2.2.

2 Health & Disease (Immunity)

Learning Objectives

Immune response, antigen, & antibody definitions Primary defences; Phagocytes & phagocytosis Structure of antibodies & mode of action T and B lymphocytes Cell signalling & memory cells Primary and secondary immune response Active. Passive, natural, and artificial immunity Vaccination in the control of disease Influenza antigenic shift challenges Sources of medicines microorganisms and plants biodiversity
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Many pathogens cannot cause disease due to non-specific barriers (physical, chemical) and cellular defences, that prevent them from entering the body. If they do enter, the immune system (the specific immune response) can prevent them from spreading through the body Body has three lines of defence against pathogens:

1st

Barriers preventing entry - non-specific

Physical Skin physical barrier (keratinised) impermeable Mucociliary escalator airways (mucus and cilia) Reflexes - sneezing; coughing; blinking Sebum antibacterial fatty acids (acidic) pH 5.4 Tears lysozyme destroys bacterial cell wall HCl acid gastric juice; lactic acid - vagina

Chemical

2nd

Non-specific responses Inflammatory response phagocytes and chemicals Phagocytosis phagocytes (+ intracellular chemicals) Blood clotting (haemostasis) Specific response (specific for pathogen or toxin) Immune response active and passive immunity T and B cells (lymphocytes WBCs)

3rd

Immune Response

Non-specific (innate / natural)

Response is always of similar magnitude Does not discriminate No memory of encountered Ag (foreign agent)

Specific (adaptive / acquired) Specific for particular initiating Ag Adaptive mechanism of eradication dependent on nature of Ag (bloodborne by antibodies; intracellular e.g. viruses by specific effector cells) Eradicate Ag rapidly and effectively Immunological memory to future infection to prevent re-infection

If innate is breached adaptive immune system responds

1st Line of defence Skin Dry; composed of dead cells containing keratin (protein) keratin cannot be digested easily protective barrier to pathogens; outer layer of cells are shed taking bacteria with them. Microbes can only penetrate when surface is broken; shedding of skin Sebum (sebaceous glands) contains long chain fatty acids lowers pH (acidic- pH 5.4) inhibits growth of microorganisms and viruses Sweat (sweat glands) contains lysozyme digests cell wall of bacteria Tears lysozyme and washing action Gut Saliva lysozyme; amylase HCL acid in stomach destroys ingested bacteria Mechanical flushing due to movement of contents and fibre

Respiratory tract Mucus (goblet cells) traps particle and microorganisms Cilia sweeps mucus towards throat
Urinary/Reproductive tract Semen (male) spermine antibacterial Vagina mucus membrane - acidic (lactic acid) Urethra acidic (due to acidic urine); washing action of urine

2nd Line of Defence

Non specific responses Inflammatory response Phagocytosis Blood clotting

Phagocytosis flow chart

Phagocytes originate from bone marrow / foetal liver

Pathogen recognised as foreign pathogen is antigenic; chemotaxis Pathogen attached to phagocyte by antibody and surface receptors Engulfed by phagocyte by endocytosis invagination of plasma cell membrane to form a phagosome (a membrane bound vesicle containing the pathogen) Lysosomes (containing lysins & hydrolytic enzymes) fuse to phagosome Release of H2O2, HCl, free radicals into phagosome Digest pathogen harmless products removed (egested / excreted) or used by phagocyte Phagocyte also displays antigenic components on external surface of plasma cell 5 membrane (antigen presentation) to start immune response

3rd Line of Defence Immune Response (Specific) Immune Response Bodys reaction to a foreign antigen or pathogen Antigen Substances capable of eliciting the immune response (production of antibodies which are usually proteins termed immunoglobulins). Any agent (foreign) to which an Ab can bind Antibody Immunoglobulin (proteins) produced in response to antigen during the immune response Agglutinate (clump) pathogens (antigens) for easier phagocytosis Coat pathogen to attract other chemicals (termed complement proteins), that destroy the pathogen Neutralize toxins Five classes IgA; IgD; IgM; IgE; IgA Fulfil a specific role within days after encountering Ag Hb long term evolution to fulfill role
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Immunity

Active Exposure to Ag Ag (pathogen) invades body Lag phase before protection develops Long-term protection Memory cells produced

Passive Ab mediated No immune response Abs not made - come from other source No exposure to Ag Immediate protection Short-term protection No memory cells produced

