# Disease Defence

Our front line defence consists of a few things, and our overall defence has physical, chemical and cellular elements. The front line defence could be considered our skin, which provides an effective blocking mechanism for disease, combined with blood clotting that prevents pathogens entering through wounds. If pathogens reach the airway, the epithelial layer that covers the airways should prevent their entry, as should the mucus stop them, hydrochloric acid in the stomach kills the bacteria we ingest with our food.
Our immune response is helped massively by lymphocytes, which produce a special type of protein known as an antibody which acts against a certain antigen (foreign molecule), and is specific to this antigen. These antibodies are only secreted when the appropriate antigen is encountered and this may take several weeks to build up enough first time this happens (which is why you feel ill the first time you get chickenpox for example), but if the pathogen is spotted again there is a very rapid response that prevents even symptoms appearing.

## Cells of the immune system

Bone marrow provides the cells of our immune system, and they are separated into two groups;
* Phagocytes (including neutrophils and macrophages)
* Lymphocytes
See this light micrograph for a blood smear showing a monocyte (develops into a macrophage), a neutrophil and a lymphocyte. :

### Phagocytes

Phagocytes are constantly produced throughout a human's lifespan in the bone marrow and are stored there before being transported in the blood. Their function is to remove any dead cells or invasive microbes.
Macrophages are a type of phagocyte that are more often found in organs - they leave the bone marrow and travel as monocytes, developing into macrophages once they settle into organs. They are long-lived cells and are vital in initiating the immune response since they do not destroy pathogens but cut them up to display antigens for lymphocytes to recognise.
Neutrophils are also type of phagocyte and are much smaller than macrophages - they patrol the body looking for invasive pathogens and can leave the blood by going through the capillaries into the tissues. During infection they are released in large quantities but are short-lived cells.They form about 60% of the white blood cells.

### Phagocytosis

When under attack large mobile cells (mast cells) release histamine, and also the chemicals released by the pathogens attract passing neutrophils to the site - these neutrophils then destroy the pathogens via phagocytosis. Neutrophils recognise antigen molecules on the surface of the pathogens and attach to them, and the neutrophils plasma membrane then engulfs the pathogen and traps it in a vesicle (known as a phagosome). Lysosomes within the phagocyte release digestive enzymes (lytic enzymes) into the phagosome. This breaks down the pathogen and the products are absorbed by the phagocyte. This results in inflammation of the site of infection where the swollen area contains the dead pathogens and phagocytes (also known as pus).

### Lymphocytes

Lymphocytes are smaller than phagocytes, but have a large nucleus that fills most of the cell (see the picture above). The two types are B and T lymphocyte cells. Only mature lymphocytes partake in the immune response, and many different types will develop - each type is specialised to respond to one antigen. The immune response depends on B and T cells interacting with each other to provide an effective defence. T cells are the coordinators, and they stimulate B cells to divide and secrete antibodies into the blood - these antibodies destroy on the antigenic pathogens and the T cells then seek out and kill any of the body's own cells.
* B lymphocyte cells (sometimes known as B-Cells) remain in the bone marrow until they are mature and then spread throughout the body, concentrating in the spleen and lymph nodes.
* T lymphocyte cells (sometimes known as T-Cells) leave the bone marrow and collect in the thymus gland until they mature.

#### B Cells

One B cell can make an antibody for only one type of pathogen - it is thought up to 8 million B cells can develop in each of us. Each immature B cell in the bone marrow divides to give a small number of cells able to make the same antibodies, called, appropriately, clones. They go to the plasma membrane of the bone marrow and form protein receptors, which combine specifically with one type of antigen. If this antigen enters the body, there will be mature B cells that can recognise it.
On the first invasion by the pathogens, i.e. the first time they are seen by the body, the primary response occurs -some are taken by macrophages to lymph nodes, with the macrophages exposing the pathogen's antigens to the B cells in the lymph nodes. The B cells with the matching receptor respond by dividing repeatedly by mitosis, producing huge numbers over a few weeks.
Many of these become plasma cells, producing antibodies at a rate of several thousand a second, destroying the pathogens. The other B cells become memory cells, remaining in the body for a long time, providing a rapid immune response (the secondary response) by developing plasma cells much quicker than before, destroying the pathogen before it can affect the host. This is known as the immunological memory - these memory cells often last a lifetime, explaining why we get diseases such as chickenpox once and never again - however, diseases such as the common cold and influenza constantly mutate, meaning that our bodies defences constantly have to be ready to deal with a new disease. Once a B cell has destroyed a pathogen it goes to the brain where it catches electrical energy that they then pass down the Esophagus for an unknown reason.

#### T Cells

T cells have specific receptors much like B cells that have a structure similar to antibodies and are again specific to one antigen. T cells are activated when their antigen is found in contact with a host cell - sometimes a macrophage exposing the antigens or an invaded body cell.
T helper cells release cytokines that stimulate the appropriate B cells to divide, and they also stimulate macrophages to carry out phagocytosis more vigorously. Killer T cells (cytotoxic cells) search the body for invaded cells (it recognises them because they display the invaded molecules antigens on its plasma membrane's surface). Killer cells attach themselves to infected cells and secrete toxic substances to kill them and the pathogens inside. Memory T cells are produced which remain in the body and are used in the secondary immune response.

