and then decreases.

Thymosins are made here, too.

Reticular cells wrap around the capillaries to form the blood thymic barrier.

1. Immunity

How the human body defends itself against damages from foreign substances such as microorganisms and harmful chemical as toxins..

Two types of immunity are distinguished by the way they respond to specific stimulations and how they memorize the events.

Nonspecific immunity: Acts against bacteria in general (non-specific) and has no-memory. Thus each event is an independent event.

Specific immunity: Can distinguish among different kinds of bacteria (pathogens) and has memory. Because of its memory, the second exposure to the pathogens brings faster and stronger immune response than the first exposure -- immunity has been established

1. Non-specific immunity - general and has no memory

a. Mechanical Mechanism

Physical barriers, such as the skin and membranes.

Mechanical Mechanisms andChemical Mediators

• Mechanical Mechanisms– Skin, tears, saliva, mucous

membranes, mucus

• Chemical Mediators– Complement

• Group of 20 proteins

• Circulate in blood in inactive form

• Become activated in cascade form: Classical or alternative pathway

– Interferons• Prevent viral replication

b. Chemical MediatorsMolecules which contribute to develop immunity.

Kill bacteria: lysozyme, sebum mucus

Others: Histamine and kinins by vasodilation; interferon production, etc.

Complement: A group of about 20 proteins in plasma activated in the form of cascade and provide protection by attacking the bacterial membrane to cause lysis. (Fig. 22-12)

Interferons: Interferon is an example of cytokine (cell to cell communication). They are small proteins released from lymphocytes, macrophages and tissue that are infected with viruses. Arriving at the normal cell membrane they bind to the receptor and trigger the production of antiviral proteins in the cytoplasm and inhibit the production viruses.

a. Cells for non-specific immunity

Review the major functions of neutrophils, macrophages, monocytes, basophils, mast cell, eosinophils, and natural killer cells. (Table 22.2 of Seeley)

c. Innate Immunity: Cells

• White blood cells– Most important cellular

components of immune system

– Methods• Chemotaxis

• Phagocytosis

• Neutrophils– Phagocytic and first

cells to enter infected tissue

• Macrophages– Monocytes that leave

blood, enter tissues– Large phagocytic cells

• Basophils and mast cells– Promote inflammation

• Eosinophils– Reduce inflammation

• Natural killer cells– Lyse tumor and virus-

infected cells

NK cells in action (Fig. 22-11): NK cells recognizes unusual cells (immunological surveillance) and make contact. Its

Golgi apparatus releases enzymes to lyses cells.

Inflammatory Response

• Tissue injury regardless of type can cause inflammation

• Response initiated by chemical mediators that produce vasodilation, chemotactic attraction, increased vascular permeability

• Types– Local: Symptoms are redness, heat, swelling, pain, loss of

function

– Systemic: Symptoms are increase in neutrophil numbers, fever and shock

e. Fever

Body temperature higher than 37.2˚C (99˚F). Pyrogen that unlocks the homeothermic body temperature regulation in the hypothalamus is released by pathogens, bacterial toxins, etc.

The pyrogen released by active macrophages is called interleukin-1.

High body temperature inhibits virus and bacterial activities, while increasing the host’s body metabolism for recovery.

1. Specific immunity – specific immunity with memory Overview – types of immunity (Fig. 22-14)

a. Introduction

Substances to stimulate specific immunity, i.e. formation of antibodies, are antigens, of which molecular weights could be as large as Mr = 10,000 or more.

A small molecule may become antigenic upon binding with other molecules. For example, Haptens are small molecules capable of combining with larger molecules to stimulate adaptive immune response.

Two types of antigens: Foreign antigens are from outside of the body, and self antigens are molecules of its own body.

For example, allergic reaction is by foreign antigens, while autoimmune disease is from self antigens.

Immunity has been divided into two types: Humoral (body fluid) immunity and cell mediated immunity.

Specificity: Recognition of antigens

The specificity is established because of the specific receptors located on the surface of the T and B lymphocyte cells.

Versatility: There are many types of lymphocytes.

Responding to many antigens many types of lymphocytes are formed to fight against each antigen.

Memory: The specific immune system has memory. With the presence of a foreign body, the lymphocytes respond by initiating cell divisions and:

Active and memory cells are made.

The active cells respond to the antigens immediately, while the dormant memory cells wait until the next onslaught of antigens.

