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This topic involves learning a lot of new terminology. Below is a list of the terms which you will need to be comfortable using:

Pathogen

Fever

Inflammation

Phagocytosis

Neutrophils

Macrophage

Immunological memory

Self and non-self

Complement proteins

Immunoglobulin

Antigen

Plasma cell

Memory cell

Major Histocompatibility complex

T-helper cell

Cytokines

Primary immune response

Secondary immune response

T-lymphocytes

B-lymphocytes

Natural immunity

Artificial immunity

Active immunity

Passive immunity

Polyclonal antibodies

Monoclonal antibodies

Vaccine

After studying this topic you should have an understanding of how the body is equipped to keep most microorganisms out and how it responds to and destroys any microorganisms which do manage to get through the body’s barriers.

How can we resist infection?

Resistance to infection is possible due to:

  • Species resistance - the fact that we are Homo sapiens - many microorganisms are species specific and will therefore not cause an infection in us.
  • Physical and chemical barriers - pathogenic organisms (those which can cause disease) might enter the body at any point where there is an ‘interface’ with the external environment. Your body has several physical and chemical barriers which try to prevent this:
    • Eyes are protected by tear production - contain antibacterial enzyme - lysozyme
    • Ears secrete wax - antiseptic properties
    • Sweat - contains an antiseptic
    • Stomach acid - many bacteria cannot withstand the low pH environment
    • Urine - antiseptic properties
    • Digestive tract - (small and large intestines and anus) contain large numbers of harmless bacteria which out compete the pathogenic microorganisms. This is known as your natural flora. Any disruption to this can lead to infection - the cause of stomach upsets whilst taking antibiotics.
    • Airways - epithelial cells lining the respiratory system produce mucus and are ciliated. Bacteria are trapped in the mucus and wafted up towards the oesophagus by the cilia.
    • Blood clotting - any open wound soon is sealed with a scab preventing entrance of pathogenic microorganisms. A clot consists of a mesh of blood proteins which trap blood cells. It is an interesting biochemical pathway - well worth further investigation!
  • Immune responses - if a pathogenic microorganism does make it past the physical and chemical barriers listed above then the body’s immune system mounts a response. This can be non-specific or specific as you will discover shortly.

What happens if a pathogenic microorganism enters the body?

The first response to an invading pathogenic microorganism is a non-specific immune response. A foreign antigen needs to be detected by the immune system to initiate this response. An antigen is usually a protein (but polysaccharides, nucleic acid and lipids also act as antigens). The entire immune response depends on the body detecting the difference between self and non-self antigens:

  • Self-antigen
    • Only found on the host's own cells and does not trigger an immune response
    • As these are proteins, their structure depends on the amino acid sequence
    • The gene for this sequence is highly polymorphic, having several alleles at each loci
    • There is great genetic variability between individuals
    • Thus, antigen is different in other people → injection would cause an immune response
    • There is only 25% chance that siblings will possess an identical antigen (transplant will not be rejected)
  • Non-self-antigen
    • Found on cells entering the body (e.g. bacteria, viruses, another person's cell)
    • Can also be displayed by cancer cells
    • May cause an immune response

Once a foreign antigen has been detected, the non-specific immune response is triggered. The temperature of the body will rise - FEVER - This higher temperature causes damage to the pathogenic cells. The site of infection will become swollen - INFLAMMATION - The area will be red, swollen, painful and feel hot to the touch. This is because the blood vessels in the affected area become more permeable thus allowing more white blood cells and important blood proteins such as antibodies to flood into the infected area and deal with the infection. Any pathogenic microorganisms found will be engulfed and destroyed -PHAGOCYTOSIS - by phagocytic cells entering the infected area. Damaged or infected tissue releases chemical mediators which attract the neutrophils and macrophages (most common phagocytic white blood cells).

  • Neutrophils primarily engulf bacteria
  • Macrophages engulf larger particles; including old and infected red blood cells

This process of chemical attraction of cells is called chemotaxis. A quick online search should provide moving images of phagocytosis. The cells enclose the pathogens in phagosomes formed by pseudopodia (cellular projections). The phagosome then fuses with lysosomes containing digestive enzymes which digest the microorganism. Pus is formed at the site of infection if no extensive vasculature is present.