Natural Infection

Artificial Vaccination

Natural Transfer of maternal Abs to foetus/baby via milk or through placenta

Artificial Administration of pre-formed Abs Tetanus injection Rabies injections Anti-venom Abs

art; pas art; act nat ; act art; act nat; pas

Active Immunity Exposure to Ag Natural (infection) or artificial (administered) Involves memory Long -lived Lag phase in primary (1o) response Ag presentation (phagocyte) Clonal selection & expansion (mitosis) Involvement of T helper cells (release of cytokines) B cell differentiation and growth into plasma cells (large cells; increased cytoplasm) Ab synthesis & release from plasma cells

Passive Immunity Ab mediated Natural (via milk; placental transfer) or artificial (administered) No exposure to Ag No immune response Abs not made -come from other source Immediate protection - high concentration of Ab immediately after injection and then falls Short-term protection No memory cells produced Advantages Immediate protection Ag / toxin neutralized / inhibited Few or no symptoms

Secondary response (2o) Immunological memory memory cells produced in clonal expansion in primary response remain in blood / lymph Rapid response + larger production of Ab in 2o than 1o

White blood cells (Leucocytes) 1%

RBCs 45%

Defence against - parasites

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Cytokines

Cytokines stimulate B cells to divide and differentiate into plasma cells and memory cells

Secrete cytokines

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Antibody Concentration Primary and Secondary Response

Primary Response
1. Infection (Ag) 2. Lag phase 3 4 5 6 Antibodies produced Antibody level rises to combat infection Ag dealt with Ab level declines short lived

Secondary Response
After the primary response, Abs do not stay in blood the level declines If the body is infected by the same Ag a second time Abs must be made again Re-infection causes much more rapid and a stronger immune response concentration of Abs rises sooner- reaches a higher concentration more plasma cells than in 1o response more cells to respond to Ag; less time to produce same number of plasma cells hence, a greater [Ab] compared to 1o response; increased affinity of Ab for Ag. This is due to the presence of memory cells (made during the primary response) no need for antigen presentation and clonal selection

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Long-lived; basis of vaccination

Primary establishes immunological memory

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Lag phase antigen presentation (by macrophage /phagocyte); clonal selection (T + B lymphocytes); production of cytokines; B cell activation; clonal expansion; formation of plasma cells; protein (antibody synthesis B cells Humoral response Has Ag receptors carries Ab (receptor) on surface Complimentary to only one Ag

Clonal selection
Each B cell molecules of single type of Ab on outer surface of plasma membrane Selection and activation of appropriate B lymphocyte / B cell and T lymphocyte by APCs (macrophages)

Clonal expansion
T cells divide by mitosis to form a clone (clonal expansion) - and secrete signal molecules termed cytokines (lymphokines) which stimulate the selected B cells to divide by mitosis to form a clone (clonal expansion) B cells specialise / differentiate to form larger Ab secreting plasma cells Abs are specific / complementary to Agnitiating the response B cells and T cells also differentiate into memory cells long lived / remain in circulation provide immunological memory to provide a secondary response on subsequent exposure to the same Ag; 2o response is more rapid and stronger; produces larger 14 amount of Ab

Phagocyte (has enzymes) Partial digestion of Ag Ag still whole Antigen presenting cell (antigen presentation)
Clonal selection receptors On T cell membrane complementary to Ag Clonal expansion (T cells) divide by mitosis

Clonal expansion (B cells)

Remain in body to produce a rapid and stronger 2o response on exposure to the same Ag 15 divide to make Ab producing plasma cells

Clonal Selection
Ag selects B Cell with right Shape of recepror

Clonal Expansion
Divide by mitosis To form a clone of Plasma cells and a Clone of memory cells

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B cell Smaller Origin bone marrow + foetal liver cells Development bone marrow + foetal liver Low nucleus to cytoplasm ratio nucleus larger relative to cytoplasm

Plasma cell Larger Derived from B cell Large nucleus to cytoplasm ratio nucleus smaller relative to cytoplasm Develops extensive RER - increase in protein (antibody) synthesis; transport More ribosomes; more mitochondria (ATP for synthesis and secretion) More Golgi apparatus for secretory vesicles;adding carbohydrate (to make glycoprteins) More space for organelles Ab (protein) made by ribosomes (RER); ATP required (mitochondria)

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An antibody molecule Produced by B lymphocytes Large globular proteins Y shaped 4 polypeptide chains (held together by S-S (disulphide) bonds

Ag binding site (Fab) Variable region varies from one Ab to another due to variable amino acid sequence (primary structure) different 3o and 4o structures; different shapes antigen binding sites - ensures specificity for a particular Ag Specific shape complementary to Ag Lock and Key Bind with a specific Ag

Hinge region allows spatial flexibility to branches of the Y shaped variable region of the Ab Allows for binding to more than one Ag
Constant region (Fc) Related to class of Ab 19 Enables Ab to bind to receptors and attach to cells e.g. Phagocytes / mast cells

