Immune response

An immune response is the body's response to a foreign organism (pathogen) entering it. Most pathogens are prevented from entering the body by the skin, or defences such as the mucus that lines the airways. Once a pathogen has entered the body the main forms of defence are the white blood cells (consisting of phagocytes and lymphocytes). The pathogen can be detected in several ways: it can be absorbed by a macrophage, which will then display the surface proteins of the absobed organism on its cell membrane, allowing other white blood cells to recognise it and start an immune response. Cells attacked by the pathogen can release histamine, which attracts neutrophils (a kind of phagocyte) to the area, starting the immune response. B or T lymphocytes can bind on to a foreign suface protein (antigen) and start an immune response).

Each type of white blood cell performs a specific function: Macrophages are found in the major organs and play an important role in initiating the immune response, as mentioned above. Macrophages absorb pathogens by phagocytosis, literally engulfing the organism and digesting them. Neutrophils patrol the bloodstream, and are produced in large amounts during an infection, they are attracted to cells releasing histamine and are one of the main parts of the immune response. They perform phagocytosis on pathogens. B-lymphocytes produce antibodies which perform a number of important functions such as "marking" pathogens, neutralising toxins or destroying some pathogens, they also produce memory cells, which stay in the bloodstream and are the basis of immunity. T-lymphocytes are divided into t-helper cells which secrete cytokines which speed up the activities of the immune system, such as the secretion of antibodies, and killer t-cells which secrete toxic substances such as hydrogen peroxide into affected cells killing the cell and the pathogens inside.

Overview

With so many external pathogens (disease causing micro-organisms) waiting to infect an animal, it's surprising disease is not more frequent than it is. Whilst we only say someone is ill or sick when they show symptoms, a person can be asymptomatic and still be actively fighting infection. This person can be said to be a carrier of that pathogen, until either they finally succumb to its effects or clear the infection entirely. For the purposes of this writeup I'll consider the immune response from the perspective of the animal kingdom only - significant differences exist in how plants protect themselves from disease.

Antigens

It's not really possible to continue with the node without defining what an antigen is and what its function will be in the following processes. Composed of proteins and/or sugars, antigens are integral molecules of a host cell or a pathogen which form part of its structure. They protrude out and are detectable by specialised body cells which can differentiate between different antigens due to their varying shapes. Every organism is innately aware of its own antigen shape, knowing them to be self-antigens. This ensures that it's immune response does not target it's own cells. If it did this is known as auto-immunity.

For the purposes of this writeup you can consider the following things as possessing antigens:

• Body tissues with self-antigens
• Bacterial pathogens
• Viral pathogens
• Toxins produced by the above

Specific and non-specific mechanisms

ca Broadly speaking an organisms defenses against pathogens include the specific and non-specific, with the non-specific being barrier mechanisms to infection such as the cornified layer of the skin and naturally produced anti-microbial fluids such as lysozyme in tears. These non-specific mechanisms are not the immune response, but provide some of the triggers that will enact it should the pathogens surpass this defence.

Phagocytosis

Present in the blood capillaries are phagocytic cells known as neutrophills and macrophages. It may help your understanding to consider these cells predatory since their function is to directly ingest and consume invading pathogens. Attracted to the site of infection by cytokines (chemical signals) produced by lysed (dying) body cells they ingest the pathogens and some of the pathogen's antigens may become embedded in their cell membrane. This is a key step in activating the immune response. The macrophages now present the antigens of their cell membrane to the relevant white blood cell, beginning the primary immune response.

White blood cells

Named white due to their lack of red, iron-containing haemoglobin, they develop in the bone marrow where they are produced from stem cells before migrating to the lymph nodes where they will mature and await activation. They are broadly divisible in to two groups:

• T-lymphocytes which detect which pathogen has infected the body and control the immune response
• B-lymphocytes which are activated by the above and are responsible for antibody secretion

Each T-lymphocyte has specifically shaped receptor proteins on it's cell surface membrane which fit exactly with the antigens now embedded in the macrophages membrane. In biological terms we say that the two molecules are complimentary in shape, a bit like a lock and key. It is therefore obvious that as each pathogen has a different antigen, it must also have a different relevant T-cell, with the appropriate complimentary receptor.

Starting the immune response

Once the relevant T-lymphocyte with complimentary receptors has been activated by a macrophage it reproduces rapidly by mitosis to produce a large clone of identical cells. This process takes place in the lymph nodes causing them to swell. Think about how you often feel aches in your neck during illness - this is due to large clusters of lymph nodes there hosting the reproducing immune cells.

However this large clone itself is useless against the pathogen which by now may have invaded several organs and be present in the blood and/or lymphatic system. The T-lymphocytes therefore operate on a biological version of divide and conquer, differentiating to form four major groups of cells:

1. Cytotoxic T-cells
2. Helper T-cells
3. Memory T-cells
4. Suppressor T-cells

NB: Where BaronWR refers to Killer T-cells, he is talking about a broader classification of the cytotoxic T-cells plus a miscellany of other very small groups of cells. Each of these groups has a very distinct function in the immune response.

• Cytotoxic T-cells

  These are the only T-cells to directly attack the pathogen (remember I said that the T-cells were mostly responsible for activating and controlling the immune system). They do so by binding to the pathogen using their complimentary shaped receptors to attach to the antigens on the pathogen. Once attached they inject toxins directly in to the pathogen known as perforins which cause the death of the pathogen. The cytotoxic cell then detaches and continues to find another pathogen. This process is not designed to defeat the infection, but keep it under control until the later stages are underway.

