Cell recog & immune system PDF

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Some notes made from a mixture of lessons from a first year student....

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Cell Recognition & the Immune System Types of immune responses:! Non specific

Specific

- Response is immediate! - Response is the same for all pathogens

- Response is slower but long lasting! - Response is specific to each antigen

Physical barriers, e.g: skin! Phagocytosis

Cell mediated response (T cells)! Humoral response (B cells)

What triggers an immune response by white blood cells?! Antigens! Proteins with specific tertiary structures found on cell surfaces allow the immune system to identify and distinguish between:! Pathogens and the toxins they produce, non-self (foreign) cells from organisms of the same species, abnormal cells (cancer cells)! Phagocytosis ! Is the breakdown of large particles (pathogens) by phagocytes before they cause harm. They are engulfed within vesicles on which digestive enzymes act. Histamine release causes dilation of the blood vessels to get phagocytes to the site of infection quicker. This causes inflammation, and pus forms (dead pathogens and phagocytes). ! Points 1&2: chemicals released by the pathogen attract phagocytes towards them (in a process called chemotaxis) and they get engulfed, forming a vesicle called a phagosome.!

NON SPECIFIC PHYSICAL BARRIERS TO INFECTION: Routes of entry

How is it transmitted

Example of disease

Defence mechanisms

Through the skin and eyes

If the skin is cut or damaged in some way

Conjunctivitis, tetanus

Normal flora (microorganism) present on the skin (also lining the digestive tract & vagina) compete with potential pathogens for sites on our bodies & nutrients. The cells in the outer layer of the skin contain a protein called keratin. The keratin fibres make the cells tough & virtually impermeable to microbes. Tear fluid contains lysosome enzyme that destroy bacteria.

Through the digestive system

Contaminated food & dirty water

Salmonella, dysentery, cholera

The stomach produces strong hydrochloric acid which kills most microbes.

Through the respiratory system

Airborne, droplet or aerosol infection when we sneeze, cough, speak or breathe & direct contact

Influenza, strep throat, tuberculosis

The whole respiratory tract is limed with mucus & cilia which trap bacteria before they reach the lungs.

Routes of entry

How is it transmitted

Example of disease

Defence mechanisms

Through the reproductive system

During sexual intercourse

HIV, syphilis, chlamydia & gonorrhoea

Harmless bacteria in the reproductive passages create an unfavourable, acidic environment for others pathogens - has a limited effect.

Through vectors

Organisms that carry disease from one person to another (when bugs suck on blood, fleas on rats)

Malaria, sleeping sickness, bubonic plague

We have no natural defences to stop insects from sucking our blood.

Off spec:! - Bacteria: syphilis, chlamydia, gonorrhoea, strep throat, tetanus, tuberculosis, salmonella, dysentery, cholera, bubonic plague, conjunctivitis ! - Viruses: HIV, influenza, conjunctivitis ! - Other parasites: malaria, sleeping sickness!

THE SPECIFIC RESPONSE: B Lymphocytes (B cells)

T Lymphocytes (T cells)

● Arise from stem cells in bone marrow

● Arises from stem cells in bone marrow

● Matures in bone marrow

● Matures in thymus glands

● Produces antibodies

● Doesn't produce antibodies

● Responds to foreign material outside body cells including bacteria and viruses

● Responds to foreign material inside body cells, such as those altered by viruses/cancer. Also responds to transplanted tissues

CELL MEDIATED IMMUNITY: Involves antigens presented on body cells and not merely antigens in body fluids. T cells respond to body cells that have been invaded by non self material. This is because of an antigen presentation. Infected body cells, phagocytes and even cancer cells can express antigens (from a pathogen) on its outer membrane surface. ! 1. Antigen presentation! Macrophages (large phagocytic white blood cells) take in pathogens by phagocytosis. Antigens from the destroyed pathogen are displayed on the surface of the cell bound to a membrane protein, MHC.! 2. Activation of helper T cells (TH)! Helper T cells have receptors (complimentary in shape) that bind to presented antigens. This activates the helper T cell which undergoes mitosis to produce a clone of T cells. This has a number of consequences:! A) Stimulates further phagocytosis ! B) Production of cytotoxic T cells (TC) which produce the protein perforin, which perforates cells, allowing uncontrolled movement of substances in and out! C) Production of memory T cells which remain in blood and tissue fluid, ready to respond to future infection! The other main effect is B cell activation.!

