Immunity

Learning outcomes

The Aim – You should be able to do the following;

(a) [PA] recognise phagocytes and lymphocytes under the light

microscope;

(b) state the origin and describe the mode of action of phagocytes;

(c) describe the modes of action of B-lymphocytes and T-lymphocytes;

(d) explain the meaning of the term immune response, making

reference to the terms antigen, self and non-self;

(e) explain the role of memory cells in long-term immunity;

(f) relate the molecular structure of antibodies to their functions;

(g) distinguish between active and passive, natural and artificial

immunity and explain how vaccination can control disease;

(h) discuss the reasons why vaccination has eradicated smallpox but

not measles, TB, malaria, sickle cell anaemia or cholera;

First Line of Defense

skinprevents entry

tearsantibacterial enzymes

salivaantibacterial enzymes

stomach acidlow pH kills harmful microbes

mucus linings traps dirt and microbes

“good” gut bacteria out compete bad

Mechanical factors

• Skin

• Epidermis

• Mucous membrane

• Body hairs

Chemical factors

• Lysozyme in sweat, tears, saliva, and

tissue fluid

• Low pH in gastric juice

• Normal microorganism in the body

competes with pathogen for attachment

and nutrient

Second Line of Defense – Nonspecific Immune

Response

These are defenses the body uses no matter what the invader

may be. These defenses include:

– Phagocytosis – done by Macrophages and Neutrophils.

– Inflammation - caused by release of Histamine from leukocytes

– Fever – caused by histamines. The fever (high temp) kills invaders by

denaturing their proteins.

Composition of Human Blood

Composition of WBC

Neutrophils 70%

Eosinophils 1.5%

Basophils 0.5%

Monocytes 4

Lymphocytes 24

White blood cells are important in the body’s natural defenses against

pathogens. The following table identifies the major WBCs function and the

type of immune response:

Phagocytic cells of the immune

system

• The phagocytic cells of the immune

system originate from the bone marrow.

• Stem cells – Cells that differentiate into

other types of cells; they are self renewing

and continually perform cell division.

• All white blood cells (macrophages and

neutrophils) arise from a type of stem cell

called the haematopoietic stem cell (HSC)

Phagocytes

• Phagocytes are produced throughout life by the bone marrow.

• They are stored in the bone marrow before being distributed around the body in the blood

• They are also known as scavengers, removing dead cells and invasive microorganisms.

Phagocytes

• There are two kinds(a) Neutrophils� Form about 70% of the WBC in the

blood.� Travel throughout the body tissues.� They are released in large numbers

from the bone marrow during an infection

� They are short-lived

Squeezing through the

capillaries to patrol tissues

(liver, spleen, lymph nodes)

NEUTROPHILS (Granulocytes)

• The most common type of

Phagocyte it makes up 50 to 70% of the White Blood Cells in the body. They then engulf and destroy any pathogens they encounter.

• They move form blood vessels to injured tissues due to chemotaxis – response to chemical signals sent by damaged cells

Neutrophils self-destruct as they

phagocytose invaders – live only

for a few days

Macrophages/Monocytes

• Larger than neutrophils• Tend to be found in organs (lungs, liver, spleen, kidney and lymph nodes) rather than be found in the blood.

• Leave the bone marrow and travel in the blood as monocytes

• Crucial role in initiating immune responses.

MONOCYTES (Agranulocytes)

• Only constitute 5% of the leukocytes, but very effective

• Long-lived, excellent phagocytes

• Some microbes can evade them

• They circulate in the blood for some time, then they migrate into body tissues and become macrophages

Monocytes or Macrophages also release

IL1 which induces fever and also stimulates

an immune response

MACROPHAGES (Agranulocytes)

• Phagocytes - they consume and destroy any pathogens they encounter. They also rid the body of worn out cells and cellular debris

• They do not destroy the pathogens completely, but cut them up to display antigens that can be recognized by the lymphocytes.

(i) Phagocytes & phagocytosis

(Non specific immune response)• Phagocytes

- produced & stored in bone marrow before distributed in blood circulation

- ‘feed’ like Amoeba on bacteria, viruses and dead body cells.

Neutrophils Macrophages

�70% of WBC in blood

�travel throughout the body (blood)

� squeeze through the capillary wall

and into the infected tissue, engulf and

digest offending bacteria

�short-lived cells released in large

numbers during infection

�Larger than neutrophils

� found mostly in lung, brain, liver,

kidney, spleen, & lymph nodes

� leave the bone marrow & travel in

blood as MONOCYTES ⇒⇒⇒⇒ then

develop into MACROPHAGES once

settle in organs

� long-lived cells which initiate

immune response by displaying

antigens to be recognised by

lymphocytes

Stages of Inflammation1. Vasodilation: Increase in diameter and

permeability of blood vessels.

Triggered by chemicals released by damaged

cells: histamine, kinins, prostaglandins, and

leukotrienes.

