Chapter 5: Cell recognition and the immune system

5.1 - Defence mechanisms

5.3 - Cell mediated immunity

5.5 - Antibodies

5.4 - Humoral immunity

5.2 - Phagocytosis

5.6 - Vaccination

5.7 - Human immunodeficiency virus (HIV)

Overall - the body consists of two types of defence mechanisms:

Non-specific:

Specific:

Definition = an immediate response that is the same for all pathogens

  • Physical barrier eg, skin, hairs
  • Phagocytosis

Definition = A slower response that is specific to each pathogen

  • Cell mediated immunity
  • Humoral response
  • vaccination and monoclonal antibodies

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Physical barrier:

Eg.

1) Skin

2) Nose + gas exchange system

3) Stomach

Outer layer consists of dead fat cells containing mainly of the protein Keratin

This forms a though barrier that microorganisms can't penetrate

Lined with tiny hair-like structures called cilia

Bathed in mucus that air born pathogens with stick to

Cilia waft the mucus up the throat to the mouth where it is swallowed and destroyed in the stomach, in tern destroying the trapped pathogens

The stomach contains HCL acid with a pH of 1.5 - 3.5

The acid kills pathogens present in food, drinks and mucus

The acid also denatures pathogens enzymes

4) Extra examples

1) Ear wax - traps pathogens

2) Anus and genital areas - contain mucus producing cells to make mucus which traps and flushes out pathogens

3) Tear Fluid - contains lysozymes

How lymphocytes recognise the body's cells:

Cell identification

Self - antigens = each cell in the body has specific antigens that allow them to be identified as body cells

Non - self antigens (Foreign) = antigens on foreign cells that trigger an immune response

When lymphocytes come in contact with self antigen presenting cells they will move on
When lymphocytes come in contact with non-self antigen presenting cells they will trigger an immune response

Why is infection rare in the foetus?

1) Within the foetus there are many lymphocytes constantly colliding with other cells

2) and because the foetus is protected by the physical barrier of the placenta and the mother lymphocytes collide almost exclusively with the body's own cells

What is done when lymphocytes mutate?

1) Most lymphocytes will have receptors for non-self antigens but some may mutate and have receptors for self antigens

2) If these appear they usually will die or be suppressed or they will undergo programmed cell death (apoptosis) before they can differentiate into mature lymphocytes

Process:

1) The phagocyte is attracted to the pathogen by chemical products of the pathogen (cytokines). It moves towards it along a concentration gradient

2) The phagocyte has several receptors on its cell-surface membrane that bind to the antigens on the surface of the pathogen

3) The phagocyte engulfs the pathogen/antigen by endocytosis, to form a vesicle called a phagosome.The plasma membrane of the phagosome is derived from the cell-surface membrane of the cell

Cells of the immune system summary:

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Cytosis:

Endocytosis:

the process of bringing the pathogen/antigen into the cell

Exocytosis:

the process of ejecting the pathogens remains

4) Lysosomes within the cell move towards and fuse with the phagosome, forming a phagolysosome

5) These lysosomes contain hydrolytic enzymes called lysozymes that hydrolyse/digest the pathogen

6) The soluble products are absorbed into the cytoplasm and the antigens 'presented' on the cells surface membrane, while the other products are ejected by exocytosis

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Why does inflammation occur at sites of infection/phagocytosis?

1) At the site of infection/damage, special immune system cells release Histamine, a hormone that increases the flow of blood to that area by dilating the blood vessels

2) This increased blood flow encourages/moves more phagocytes to the site

3) The area can contain 'pus' which often consists of dead phagocytes and the dead/hydrolysed pathogens

Cell involved:

T lymphocytes:

Site of maturation = made in the bone marrow, matured in the thymus gland

Type of response = cell mediated immunity

Secretes antibodies = NO

How they recognise foreign and self cells is explained in 5.1 - defence mechanisms (How do lymphocytes recognise the bodies cells:)

7) Keep in mind - the main two phagocytes focused on in the spec are neutrophils and macrophages, but only macrophages present the antigens afterwards

Process:

1) A pathogen enters the body and is processed by phagocytes

Examples of foreign cells in the immune system:

1) Pathogens antigens presented by phagocytes/macrophages that have been processed in phagocytosis

2) Body cells invaded by a virus present some of the viral antigens on their own cell-surface membrane

3) Transplanted cells from individuals of the same species have different antigens on their cells-surface membranes

4) Cancer cells are mutated from normal body cells and present foreign antigens on their cell-surface membranes

2) The phagocytes (specifically macrophages) present the pathogens foreign antigens on their cell-surface receptors

3) T helper cells are naturally floating around the body, a T helper cell with a complementary receptor on its cell-surface membrane binds to the antigen on the macrophage

4) This attachment activates the T helper cells to divide/clone by mitosis and then differentiate into 4 different cells

4 types of differentiated t cell:

1) Memory T cells:

2) Killer (Cytotoxic) T cells:

3) Helper T cells:

4) Suppressor T cells:

Function: retain the information for of the complementary cell surface receptors of a specific antigen/pathogen

Secondary response: After primary infection they remain present in the blood, when re-infection occurs they divide and differentiate into helper t cells

Function: specifically target abnormal body cells (ie. cancer) and cells that are infected by pathogens (in doing so, preventing the pathogen from being able to replicate)

Process: bind to specific antigens (either of abnormal body cell or pathogen found on the surface of the infected cell) with complementary cell-surface receptors

releases a protein called perforin, which makes holes in the membrane of the cell

these holes mean the membrane become freely permeable to all substances and the pathogen dies as a result

Function: originally present in the blood to start the process of mediated immunity through mitosis and differentiation, but also have separate functions within the body:

Secrete chemicals (cytokines) that stimulate:

1) cytotoxic cells

2) activate phagocytes and encourage inflammation

2) activate b lymphocytes to start humoral immunity

Function: keep the immune system in check so that once the pathogens have been dealt with, the system is switched off

Cell involved:

B lymphocytes:

Site of maturation = bone marrow

Type of response = humoral immunity

Secretes antibodies = YES

Process:

1) A pathogen enters the body - its then processed by phagocytes and used to activate t cells in mediated immunity

2) B cells present in the blood with complementary cell-surface receptors bind to the antigen/pathogen and engulf it through endocytosis. It is then processed and the antigen presented on its surface (ie, antigen presenting cell)

3) Complementary activated t helper cells bind to the presented antigen/ie, bind to the b cell and exchange chemicals, activating it. Activated b cells then clone by mitosis and undergo differentiation into memory b cells and plasma b cells:

2 types of differentiated b cell:

1) Plasma cells:

Function: secrete complementary antibodies to that specific pathogen

2) Memory b cells:

Function: remain after primary infection, storing the information for that specific antibody production. When coming into contact with the pathogen during re-infection they divide rapidly into plasma cells and begin producing antibodies (in secondary response)

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Important note:

Every pathogen contains a variety of different antigens on its surface

Each antigen is complementary to a protein receptor on a B lymphocyte

So a variety of B lymphocytes will be involved in response to a pathogen, ie. many different b cells will be activated at once in response

Structure:

Function:

Uses of monoclonal antibodies:

Ethical use:

'Y' shaped protein consisting of 4 polypeptide chains (2 heavy + 2 light), held together by disulphide bridges

Variable regions: 2 uniquely shaped regions that form 2 binding sites which are complementary to the antigen

Constant region: the same in all antibodies

Hinge region: the area holding together the Y intersection, this is flexible which allows the arms to stretch for antigens

Many antibodies bind to one pathogen which allows for other immune system cells to destroy it, this is done by:

1) agglutination - antibodies can bind to more than one pathogen due to their two flexible arms. This forms a large mass as the pathogens are all stuck together

This makes them more noticeable to other cells and restricts their movement. When a antibody bind to the antigen it forms a antigen-antibody complex

2) act as chemical markers for phagocytes

3) can act as antitoxins, when binding to a toxin of a pathogen they neutralise it

4) Inhibit viruses - can bind to viruses attachment proteins which prevents them from entering the bodies cells and replicating

ELISA test: The Enzyme-Linked Immunosorbent Assay test

Types of antibodies:

Polyclonal - different antibodies from different b cells that join together to fight one pathogen

