Host Defence: long but easy to understand.

Discussion in 'Fibromyalgia Main Forum' started by tansy, Aug 6, 2005.

  1. tansy

    tansy New Member

    Host Defence

    I Nonspecific Versus Specific Host Defenses

    II Sites of Infection and Nonspecific Defenses

    1. Body Surface - Skin

    2. Respiratory and Digestive Tracts &emdash; Mucous Membranes



    III Phagocytosis

    1. Kinds of Phagocytic Cells

    2. The Process of Phagocytosis



    IV Blood and Lymph

    1. Blood System

    2. White Blood Cells

    3. Lymphatic System



    V Inflammation and Fever

    1. Definition and Characteristics of Inflammation

    2. The Acute Inflammatory Process

    3. Repair and Regeneration

    4. Chronic Inflammation

    5. Fever



    VI Molecular Defenses &emdash; Interferon & Complement

    1. Interferon

    2. The Complement System



    --------------------------------------------------------------------------------
    I. Nonspecific Versus Specific Host Defenses

    There are two main kinds of defenses against pathogens &emdash; nonspecific and specific (i.e. the immune system). Nonspecific defense acts in a general way against all invading microorganisms. In contrast, the immune system is designed to recognize and remember specific microorganisms (see notes on Immunity, Chapters 15-17).

    Nonspecific defense works in two ways:

    a) To keep the pathogen out

    b) Destroying the pathogen or hindering its progress inside the body

    Nonspecific Barriers to Entry:

    Anatomical barriers such as skin & mucous membranes

    Antimicrobial substances such as saliva and mucus

    Nonspecific Internal Mechanisms:

    Cellular defenses

    Inflammation and Fever

    Molecular defenses (Interferon and Complement)



    II Sites of Infection and Nonspecific Defenses



    1. Body Surface - Skin

    Skin is reasonably tough and acts as a good mechanical barrier. Consists of three layers: epidermis, dermis and subcutaneous layer. Skin is fairly dry and has a moderately low pH (3 to 5) because of the secretions of sebaceous and sweat glands. However these secretions also provide salt and nutrients that allow growth of some microorganisms.

    Defensins are peptides made by animals that are secreted onto the surface of the skin. They kill bacteria by making holes in their cell membranes.

    Anything that grows on skin must be able to survive an acid pH (3 to 5) and tolerate fairly dry conditions with an occasional salty bath. It must also compete with the normal flora. The most common skin infections are due to fungi because they do okay in such conditions. However, they usually don't compete well with normal flora.

    Some bacterial infections begin with a break in the skin &emdash; a cut, wound, or burn. Bacterial infections can also begin by invasion of a sebaceous gland or hair follicle.

    The surface of the eye is the cornea, a tough protective layer. Eyelashes and eyelids keep things from getting into the eye. Tears wash the eye and contain lysozyme, an enzyme that dissolves bacterial cell walls.



    2. Respiratory and Digestive Tracts &emdash; Mucous Membranes

    Outer layer of respiratory tract is made of mucous membranes rather than skin. Mucus is secreted by these membranes and traps microorganisms and dust particles. The mucus plus trapped particles is then swept out by cilia. Nasal hairs also filter out some particles. Mucus also contains lysozyme.

    Ideally microorganisms should be kept out of the lower respiratory system. However, sometimes they do get into the lungs etc. When that happens, phagocytes (see below) help defend against infection.

    The respiratory tract is one of the areas most frequently infected. We are inhaling particles all the time and some carry infectious agents. It is moist and warm in the respiratory tract and provides a good environment for a number of bacteria and viruses.

    Outer layer of digestive tract is mucous membranes as for respiratory tract. The digestive tract is also infected quite frequently. Saliva constantly washes microorganisms out of the mouth and contains lysozyme. The stomach is highly acidic and forms a barrier that kills most microorganisms before they reach the intestines. Helicobacter pylori can live in the stomach despite the acid and is now recognized as a causative agent of ulcers.

    The lower part of the intestinal tract is inhabited by a large population of bacteria including E. coli, many anaerobes and some other organisms.



    III Phagocytosis

    Phagocytosis is the process in which an animal cell swallows a particle. Phagocytes are cells that eat. Their function is to swallow and destroy invading microorganisms.