Another event in the non-specific immune response is the activation of the complement protein cascade. The complement proteins are blood proteins, which due to inflammation enter the site of infection. Damaged tissue is capable of activating this biochemical cascade which results in the formation of a protein complex which is then able to lyse (burst) the invading microorganism. Looking at an image will help you to understand this system better - again an internet image search will help.

If, despite the initiation of the non-specific response (FEVER, INFLAMMATION, PHAGOCYTOSIS) the infection still remains, the specific immune system will begin to act. This as its name suggests depends on recognition of SPECIFIC antigens present on the invading microorganism. Activation of this response results in the formation of antibodies and immunological memory to protect you from further infection by that SPECIFIC microorganism.
There are two types of specific immune response:

  • The Humoral, or antibody-mediated response
  • The Cell-mediated response

The Humoral Response

The humoral response is mainly involved in the elimination of pathogenic microorganisims which do not enter body cells - bacteria. As mentioned above, this response relies on the production of antibodies. Antibodies are secreted by B-lymphocytes and produced in response to a specific (foreign) non-self antigen. The B-lymphocyte's receptor site will match the non-self-antigen. Each antibody is produced by one type of B-lymphocyte for only one type of antigen. In diagrams you can recognise the antibody as they are a Y-shape. An internet image search for a diagram of an antibody would help here:

  • The two ends of the Y are called the Fab fragments
  • The other end is called the Fc fragment
  • Fab fragments are responsible for the antigen-binding properties
  • Fc fragment triggers the immune response

Primary response

The antigen binds to specific Fab fragment of B cell receptor immunoglobulin

  • This produces a short and weak response
  • T helper cells are required to trigger the true potential of B cells

Once activated, the B cell grow and produce many clone cells. The clone cells have the same Fab fragment that recognizes the same antigen. Most of these clone cells differentiate into plasma cells which secrete large amounts of antibodies. Some of the clone cells differentiate into memory cell.
The antibodies which are released are specific for the original antigen and are capable of a variety of effects:

  • Agglutination - making the pathogens clump together
  • Acting as an antitoxin - to neutralise toxins produced by bacteria
  • Lysis - digests bacterial membrane, killing the bacterium
  • Opsonisation - the pathogen is coated in protein that identifies them as foreign cells making them more obvious targets for phagocytosis and destruction.

Secondary response

Exposure of same antigen causes activation of memory cells. They are present in the glandular tissue and will immediately recognize the antigen if presented with it. They are capable of producing larger amounts of antibodies in a much quicker time meaning that the pathogenic microorganisms are destroyed quickly and the infection never takes hold. This is immunological memory.

Cell-Mediated Response

Pathogens that quickly enter cells (viruses, tuberculosis) are more difficult to remove. The only way of clearing the infection is to destroy infected cells. No antibodies involved in the cell-mediated response. It is done by binding to the self and non-self antigen which prevents destruction of harmless body cells. The self antigen is a MHC (Major Histocompability Complex) protein present on almost all body cell and the non-self antigen (from viruses, bacterium, cancer, foreign cell, parasite) is an antigen which has been processed and displayed on the surface of the infected cell.

Primary response

A macrophage engulfs the pathogen and processes its foreign antigen. The non-self antigen is transported to the plasma membrane surface of the macrophage. This cell is now called an antigen presenting cell (APC). Activated B-cells can also act as antigen presenting cells.
T Helper cells (Th cells) recognise the foreign antigen present on the APC. They then activate cytotoxic T cells and B cells to destroy the infected cell:

  • T killer cells (cytotoxic T cells)
    • Must recognize self and non-self antigen to attach to infected cell
    • Directly kill pathogen by injecting proteases into the infected cell
    • Detach to search for more foreign cells
  • T-Suppressor cells switch off the T and B cell responses when infection clears otherwise your T killer cells would destroy your healthy body cells long after the infection had gone. This is the basis of autoimmune disease. Experiments with mice have shown that destroying their T-suppressor cells leads to the development of conditions very similar to human autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.

Secondary response

As with the humoral response, this involves the development of memory cells. Some of the T cells differentiate into T-memory cells which remain in the circulation and respond quickly when same pathogen enters body again.

HIV

The HIV virus has specific proteins which recognise the T helper cells. It enters and destroys these cells and therefore immunosuppress the patient as:

  • Other immune cells are not activated
  • The humoral response cannot be launched without Th cells / require co-stimulation of Th cells

AIDS develops as the immune system becomes totally suppressed. A patient with end stage AIDS will have multiple opportunistic infections (caused by microorganisms usually present but non pathogenic on or in the body) and possibly large numbers of tumours as a result of the suppressed immune system.