• Helper T-cells

  Are the primary cells controlling the response and work in opposition to the suppressor-T cells. Their major function is to activate the B-lymphocytes and cause them to reproduce rapidly. We'll look at this function later. Additionally the helper-T cells signal to macrophages via chemical signals known as cytokines, that they should migrate to this area to ingest dead bacteria killed by the cytotoxic-T cells.

• Memory T-cells

  Could be considered the pacifists of your bodies immunological army, having no effect on the pathogens directly. Their function is to remain in the lymph nodes to reproduce rapidly if the same pathogen invades a second or subsuqent time. This explains why you rarely catch some diseases twice (eg. chicken pox) - your body has developed an immunological memory to the disease and it's antigen.

• Suppressor T-cells

  Finally after a period of about 1-2 weeks, many of the above T-cells are surplus to requirements, so suppressor T-cells send out cytokines causing apoptosis of the surpluss cells. Apoptosis is programmed cell death and ensures that not too many useless cells are present in the body causing a drain on resources. The supressor-T cells also die at this point and the immune response in terms of T-cells is said to have stopped.

Production of antibodies

B-lymphocytes

Since the above mechanisms, known as the cell mediated response, have only controlled the pathogens numbers, a second line of defense is required to eliminate the pathogen entirely. This is the role of the B-lymphoctes, which again are produced in the bone marrow from stem cells. Where they travel to to be made competent is currently unknown, but they eventually migrate again to the lymph nodes. Structurally a B-cell has many proteins embedded in it's membrane, each of which is known as an antibody. A B-cell posesses only one type of antibody and it is specific to one type of pathogen and therefore it's respective antigen.

Activation and differentation

After being activated by a helper-T cell, the relevant B-lymphocyte posessing the correct antibody reproduces rapidly, again producing a large clone. Here differentiation takes only two courses to produce either memory-B lymphocytes or plasma cells. Since the prior has broadly similar functions to it's T-cell counterpart I won't discuss it further. The latter plasma cells, are signalled to the site of infection by the helper-T cell's cytokines where they will have their effect.

Antibody structure and function

To understand the function of the antibodies of the B-cells, it is first necessary to look at their structure. Consisting of four protein chains (two heavy and two light) they have a variable region and a constant region. Shaped losely like the letter Y, the two prongs have variable ends with a complimentary shape to the antigen of the pathogen. The constant region is merely there to give the antibody strength and weight. The whole creation is bound by disulphide bonding between the chains. Sounds complicated and to some extent it is; the methods of action however are quite simple however.

Synthesis and secretion

After building up in numbers and producing additional antibodies, the plasma cell now secrete their antibodies in vast quantities in to the blood, tissue fluid and lymph, where they bind to the correct pathogenic antigen for which they were designed. The fact that antibodies have two binding sites is crucial, allowing them to bind to multiple pathogens. When many antibodies do this, pathogens become clumped together in an immobile structure known as an antibody-antigen complex. Immobilising pathogens via binding to their antigens has a great many benefits to the host organism.

Effects of the antibody-antigen complex

Where the complex is formed several processes take place, depending upon what the antibody was designed to do, and what the antigens were attached to.

• Agglutination

  Losely meaning imobilisation or clumping, this is the most common and also most important effect. It stops pathogens from attacking or entering host cells and provides a static target for phagocytosis. The pathogen can now no-longer reproduce effectively, and numbers begin to fall due to the arrival of macrophages and neutrophils which ingest rapidly the clumped pathogens.

• Precipitation

  Where the antigen is part of a toxin secreted by a pathogen, the binding of a large number of antibodies causes it to precipitate out of solution due to increasing weight caused by the heavy chains of the antibody. As it is no-longer in solution it is unable to have any damaging effect on the host's metabolism.

• Opsinisation

  Is a process whereby the antibody-antigen complex stimulates blood plasma proteins to come out of solution and form a substance known as complement. Complement binds to the complex, killing pathogens and further attracting mcarophages to the consume the dead pathogens. Again these processes rapidly decrease pathogen numbers where a antibody-antigen complex has formed.

Cleanup and immunological memory

After the above processes and shutdown by the supressor-T cells, various menial and uninteresting cleanup tasks are performed by the host organism. Macrophage activity will continue for some time, and a resident population of these pseudo-predatory cells will remain in the blood at all times. Antibody concentrations will fall gradually, either being digested by the body itself, or where appropriate passed across a placenta to a foetus or via colostrum to newly born offspring.

Immunological memory

Memory T and B cells present from the above remain in the lymph nodes, and in very large numbers in the spleen. It is for this reason that splenectomised patients often require antibiotics as they have no lasting natural immunity after exposure. The above process of immunity is known as the primary immunological response and takes about 14 days to completion (although symptomatically this appears less). With the relevant memory cells, the process can be complete in less than 4 days. This is due to a lower latent period between T-cell activation and B-cell antibody production. It is this effect that is exploited in vaccination programmes, encouraging the body to produce memory cells to antigens of dead or non-pathogenic organisms, so that on later exposure to a real pathogen, a faster response can be enacted.

Conclusions

The above description is simplified where necessary, either because additional detail is menial and of trivial importance, or because finer details exceed my knowledge on this subject. Lasting immunity and vaccination is a topic dealt with extensively by the world health organisation through their vaccination programmes and if you have found the above interesting it might be worth checking out some of the information available on their website: www.who.int/en

Considering the complicated series of steps your body goes through to defend itself once infected, it's surprising that we don't get ill more often. Next time your sick or don't feel to well, take some comfort in the fact that whilst you don't feel so good, you don't have to take conscious responsibility for the process of getting better again.

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I've omitted some ofthe more trivial cells of the immune response for the purposes of clarity. /msg me if your interested in what I've omitted, but for a complete picture you will need to do your own additional research.