S-S (covalent) bonds hold polypeptide chains (H & L) together

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Mode of Action of Antibodies

Neutralisation and agglutination

-also promotes phagocytosis by the constant region attracting -phagocytes

Immobilise pathogens (bind with flagellum) Destroy bacterial cell wall (lysis) 21 Stop spread

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Cell Signalling in Immune Response

Communication between cells

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Some Th cells become memory cells

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Cell mediated immunity (CMI)

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T cells

Ag presentation by phagocytes Receptors on T cell surface complementary to Ag specificity Clonal selection Ag selects only those T cells with complementary receptors and activates them Clonal expansion - activated T cells divide by mitosis into a clone Th cells release cytokines (signalling chemicals) Stimulate B cells to divide by mitosis to form a clone of B lymphocytes (low nucleus to cytoplasm ratio) These differentiate into larger plasma cells (large nucleus to cytoplasm ratio) Secrete antibodies Tcyt kill cells with intracellular parasites Tk kill abnormal cells with markers for cancer Tsup regulate immune response Memory T cells able to differentiate rapidly into Th, Tcyt, Tk cells on stimulation with Ag

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Flow chart to represent the immune response

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Vaccination

Types of Vaccines Live live pathogens Dead killed pathogens Attenuated weakened pathogens

Toxoids toxins (made harmless)

DNA Edible vaccines

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Vaccination Inducing a specific immune response to a pathogen artificially Antigen injected or taken orally not caught Living attenuated (weak) microbes Administration of microbes that have lost the ability, either naturally (through mutation) or by treatment in the laboratory, to produce the dangerous, clinical disease e.g the cowpox virus, measles, mumps and rubella (MMR vaccine) and polio (oral) vaccine virus. Vaccination - consists of infecting a person with a living attenuated microbe which then produces a limited infection. The immune system of normal healthy people quickly kills and eliminates them from the body. The infection elicits a primary immune response that results in the production of memory cells. The host is protected from infection (disease) by the virulent, disease-producing form of the injected microbe used in the vaccine. Live vaccines produce the best immunisation because they closely imitate the real thing. Immunity lasts for life. Dead Microbes Cultures of the pathogenic microbial strains killed in such a way that they retain their ability to stimulate the body to produce an immunological response to the live form e.g. anthrax and rabies vaccine; polio (injected form); influenza

Immunity lasts several years.

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Vaccination using components of pathogens Vaccines consisting of substances isolated from the virulent strains, such as polysaccharide material or proteins components. No whole organisms, living or dead are present in these vaccines e.g. polysaccharide from pathogenic Pneumococci; hepatitis A and B; Haemophilus influenzae

Toxoid vaccines Made by treating toxins (or poisons) produced by pathogens with heat or chemicals (e.g. formalin) destroys ability to cause illness - e.g. diphtheria, tetanus, botulinum. Vaccinations by eating ( edible vaccines) Experiments are underway to deliver vaccines through common foods like potatoes and bananas. Genes that make an antigen effective against a microbe are cloned into a common food. The food is eaten by the "patient" and the cloned-antigen stimulates the immune system.
DNA Vaccines Vaccines consisting of DNA fragments that can be transformed into host tissue. Once in the host tissue, the DNA is transcribed and translated and the protein produced is seen by the specific immune system as foreign material and an immune response is induced.
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Artificial active immunity (Vaccination) Ag injected/taken orally (not caught) Vaccine Administration of Ag or attenuated/weakened/dead/similar pathogen to activate Immune system causes immune response Engulfed by phagocytes Ags presented on cell surface membrane Selection/production of active Th cells (lymphocytes) T cells divide by mitosis to form a clone Some form memory cells Secrete cytokines (lymphokines) Activate B cells B cells divide by mitosis to form a clone Majority mature into antibody secreting plasma (effector) cells Some form memory cells remain in body Allows a more rapid and stronger secondary response No symptoms of disease on vaccination Use of vaccines in eradication programmes Herd vaccination (vaccinate most/all of people) stops infection spreading within population Ring vaccination vaccinate all people around victim contains spread within ring 31 stops transmission Trace and isolate contacts; travel restrictions; make disease notifiable

Vaccination not effective in eradication of some diseases - factors Difficult to diagnose disease Not enough population vaccinated need herd immunity Poor response to vaccine Migrants bringing disease into a community Length of time vaccine remains effective (boosters) Mutation of pathogen Severity of disease affects decision to get vaccinated Concerns as to side-effects people reluctant to be vaccinated The safety of medical procedures and agents always carry a degree of risk, The live vaccines present the highest risk because it is always possible that a mutation may occur that reverts the avirulent strain to virulence or that a particular individual will be susceptible to the avirulent strain; i.e., that it will be "virulent" only for that individual. This has happened in the case of smallpox where an occasional person, usually a child, develops a severe, often fatal, disease caused by the smallpox vaccine.