Monoclonal - when a single/specific antibody is identified and isolated within a lab

Process:

1) A known antigen is bound/stuck to the bottom of a well in a microtiter plate/dish

2) A blood sample is added, if it contains the complementary antibodies, they will bind to the antigens

3) The well is washed

4) A second (monoclonal) enzyme linked-antibody is added. This will bind to the first antibody

5) The well is washed

6) A colourless solution is added which the enzyme will react with. If a colour change occurs it indicates that the enzyme-linked antibodies bound and therefore there was the specific antibodies present in the blood

Uses:

Targeting medication to specific cell types by attaching a therapeutic drug to the antibody:

Medical diagnosis:

Pregnancy testing:

Direct monoclonal antibody therapy - used to treat cancer

Antibodies target/are specific to one particular antigen, monoclonal antibodies specific to the cancer cells are given to a patient

These antibodies bind to the cell-surface receptors on the cancer cells and block the chemical signals they release that stimulate their uncontrolled growth

An example, breast cancer is treated with herceptin, this treatment is used because antibodies as non-toxic and highly specific so reduce side effects

Indirect monoclonal antibody therapy - used to treat cancer

A radioactive or cytotoxic drug is attached to the antibodies, this means that when the antibody attaches to the cancer cells, they're killed

Monoclonal antibodies when used like this are called 'magic bullets' and can be used in smaller doses which reduces costs and reduces side effects

Used in diagnosing illnesses (ELISA test) - examples include the influenza virus, hepatitis, chlamydia and certain types of cancers.

An example - Prostate cancer, men with prostate often produce unusually high levels of a protein called prostate specific antigen (PSA)

The ELISA test can be used to identify these high levels, not necessarily giving an official diagnosis but at least giving an early warning

The test is based on the fact that the placenta produces a hormone called human chorionic gonadotropin (hCG) that can be found in the urine

Urine is added to the strip, monoclonal antibodies on the strip are attached to coloured particles and if hCG is present they will bind. The hCG-antibody-colour complex moves along the strip until its trapped by a different type of antibody, creating a coloured line

Positive:

Negative:

Ethical issues with the use of mice: mice are used to produce both the antibodies and tumour cells, meaning tumours are deliberately induced on the mice. Although there are guidelines some people still have reservations about this method

Effective + positive use in medicine: used to successfully treat many diseases, in tern saving many lives

Deaths involved with their use, in medicine: use in the treatment of multiple sclerosis has resulted in a few deaths, it's important for patients to fully understand the risks and benefits of this treatment

Monoclonal drug trials: March 2006, 6 volunteers took part in a trial for (TGN1412) monoclonal antibody in London. The trial went wrong due to the t cells either overproducing chemicals that stimulate an immune response or attacking body tissues, resulting in almost immediate organ failure. This brings into question issues with drug trial conduct

How are monoclonal antibodies produced?

Need for this method:

Production of large quantities of a specific antibody are needed for medical use

But B cells that produce the antibodies are very short lived and only divide inside living organisms (in vitro), so a new method was needed in order to allow the production of a large amount of antibodies outside of an organism

Process:

1) A mouse is exposed to the antigen that the antibody is needed against

2) The B cells in the mouse then produce the specific antibody, and are extracted

3) To allow the B cells to divide outside, they are mixed with cells that divide readily outside, eg. tumour cells

4) Detergent is added to the mixture to break down the cell-surface membranes of both types of cell which enables them to fuse together. These fused cells are called hybridoma cells

5) The hybridoma cells are separated and each cell is cultured to form a clone which should be producing the required antibody

6) The clones are grown on a large scale and the antibodies are extracted

Types of immunity:

How do vaccines work:

Features of a successful vaccination programme:

Herd immunity:

Why vaccination my not eliminate a disease/work:

Ethics of using vaccines:

Passive immunity:

Active immunity:

Introduction of antibodies from an outside source, eg, a fetus has immunity from the mother which diminishes after birth

Short lived immunity

These antibodies are not replaced by the individaul

Antibodies produced by the individuals own immune system

Long lasting immunity

These antibodies are replaced by the individual

Types:

Natural active immunity: results from the individual becoming infected with the pathogen under normal circumstances