B CELLS AND ANTIBODY PRODUCTION: Gives rise to what we call humoral immunity. B cells with antibodies on their outer surface are already present in blood. When an antigen with a specific complimentary shape to the antibody is present, the two attach to one another and the antigen is taken into the cell via endocytosis.!

3. Antigen presentation and activation of B cells! B cells process the antigen and present them on their outer surface. TH cells bind to the antigen activating the B cell.!

Signal

4. Production of plasma and memory cells! The activated B cell divides by mitosis to form a clone of plasma B cells. This process is called clonal selection. These only survive a few days but produce large amounts of antibodies specific to the invading pathogen. (Primary immune response)! Memory cells are produced that remain after infection and provide long term immunity. They circulate in blood and tissue fluid and divide rapidly into plasma cells to produce antibodies when pathogen next encountered. (Secondary immune response)! !

Antibody Definition: A protein produced by lymphocytes in the presence if a specific antigen. Also known as immunoglobulin (Ig).! Structure: !

Antibody Action:! They can coat virus particles, preventing them from entering host cells. They can clump pathogens (notably bacterial cells) together, and this is called agglutination. This makes it easier for phagocytes to locate, recognise and destroy pathogens. They neutralise toxins produced by bacteria.!

Uses of monoclonal Abs:! Targeting medication to specific cell types by attaching a therapeutic drug to an Ab:! Monoclonal antibodies (mAb) can target specific substances and specific cells as Abs are specific to an antigen, ie, cancer. ! ● mAbs are produced that are specific to antigens on cancer cells! ● They are given to a patient and attach themselves to the receptors on their cancer cells! ● They attach to the surface of their cancer cells and block the chemical signals that stimulate their uncontrolled growth, ie, herceptin (breast cancer) - direct mAb therapy (most successful), the Abs aren’t toxic and highly specific so fewer side effects.! Indirect mAb therapy involved attaching a radioactive/cytoxic drug (kills cells) to the mAb, so when attached to cancer cells, they die. mAbs used in this way are called magic bullets - can be used in smaller doses (cheaper and reduces negative side effects).! Pregnancy testing:! A mother needs to know ASAP when she is pregnant fo ensure welfare of baby and herself. The use of testing kits that can be used at home easily - early detection of pregnancy. Kits rely in the fact that the placenta produces the hormone ‘human chorionic gonadotropin (hCG) which in found in mother’s urine. mAbs present on the test strip of the home pregnancy testing kit are linked to coloured particles.! If hCG is present in urine, it binds to these Abs. The hCG Ab colour complex moves along the strip until it is trapped by a different type of Ab creating a coloured line.! Medical diagnosis:! mAbs are an invaluable tool in diagnosing disease with over 100 different diagnostic products based on them - used for diagnosis of influenza, hepatitis, chlamydia infections - produce much more rapid result than conventional diagnosis methods. They are important in diagnosing certain cancers, ie: men with prostrate cancer produce more of ‘prostrate specific antigen’ (PSA) which leads to unusually high levels of it in the blood. ! By using a mAb that interacts with this antigen, it is possible to obtain a measure of the level of PSA in a sample of blood. A high level gives an early warning and need for further tests.! Ethical uses of mAbs:! Development of mAbs = society power and opportunity to treat diseases = responsibility. ! ● Production of mAbs = use of mice to produce Abs and tumour cells. Deliberately inducing cancer in mice- there are guidelines to minimise suffering but it is still unethical.! ● There have been some deaths in their use as treatment of multiple sclerosis- patients need full knowledge of risks and benefits before agreeing (informed consent).! ● Conduct of drug trails - march 2006- 6 healthy volunteers in trial of a new mAb (TGN1412) in London within minutes, they had multiple organ failure (all survived).! ● Due to T cells overproducing chemicals that stimulate an immune response/attacking body tissues.! We need to take these issues into account so we can make informed decisions about the ethical uses of mAb drugs.!