Killed vaccines have had safety problems when the lethal treatment failed to kill 100% of the microbes. The problem is that if you over treat the microbe to be certain that all the organisms are dead you can destroy the immunising components and make the vaccine ineffective. So the killing treatments must balance. . 32

Successful Vaccine e.e. Smallpox Stable pathogen does not mutate one type of Ag Live vaccive more effective (c. 100%) Easy to produce; cheap; high availability Easy storage; freeze-dried; heat stable Infected people easy to identify and cooperative Easy to administer; reusable needle; no booster needed (only one inoculation) No other reservoir of infection only human host Funds Volunteers /spotters used to find new cases

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Also it is difficult to detect the one live organism present in a 1,000 liters of treated material, yet one live organism is sufficient to produce a lethal infection. The use of chemical components of pathogens also carries some risks. Some people will react violently to these substances, usually in an allergic reaction, and they can be seriously harmed or even killed as a result. The DPT vaccine combination has caused such reactions Modern vaccines are about as safe as anything in this dangerous world. Everyone who drives or is driven on the highways is in far more danger of harm than they are being vaccinated.

The UK is one of the safest countries in the world when it comes to communicable diseases, but we probably are not the safest. Diseases are always present and they do not recognise borders.
We are so intimately connected with the rest of the world today that diseases can appear from anywhere. The strawberries or lettuce you just purchased at the supermarket yesterday may have come from a country with far less sanitation than we practice, or the person you sit by on the bus may be a recent immigrant or traveller coming from another country that is carrying a disease the UK is "free" of. In these cases your only real protection is vaccination. Think about it!
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Treatment of Influenza Challenges use of science to inform decision making Influenza (flu) virus Capable of mutation Changes antigenic structure change in glycoprotein structure -antigenic shift Vaccine against one strain not effective against another strain of the influenza virus Need to develop new vaccines each year for prophylaxis Surface proteins (neuraminidase + haemagglutinin) act as antigens

Antigens change structure regularly forming new strains of the virus

Memory cells from infection from previous strain do not recognize new strains (antigens) WHO + CDC monitor emergence of new strains and collect samples

New vaccines developed (in chicken eggs) against the new strains one chosen that is most effective against the recently circulating strain
Authorities implement a programme of vaccination Bacteria mutate - antibiotic resistance (e.g. MRSA); ineffective vaccines
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Malaria vaccines Loss of immunity on leaving a malarial area No repeat infections no further exposure to Ag no booster Lose immunological memory limited life for memory cells reduced number of memory cells No secondary response No effective malarial vaccine Different strains / species of Plasmodium; different antigens due to mutation / variation More than one stage of life cycle (within human); different stages have different Ags Need a different vaccine for each strain / stage Parasite concealed in cells RBCs and hepatocytes Parasite only exposed in circulation for short time

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Sources of Medicines Many drugs obtained from or made from natural substances found in plants, animals, microorganisms (bacteria) , and fungi e.g. Streptomycin antibiotic in TB from bacteria Penicillin antibacterial from Penicillium (fungus) Quinine antimalarial Cinchona tree Insulin (hormone) antidiabetic pigs; cows Enzymes pancreatic for CF from animals Aspirin analgesic / antiinflammatory - bark of willow tree Tamoxifen anticancer Pacific Yew tree Cinnamon antidiabetic Star anise Tamiflu antiviral from shikimic acid Only a limited number of organisms investigated so far numerous others exist to be investigated Need to protect above sources of drugs by protecting the species and maintaining biodiversity Species may die and become extinct before being studied Organisms already studied could provide additional substances for use as drugs due to development of powerful new techniques for identifying, purifying, and testing compounds. Use of bacteria in genetic engineering 37

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Passive immunization is provided in the following circumstances: When people cannot synthesize antibody. When people have been exposed to a disease that they are not immune to or that is likely to cause complications When people have a disease and the effects of the toxin must be ameliorated.

Boyulinum antitoxin Diphtheria antitoxin Immune globulin (poled human antibodies) prophylaxis; immunodeficiency disorders Rabied immune globulin Tetanus immune globulin Antivenom antibodies (spiders; snakes; scorpions; ticks; caterpillars; jellyfish

Preparation Inject Ag (toxin) into animal produces antibodies antibodies harvested must conform to WHO standards prior to use

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