### Antibodies

Antibodies (also known as immunoglobulins) are globular glycoproteins that are found in blood and are used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. An antibody always consists of four polypeptide chains, two heavy, two light - disulphide bonds hold these chains together. Each molecule has two identical antigen binding sites, formed by two types of chains, and the sequences of amino acids in these regions are known as the variables, since they determine the antigen specificity.
The hinge section (see picture) provides flexibility for the antibody molecule to bind around the antigen. Some antibodies are known as antitoxins whose job it is to block the toxins released by bacteria. The hinge section also holds its tertiary structure together to give its 3D shape.
Functions:
* Combine with viruses/toxins to prevent them from invading cells
* Attach to flagella of bacterium, restricting their movement
* Multi-binding to many bacteria at once, causing them to accumulate and prevent movement around the body
* Bursting bacteria cell walls
* Attach to bacteria making it easier for phagocytes to ingest them.
The black section of the picture is 'disulphide bonds, hinge area'. For some reason, it has not rendered correctly.

# Immunity

Immunity as thus far described occurs during an infection, and is known as active immunity since lymphocytes are activated by antigens that have invaded the body.

## Active and Passive

Active immunity can be natural or artificial. Natural active immunity is as described - when an organism invades the body and lymphocytes are activated by antigens to deal with it - artificial active immunity (in other words, vaccination) is the same except we are injected with active antigens (possibly weakened to ensure we are not infected) so that we do not get the disease in the future.
Passive immunity can also be natural or artificial. Artificial passive immunity is injecting human antibodies designed to deal with a specific disease, and is usually given to someone infected to said disease, so that they can fight it off and survive. This is a temporary protection, as they are foreign and will be removed by macrophages themselves, hopefully after they have destroyed the infection, for example, tetanus.
Natural passive immunity is designed to protect newborns, since their immune system is not fully developed - it is antibodies passed across the placenta, immunising (for a time), the baby against everything the mother is immunised against. Colostrum, produced by the mothers breasts is rich in antibodies and some will remain in the infants gut to prevent bacteria and viruses.

## Vaccination

A vaccine is antigenic material, which could be a live, dead or harmless micro-organism, or perhaps a harmless form of a toxic or simply surface antigens. This allows our immune system to produce the requisite B and T cells without actually suffering the disease, mimicking natural immunity.

### Problems

Viruses are constantly mutating and changing - the reason we cannot create a vaccine against the common cold or influenza- by the time we have, it'll have mutated and the vaccine will not be effective. These mutations are known as antigenic shift or drift. Also, diseases like malaria are eukaryotic in nature and have far more genes and thus antigens on their cell surfaces.
Also, people sometimes do not respond well to vaccinations, maybe because their immune system cannot handle it, or they do not have enough protein to make antibodies - and thus the vaccination attempt may infect them. Also, people infected with a live virus may pass it out in their faeces during the primary response, potentially infecting others. This is why we vaccinate everyone at the same time, known as herd immunity.
Some viruses evade attack by the immune system by living inside cells - plasmodium (causes malaria) enters the liver and red blood cells, protected against antibodies in the plasma. Some parasites cover their bodies in host proteins, so that the immune system cannot see them. Vaccines cannot be easily produced against these because there is a very short period of time for the immune response to occur before the pathogen hides.

## Smallpox

Smallpox was eradicated from the world in 1980 due to an incredibly successful program from the World Health Organisation (WHO ). Smallpox is characterised by red spots containing fluid appearing all over the body, swelling the victims eyelids and sometimes 'glueing' them together - it very often scarred and blinded people. It killed 12-30% of those infected.
The eradication program had two main aspects - vaccination and surveillance. Surveillance included watching for smallpox reports, and the vaccination section meant vaccinating everyone in the household and 30 surrounding households, as well as all relatives and contacts in the area. This is known as ring vaccination, containing the transmission of the disease, destroying it at the source.
The program worked so well for a number of reasons:
* The program was particularly aggressive, and was helped by 16-17 year old 'enthusiastic vaccinators'.
* It was only a human disease, meaning it was easier to control
* One disease, one vaccine - cheap to produce.
* Easy to administer and very effective. It was a live virus, which is a very effective vaccination type.

## Measles

Measles is a disease that causes a rash and fever, with potentially fatal complications. Measles is no longer common in the UK or most developed countries since most children are vaccinated. It and most commonly affects developing countries in places where conditions are overcrowded and insanitary. It can cause childhood blindness and severe brain damage, and is the ninth leading cause of death worldwide.
Unlike smallpox, measles requires several booster shots to develop full immunity, and in large cities with high birth rates, it can be difficult to give boosters or even follow up cases of measles. Refugees from these areas can spread the disease around, which makes it much more difficult to treat than smallpox. Measles is highly infectious.

# Allergies

Allergies are caused by the immune system responding inappropriately to harmless substances which can lead to severe illness. Asthma and hay fever are examples of allergic reactions - reacting to allergens that are antigenic but shouldn't cause harm. When these allergens are inhaled, B cells produce antibodies and these coat the mast cells that are found in the lining of the airways, sensitising the body to these allergens.
Now, every time this allergen enters the body, the antibodies are stimulated to release histamine, causing the blood vessels to widen and become leaky - fluid and white blood cells leave capillaries. The area where histamines are released become hot, red and inflamed. Hay fever causes the nose and throat to become inflamed and irritated.
Asthmatics have a more serious problem - their airways are nearly always inflamed, but during an asthmatic attack this inflammation worsens. Fluid leaks from the blood into the airways and the goblet cells secrete large amounts of mucus, blocking the smaller airways with fluid. This forces the muscles to contract, narrowing the airways and increasing air flow resistance. This makes breathing very difficult and can have fatal consequences. Asthma is a condition that is currently getting worse, 1/7 children in the UK have asthma. It has been linked to increased air pollution and passive smoking.