In this manner, the second response to the same antigens will be fast and stronger

Tolerance: Self vs. non-self cells.

Introduction to immune response see Fig. 22-15

i. T-cells and cell mediated immunity

T-cells are made in response to a specific antigen and in a large quantity

(a)Antigenic determinants and antigen receptors

An antigen may have many antigenic determinants (epitope)

Each antigenic determinant can activate a specific lymphocyte.

Thus it is possible that an antigen with many epitopes can activate many different lymphocytes.

Each lymphocyte from the same clone will have the same antigen receptors.

For example, a membrane bound T-cell receptor has variable and constant regions. (Fig. 22.13). The variable region, which is outside the membrane, will have a specific antigen binding site. Thus a clone of T-cells, having the same receptor, will bind only a specific antigenic determinant of an antigen. The other T-cells may have different antigen binding sites.

The B-cell receptor is similar, but larger.

(b) Major histocompatibility complex antigens

Most lymphocyte activation involves glycoproteins on the surface of cells called the major histocompatibility complex (MHC) molecules. -

All the cell membranes have MHC.

–Class I molecules display antigens on the surface of nucleated cells, resulting in destruction of the cells, if the antigens are foreign.–Class II molecules display antigens on the surface of antigen-presenting cells, resulting in activation of immune cells

MHC class I molecules: (Fig. 22-16a)

(i) MHC class I molecules: (Fig. 22-16a)

On nucleated cells.

Foreign or self proteins are fragmented in the nucleated cells and become antigens.

They combine with MHC class I molecule in the cell and the complexes are transported on the surface of the cell.

The antigens will be presented on the surface of membrane and attract T-cells only to the foreign antigens and the infected cells will be destroyed.

If it had also attracted to the self antigen, the auto-immune disease might occur. (Transplant)

MHC class II molecules (Fig. 22-16b)

(2) MHC class II molecules (Fig. 22.16b)

These molecules are found in antigen-presenting cells, such as B-cells, macrophages, monocytes and dendritic cells.

Antigen-presenting cells phagocytically ingest unprocessed antigens, process them and let them combine with MHC II molecules. Note the vescicles.

The complex will be presented on the surface of the cells.

They stimulate the other immune cells to divide leading to destruction of antigen presenting cells.

(c ) Antigen recognition and Costimulation (Fig 22-17)

Inactive T-cells have receptors that recognize Class I and II MHC proteins (Fig. 22-17).

The receptors also have binding sites that detect the presence of specific bound antigens presented by MHC proteins.

If these antigens are not the target of the T cell receptor, the T cell remains inactive.

If it is one of the target antigen, there will be a binding between the infected cell and T cell. This is antigen recognition.

The cluster of differentiation (CD) marker proteins are bound on the membrane of T-cell (Fig. 22-17). More than 70 CDs have been identified and they are given numerical ID.

All the T cells have CD3.

CD8 markers are on cytotoxic T cell and suppressor T cells. – CD8 T cells. CD8 T cells respond to antigens presented by class I MHC proteins.

CD4 markers are found on help T cell – CD4 T cells. CD4 T cells respond to antigens presented by Class II MHC proteins.

Both CD8 and CD4 make a complex with CD3 receptor complex.

After the antigen recognition, and interaction of CD, the secondary binding process, costimulation, must take place before activation of T cells. (Fig. 22-17) Costimulation proteins are similar to cytokinins.

(d) Activation of CD8 T cells for Class I MHC proteins

Cytotoxic T Cells or Killer T cells

Highly mobile killer T cells destroy abnormal and infected cells in the three different manners shown in Fig. 22-17. Release of lymphotoxin, cytokine and perforin.

Usually requires a secondary activation of T-cells, thus taking a week to be effective. (Fig. 22-24)

(c ) Antigen recognition and Costimulation (Fig 22-17)

Memory T cells (Fig. 22-17)

Some of the T cells after activation and cell division, they become memory cells and do not participate in destruction of other cells.

The number of memory cells are large enough to respond quickly and in a large quantity when the second round of antigenic attack takes place.

Suppressor T Cells

Suppress the responses of other T cells and B cells by secreting suppression factors – inhibitory cytokines.

Slow in action

(e) Activation of CD4 T Cells for Class II MHC

Activation is similar to CD8, but possible without costimulation.