Immunity + Vaccines:! = a vaccine is the administration of a weak/dead pathogen.! Vaccines may be given orally or by injection and comprise of:! - Weakened sample (lower virulence, less harmful)! - Dead sample! - Subunit of the microorganism ! - Product of the microorganism (ie, toxin)! Types of immunity: Active: ie, skin contract, droplets (sneezing), body fluids.! Immunity acquired when the body actively makes a response to a pathogen/antigen, by producing T & B lymphocytes and antibodies. Slower but long lasting immunity.! Passive: ie, mother’s breast milk! Immunity acquired from antibodies provided by an external source. No memory cells produced = short lasting but immediate.! Natural: Naturally acquired immunity, obtained through usual circumstances.!

Artificial: Received by external means/induced immune response that is asymptomatic. ! Herd Immunity: When a sufficiently large proportion of the population has been vaccinated against one single pathogen, it becomes difficult to spread because:! ● It is not probable that you will meet an injected person! ● Transmission is interrupted ! ● Those who are not immune are protected!

VACCINATION PROGRAMMES: Successful

Unsuccessful

● Must be a few side effects otherwise people will be discouraged from it.! ● Need to be able to produce, store and transport the vaccine - involves technologically advanced equipment, hygienic conditions and refrigerated transport.! ● Must be able to administer the vaccine properly at the right time - involves training staff to have the skills.! ● Must be possible to vaccinate the vast majority of the vast population to get herd immunity.! ● You need a large quantity of the vaccine so that 95% of the population can be vaccinated.! ● Must be economically available.

● Individuals may develop the disease in the time it takes for the vaccine to be effective.! ● Pathogens are able to hide from the immune system (ie, inside body cells).! ● Objections on the ground of medical, religious or ethical reasons.! ● Antigenic variability: spontaneous mutations of the pathogen may result in different antigens being produced, which goes unrecognised by the immune system.! ● Too many varieties of a single pathogen to produce an effective vaccine.! ● Unable to induce immunity in certain individuals (ie, those with defective immune systems).

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HUMAN IMMUNODEFICIENCY VIRUS (HIV): ELISA test for HIV: ! (Enzyme linked immunosorbant assay)! HIV antigens are attached to the surface of a plate, and a sample from a patient is poured over it. Should that sample contain antibodies against HIV (those being tested for), those Abs and antigens would bind together. A second Ab linked to an enzyme is added, which binds to HIV Ab. Substrate is added, and is broken down by the enzyme, causing a colour change (only is all molecules have attached).!

HIV Infection: !

HIV REPLICATION: 1. Following infection, HIV enters the bloodstream and circulates around the body.! 2. A protein on the HIV binds to the CD4 protein, most commonly found on Helper T cells.! 3. The protein capsid fuses with the cell surface membrane of the T cell and the viral RNA and enzymes are injected into the host (T cell).! 4. HIV then uses reverse transcriptase enzyme to convert the virus’ RNA into viral DNA. Viruses that convert RNA into DNA like this, belong to a group called retroviruses.! 5. The newly formed viral DNA is inserted into the T cell nucleus, where it becomes incorporated into its own genetic material.! 6. HIV DNA is used in transcription in the nucleus, where messenger RNA is created, which has the instructions to make new viral proteins/enzymes/nucleic acid...! 7. Messenger RNA (mRNA) exits the nucleus via a nuclear pore, and complete protein synthesis at ribosomes to make new HIV particles.! 8. HIV particles break away from the Helper T cells, with a piece of cell surface membrane surrounding them - this forms the lipid envelope as new viruses form.! 9. The person is now said the br HIV positive. HIV replication however goes into dormancy and only recommences leading to AIDS much later.!...