2. Phagocyte Migration and Margination:

Margination is the process in which phagocytes

stick to lining of blood vessels.

Extravasation (Emigration): Phagocytes

squeeze between endothelial cells of blood

vessels and enter surrounding tissue.

Stages of Inflammation (Continued)

Phagocytes are attracted to site of infection

through chemotaxis.

Phagocytes destroy microbes, as well as dead

and damaged host cells.

3. Tissue Repair: Dead and damaged cells

are replaced.

Second Line of Defense in Action/ Inflammatory Response

The Inflammatory Response IS A NONSPECIFIC

DEFENSE REACTION OF THE BODY TO TISSUE

DAMAGE. 1. Despite the initial defenses of the skin and mucous

membranes, pathogens sometimes enter the body.

2. When pathogens enter the body, the immune system has a

second line of defense. The body's second line of defense acts

when tissues are injured.

3. The mast cells found in connective tissues and basophils

release a chemical called HISTAMINE, when injured - which

starts a series of changes called the inflammatory response.

4. Histamine increases blood flow to the injured area and

increases the permeability of the surrounding capillaries, as a

result, fluid and neutrophils leak from blood vessels into nearby

tissue to destroy pathogens by phagocytosis.

5. Pathogens are attacked by phagocytic white blood cells (leukocytes) such as Neutrophils and Monocytes in response to chemokines – chemical signals

6. Certain toxins released by pathogens may raise body temperature, but leukocytes can do the same by releasing molecules called pyrogens –fevers inhibit microbial growth, speed up chemical reactions and tissue repair

7. Antimicrobial agents collectively called the complement system lyses invading cells

8. Interferons are proteins secreted by virus-infected cells that limit cell-to-cell spread of the virus

The Second Line of Defense in Action –

cont’d.

(c) describe the modes of action of B-

lymphocytes and T-lymphocytes;

(d) explain the meaning of the term immune

response, making reference to the terms

antigen, self and non-self;

The Immune ResponseImmunity: “Free from burden”. Ability of an organism to recognize and defend itself against specific pathogens or antigens.

Immune Response: Third line of defense. Involves production of antibodies and generation of specialized lymphocytes against specific antigens.

Antigen: Molecules from a pathogen or foreign organism that provoke a specific immune response.

ANTIGENS ☺

• All cells possess antigens in their cell surface membranes which acts as markers, enabling cells to recognize each other.

• The body can distinguish between its own antigens (“self”) and a foreign antigen (“non-self”) and usually make antibodies against non-self antigens.

• Microorganisms carry antigens on their surface.

Antigens

• An antigen is a molecule which can cause

antibody formation

• Each antigen is recognized by a specific

antibody

• All cells possess antigens in their cell

surface membranes

• Usually proteins or glycoproteins

B cells and T cellsSimilarities• Both B & T cells are produced before birth in bone marrow.

• Only mature lymphocytes can execute immune response.

• When mature, all B & T cells circulate between blood & lymph

Differences

B cells T cells

�remain in bone marrow until they

are mature

�then spread throughout the body

concentrating in lymph nodes &

spleen

�Membrane bound antibody

�T cells mature once migrated from

the bone marrow to the thymus

gland.

�Concentrating in the blood

� T cell receptors

• When the pathogen first enter the body, macrophages engulf and digest microbes (including their antigens) through a process of called phagocytosis.

• Some of the digested antigens are then displayed on the surfaces of the macrophages. This is called antigen presentation

• Any B cells whose cell surface receptors fit the antigensrespond by dividing repeatedly by mitosis & after several generations will differentiate into PLASMA CELLS

MHC class 2 (antigen presenting cell) ; MHC class 1 (all nucleated cells)

Clonal selection

(f) relate the molecular structure of

antibodies to their functions;

• 1 type of antibody molecule which responds to 1 antigen

• Each cell then divides to a small group of identical cells able to produce the same type of antibody. This is known as a clone

• WHAT ARE ANTIBODIES?

� Immunoglobulin

� Y-shaped globular glycoproteins that identify and neutralize foreign particles

- consist of 4 polypeptide chains: 2 heavy & 2 light chains

hold by disulphide bridges

- the variable region which is different in each type of antibody

is dictated by the amino acid sequences

- The hinge region gives the flexibility for

antibody to bind to antigen

• Combine with viruses/toxins to prevent them from invading cells

• Antibodies with multiple antigen binding sites cause agglutination of bacteria reducing the chances of spread throughout the body

• Bursting bacteria cell walls – together with other molecules some Ab ‘punch’ holes in the cell walls of the bacteria causing them to burst

• Attach to bacteria making it easier for

phagocytes to ingest them.

• Combine with toxins, neutralizing them and making the, harmless, these antibodies are called antitoxins

The cells involved are lymphocytes, called T cells

• Unlike B cells, which can recognize antigen alone on its membrane bound antibody, T cell receptors can only recognize antigen that is bound to cell membrane protein MHC.