Upon activation and cell division, memory T cells and helper T cells are made. (Fig. 22-18)

The helper T cells secrete a variety of cytokines and coordinate specific and nonspecifice defenses and stimulate cell mediated and antibody-mediated immunities.

Fig 22-18 Helper T cells

Fig. 22-19 summarizes the pathways of T cell activation

(ii) B Cells and Antibody-Mediated Immunity

(a) B-cell Sensitization and activation (Fig. 22-20).

(a) B-cell Sensitization and activation (Fig. 22-20).

Before B-cells to be activated, they must also have processed the antigen, which is presented by a class II MHC.

The helper T-cell recognizes it and forms a bond to activate the B-cell.

The activated B-cell begins to be proliferated and the daughter cells make antibodies or become memory B cells.

(b) Antibody Structure

Antibodies are produced in B-cells in response to an antigen and found in plasma.

Plasma proteins have four major components: Albumin, and alpha, beta and gamma globulins.

Antibodies are found in gamma globulin group, thus sometime called gamma globulins or immunoglobulins (Ig)

There are 5 types of immunoglobulins (Table 22-1)

IgG, IgM, IgA, IgE, and IgD.

They all consist of 4 peptides. (Fig. 22-21a,b) Connected with disulfide bonds and have constant regions and antigen binding variable regions.

The constant regions attach to cells, such as macrophages, basophil, B-cells, etc.

Also recall antigen, antibody and antigenic determinants and role of hapten (Fig. 22-21 c,d)

(c) Action of antigen-antibody complex

The function of antibody is to find antigen and destroys it.

Neutralization, agglutination and precipitation, activation of complement, attraction of phagocytes, enhancement of phagocytosis, and stimulation of inflammation.

Antibodies can counteract the action of antigens in several ways. (Fig. 22.19 of Seeley)

(1) Upon binding with an antigen, the antibody inactivates the antigen.

(2) Inactivation may lead to co-precipitation of antigens and antibodies.

(3) Binding of too may stimulates phagocytic activities.

Actions of Antibodies

(d) Primary and Secondary Responses to Antigen Exposure

Fig. 22-22 Primary and secondary immune responses

Antibody Production

(1) The primary response

The first encounter with an antigen, a B-cell divides and differentiate leading to antibody production. (Fig. 22-22a)

Antibodies, IgM and IgD, are on the surface of B-cells.

B-cells, which are small lymphocytes, activated by antigen starts cell divisions.

Some become large plasma cells, which produce antibodies.

And the others become small memory B-cells.

The primary process takes 3 - 14 days,

The antigen may cause tissue damage during this period.

(2) The secondary, or memory, response

When the immune system is exposed to the same antigen after the primary response, the memory cells quickly divide to produce plasma cells and large quantity of antibody is released, providing quick immune protection. (Fig. 22-22b)

The response is quick, hours to a few days, and the quantity of antibody production is large.

Good defense against the disease.

The memory cells, which may survive for years, are also formed.

5.Summary (Fig. 22-23, 24)

6. Immune disorders

• Hypersensitivity reactions

• Autoimmune disease

• Severe combined immunodeficiency disease (SCID)

• Transplantation– Acute rejection– Chronic rejection

i. Auto-immune disorders

Identify own body cells as antigens and B-cells make autoantibodies.

May be due to a reduction in suppressor T cell activity, excess stimulation of of helper T cells.

Rheumatoid arthritis, IDDM, thyroiditis etc.

Some viruses, measles and influenza, have a sequence similar to those of myelin proteins. Thus, antibodies which attack viruses may also attack myelin sheath.

Unusual types of MHC proteins.

ii. Iimmunodeficiency Diseases

Trouble with the embryological development of lymphoid organs and tissues

Viral infection that leads to immuno depression

Exposure to immuno suppressive agents, such as radiation, drugs etc.

Severe combined immunodeficiency diseases (SCID) fail to develop antibodies.

AIDS – viral infection that targets helper T cells.

iii. Allergies

Excessive immune responses to antigens, allergens.

iv. Stress can reduce the immune response.

iii. Effects of Aging

• Little effect on lymphatic system

• Decreased ability of helper T cells to proliferate in response to antigens

• Decreased primary and secondary antibody responses

• Decreased ability of cell-mediated immunity to resist intracellular pathogens

Ways to Acquire Adaptive Immunity