Artificial active immunity: forms on the basis of vaccination (immunisation) ie. inducing an immune response without then suffering the symptoms of the disease

Vaccine = a preparation/injection of antigen or pathogen that has been weakened (attenuated) or is dead

By introducing the pathogen or antigen, it stimulates an immune response without the individual suffering symptoms. This results in the build up of long term immunity so if infection occurs the individual is able to fight it off

Economic - vaccine must be economically available in sufficient quantities to immunise most of the vulnerable population

Few side effects - unpleasant side effects discourage individuals from being vaccinated, so side effects must be minimised

Delivery - means of producing, storing and transporting the vaccine must be available, usually involving technologically advanced equipment, hygienic conditions and refrigerated transport

Trained staff - there must be means of administering the vaccine properly at the appropriate time, includes trained staff and vaccination centres

Herd immunity - it must be possible to vaccinate the vast majority of the vulnerable population

Definition = when a sufficiently large proportion of the population has been vaccinated it is difficult for the pathogen to spread because those it comes into contact with are already immune

1) Fails to induce immunity - eg, in people with defective immune systems

2) Individuals may develop the disease immediately after vaccination but before their immunity levels are high enough to prevent it, these people may harbour and spread the pathogen

3) The pathogen may mutate frequently which causes a significant sudden change in the shape of its antigens, this means the vaccine is ineffective as the pathogen is no longer recognised by the immune system. Eg, antigenic variability occurs with the influenza virus so every year a new vaccine has to be developed

4) The number of varieties of a particular pathogen makes it impossible to develop a vaccine that is effective against them all, eg, over 100 varieties of the common cold

5) Certain pathogens 'hide' within the bodies cells or conceal themselves in places out of reach eg, cholera in the intestines, so the immune system is unable to find them

6) Individuals may not accept the vaccine due to religious and personal beliefs or medical reasons,eg, after the MMR scare many people still have misinformed beliefs

1) Ethics behind the use of animals in vaccine development

2) Evaluation of risks of side effects/unknown long term side effects

3) Ethics behind who is tested in vaccine trials

4) Ethics of drug trials and their risks

5) Should the vaccine be compulsory, on what grounds can people opt out

6) Costs

7) How are risks to individual health balanced with the benefit of the general population

Structure:

MMR Vaccine:

Replication:

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Features:

Lipid envelope - a layer that encloses the whole virus

Attachment proteins - found on the lipid layer, used by the virus to identify and attach to host cells

Capsid - a layer of proteins that encloses the viruses genetic material (RNA)

RNA and reverse transcriptase - stored in the capsid, rt is an enzyme that catalyses the production of DNA from RNA

1) Enters the blood system and finds a t lymphocyte host cell, attachment proteins on the virus bind to a protein called CD4 on the t cells surface

2) The virus fuses with the cell-surface membrane and the RNA and reverse transcriptase enter the cell

3) The reverse transcriptase converts the viruses RNA into DNA and its moved into the nucleus where its inserted into the cells DNA

4) When activated, the t cell creates mRNA containing the instructions for making new viral proteins and the RNA to go into the new HIV

5) The mRNA moves out of the nucleus and used the cells protein synthesis mechanisms, once ready, the HIV breaks away from the t cell, taking some of its cell-surface membrane with it

Effect of HIV:

Normal person on average has between 800 to 1200 helper t cells but someone with AIDS can have as low as 200 mm-3

Results in AIDS (acquired immunodeficiency syndrome) where the immune system is to produce an adequate immune response and becomes susceptible to other infections and cancers

One does not die from HIV or AIDS, they die as a result of any infection they are unable to fight off

Why are antibodies ineffective against viruses (eg, HIV):

Antibiotics work by targeting the murine wall of bacterial cells, it prevents proper formation which means water enters by osmosis until the cell 'dies by osmosis'

Some antibiotics, eg, penicillin, inhibit enzymes required for the synthesis and assembly of the peptide cross-linkages in bacterial walls, causing death by osmosis

Viruses rely on host cells and therefore lack the structures that antibodies target as well, as having a protein coat rather than a murein wall or are located within body cells were antibiotics cant reach them