• T cells develop surface receptors called T-cell receptors where they become ‘programmed’ for the antigen of their specific enemy

• If an antigen is presented to a T cell with a complementary shaped receptor, the T cell is stimulated, increases in size and starts to divide

• T cells reproduce rapidly, however they do not produce antibodieslike B cells

T Helper Killer T

� recognise the non-self antigen

(from the foreign cells) that the

macrophages display on their outer

surface.

�release a powerful group of

chemicals called cytokines to

stimulate B cells to proliferate

�stimulate macrophages to carry out

phagocytosis more vigorously.

� Cytotoxic (kill cell)

�attack & kills body cells that have

been infected by virus, bacteria or

fungus.

�Kill the infected cells by secreting

proteins (perforin) that punch holes

in the membrane of the cell, and the

contents ooze out.

�In addition to helper & killer cells, memory T cells are produced which

remain in the body & become active quickly during secondary response

(e) explain the role of memory cells in long-term

immunity;

Memory cells• Remain circulating in the

body for a long time for rapid response

• If the same antigen is reintroduced a few weeks or months after the first infection, memory cells will divide rapidly and develop into plasma cells and more memory cells.

• This allows rapid response to future infection.

Primary response is slow because at this stage there are very few B cells that are specific to the antigen

Secondary responseis faster because there are many memory cells which quickly divide and differentiate into plasma cells

• Many more antibodies are produced in the secondary response

• Memory cells are the basis of immunological memory

• The ability of the immune system to respond quickly to antigens that it recognizes as having entered the body before

• Each time a pathogen with different antigens infects us, the primary response must occur before we become immune and during that time we often feel ill.

(g) distinguish between active and passive,

natural and artificial immunity and

explain how vaccination can control

disease;

• Natural active immunity (immunity gained following infection)

⇒⇒⇒⇒ body manufactures antibodies when exposed to an infectious agent.

• Artificial Active Immunity

(immunity gained by antibodies made other than in the host)

⇒⇒⇒⇒ vaccination or immunisation

• small dose of antigen is usually safe because the pathogen

is either killed or attenuated

• individual does not contract the disease itself, but is

stimulated to manufacture antibodies against the antigen.

• second, booster, injection is given and this stimulates a

much quicker production of antibody

• Natural passive immunity

(immunity gained by antibodies made other than in the host)

⇒⇒⇒⇒Antibodies made in one individual are passed

into another individual of the same species.

• Artificial passive immunity

⇒⇒⇒⇒Antibodies which have been made in one

individual are extracted and then injected into the

blood of another individual which may, or may not,

be of the same species.

(h) discuss the reasons why vaccination has

eradicated smallpox but not measles, TB,

malaria or cholera;

Eradication of smallpox

• Smallpox was caused by variola virus & transmitted

by directed contact

It is distinguished by red spots containing transparent

fluid appearing over the body & swollen eyelids

• 12-30 % of sufferers died while many who recovered

were often blinded.

• Reasons for the success of the vaccine included:

- The variola virus did not mutate and change its antigens.

- It was made from a live harmless strain of a similar virus

- Infected people were easy to identify.

- Smallpox does not infect animals.

- It could be freeze-dried & kept for 6 months aiding distribution

Measles

• Measles is caused by a virus by airborne droplets. It causes

rash & fever & fatal complications e.g. blindness & brain damage

• However, measles is still a major disease in overcrowded cities, insanitary conditions & places with high birth rate

• This disease easily transmitted among malnourished

infants suffering Vit. A deficiency, thus have low resistance

• This disease offers the promise of eradication if

worldwide surveillance was followed-up by vaccination.

• However, so far it has failed because:

- poor response to the vaccine been shown by some children, who need nutrition.- High birth rates and shifting populations make following-up cases difficult.

-Migrants and refugees may spread the disease.- Measles is highly infectious & 95% immunity of a population is required to

prevent transmission.

- The vaccine only has a 95% success rate.

�Poor response

- Some people do not respond at all, or not very well, to vaccination

- This could be due to defective immune system & thus, do not develop B & T cells OR suffer from malnutrition& do not have protein to make antibodies

�Antigenic variation

- Although each time you get a cold you have a similar set of symptoms, each new cold is in fact caused by a slightly different virus with slightly different antigens. The virus that causes colds has > 113 different strains due to high mutation rate

- No effective vaccines against malaria & sleeping sickness

- This is because the pathogens (e.g. Plasmodium & Trypanosoma) can have

numerous antigens on their surfaces at different stages in its life cycle.

- This makes it impossible for immune system to respond effectively

� Antigenic concealment

- Some pathogens escape from attack by immune system by living inside

cells e.g. Plasmodium enters liver cells or RBC & protected from

antibodies

- Some pathogens remain invisible to immune system by covering their

bodies in host proteins

- It is difficult to develop effective vaccines because there is a short period

of time for an immune response to occur before the pathogen “hide”