Vaccines

The immune responses discussed above are examples of natural active immunity. If antibodies are acquired by an individual then this is an example of passive immunity. Natural passive immunity happens when antibodies are passed from mother to foetus across the placenta and from mother to baby in the colostrums and milk during breast feeding.

Artificial immunity can be initiated in individuals. Artificial active immunity is the result of vaccination. If a patient is given an ‘agent’ containing the same antigens as the pathogenic microorganism then their body will produce antibodies against the pathogen. There are many different types of vaccine used:

  • Live attenuated: organism is alive but has been modified/weakened so that it is not harmful
    • MMR (measles, mumps, rubella) - vaccine does NOT cause autism!
    • BCG for tuberculosis
  • Inactivated: dead pathogen but antigen is still recognised and an immune response triggered
    • Pertussis (whooping cough)
    • Poliomyelitis
  • Toxoid: vaccine contains a toxin
    • Diphtheria
    • Tetanus
  • Subunit: contains purified antigen that is genetically engineered rather than whole organism
    • Haemophilus influenza b - causes epiglottitis, meningitis
    • Meningococcal C - causes serious septicaemia, meningitis
    • Pneumoccocal - causes meningitis which results in permanent disabilities in >30%!

A vaccine may cause swelling, mild fever, and malaise and you should NEVER give live vaccines to children with an impaired immune system!

Active (Antibodies made by the human immune system, long term acting due to memory cells)

Passive (Given-Antibodies, short term acting)

Natural

- Response to disease
- Rejecting transplant

- Acquired antibodies
(via placenta, breast milk)

Artificial (immunisation)

Vaccination
(Injection of the antigen in a weakened form)

- Injection of antibodies from an artificial source, e.g. anti venom against snake biter

Differences

- Antibody in response to antigen
- Production of memory cells
- Long lasting

- Antibodies provided
- No memory cells
- Short lasting

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Monoclonal Antibodies (Magic Bullets)

Monoclonal antibodies are produced by just one type of B cell. They are therefore highly specific and are suitable for use in many research situations. The methods used to produce them are outlined below.

Hybridoma

  • B cells are fused with tumour cells in the lab
  • Divide rapidly to form a clone of identical cells
  • Specific monoclonal antibodies are continuously produced and useful as
    • Tumour markers (antigens not present on non-cancer cells / attach to cancer cells only)
    • Anti-cancer drugs attached to monoclonal antibodies - deliver drug directly to cancer cells, fewer side effects

Uses of monoclonal antibodies

  • Monoclonal antibody is an antibody that is of just one type
  • Used to target the treatment of cancer cells or to screen (AIDS) in contaminated blood
  • Antibody direct enzyme prodrug therapy techniques (ADEPT)
    • Monoclonal antibodies are tagged with an enzyme that converts the prodrug (inactive drug) to an active form that kills cells (i.e. is cytotoxic)
    • The prodrug is injected in high conc
    • Attached to a monoclonal antibody, enzyme activates the drug and kills only cancer cells
  • In immunoassays, they can be labelled (radioactively) making them easy to detect
  • In the enzyme-linked immunosorbant assay (ELISA) technique, they are immobilised on an inert base and a test solution is passed over them
    • Target antigen combines with immobilised monoclonal antibodies
    • Second antibody attaches with an enzyme and binds to the monoclonal antibodies and to the target antigen as well
    • Substrate is added which is converted to a coloured product by the added enzyme
    • Conc. of colour tells us the amount of antigens present in the test solution
  • Used to detect drugs in urine of athletics or in home pregnancy tests (where an antigen in human chorionic gonadotrophin (hCG) is secreted by the placenta)
  • Transplanted organs have non-self-antigens triggering antibodies to attack the organ, leading to its rejecting
  • T-Lymphocytes are needed for B-lymphocytes to function
  • Monoclonal antibodies against T-lymphocytes can be used to prevent B-lymphocytes from functioning, thus blocking the rejection of transplanted organs
  • [EXAM] Helping to diagnose between two pathogens because
  • Antigens are on cell-surface membrane
  • Monoclonal antibody reacts with specific antigen only
  • Thus, detects presence of special bacteria because of a different antigen on another, different bacteria