    1. Kinds of Phagocytic Cells

    Neutrophils are the most important phagocytes. They originate in the bone marrow and enter the bloodstream. They only live a couple of days. Humans contain around 50,000 million neutrophils. They usually arrive at site of infection first. Eosinophils are probably also phagocytic.

    Monocytes may stay fixed in places like lymph nodes or other tissues or go out into the bloodstream where they develop into macrophages ("big eaters"). These are very important as phagocytes. They arrive later than the neutrophils but are bigger, last longer, and consume the remains of neutrophils that died in the earlier stages of defense.

    If there are enough microorganisms some will escape. Worse, some microorganisms can be engulfed but not destroyed. Mycobacterium tuberculosis and Mycobacterium leprae can both survive inside macrophages. Mycobacteria are covered with an extra waxy layer (wax D and mycolic acids) that cannot be digested by the bodies enzymes. Also, so can Shigella (dysentery). Francisella tulerensis (tularemia) and Brucella spp. (brucellosis) can remain dormant in a phagocyte for months or years.

    The Rickettsias are obligate intracellular parasites that cause typhus and Rocky Mountain spotted fever etc. Therefore they must grow inside cells and can grow inside macrophages as can some chlamydias and viruses (herpes, poxviruses).



    2. The Process of Phagocytosis

    There are four stages to phagocytosis: Chemotaxis, Adherence, Ingestion and Digestion.

    Chemotaxis = movement of cells in response to a chemical.

    Taxis refers to movement. When there is tissue damage, the tissues release chemicals which attract macrophages. Also many microorganisms release chemicals that are attractants, too.

    Adherence - after reaching the microorganism the phagocyte attaches to its surface. Some encapsulated organisms escape phagocytosis at this point (e.g. S. pneumoniae and Hemophilus influenzae type b). In fact adherence works much better if the microorganism is coated with antibodies, a process called opsonization (see chapters on immune system).

    Ingestion &emdash; after adherence, the phagocyte sends out projections, like arms, that surround the microorganism. Then the cell membrane bulges inwards and forms a vacuole surrounding the microorganism. This is the phagosome.

    Digestion involves lysosomes. These are another kind of vesicle, which contain digestive enzymes. The two vesicles merge together forming the phagolysosome. Bacteria are killed in about 10 to 30 minutes. They are killed by the enzymes from the lysosome and also by hydrogen peroxide, nitric oxide and hypochlorite made by the phagocyte.

    The digestive enzymes from the lysosome include lysozyme, which breaks down peptidoglycan in the bacterial cell walls, and other enzymes which break down proteins, carbohydrates, lipids and nucleic acids.



    IV Blood and Lymph

    Fluid circulates between the bloodstream, the intercellular spaces ("reticuloendothelial system") and lymph. Cells of the immune system lurk in all three systems waiting for invaders.

    1. The Blood System

    Blood consists of cells plus plasma. Serum is almost the same as plasma, it is the liquid left after blood has clotted. Plasma contains nutrients, dissolved gasses, waste products (urea) and inorganic salts as well as proteins.

    Serum/plasma contains many proteins, especially:

    Albumin

    Globulin is mostly a mixture of different antibody molecules.

    Fibrinogen is used in blood clotting by converting it into fibrin.

    Hormones (some hormones are proteins) carrying signals around the body.

    Hematopoiesis refers to the production of blood cells. These are made in the bone marrow. Blood cells don’t live very long and have to be constantly replaced. Stem cells are precursor cells that have not differentiated. The stem cells replicate in the bone marrow and some of them then turn into the various specialized blood cells. Once they start down the path of specialization they can no longer carry on dividing.

    Blood cells include:

    Red cells (erythrocytes) carry oxygen and carbon dioxide

    Platelets (thrombocytes) are involved in blood clotting, they are derived from the break-up of megakaryocytes.

    White cells (leukocytes) &emdash; a complicated mixture of cells involved in both general defense and specific immunity.

    2. White Blood Cells

    Leukocytes = White blood cells &emdash; three groups:

    Granulocytes (neutrophils, eosinophils and basophils)
    Monocytes (and macrophages)

    Lymphocytes (B cells, T cells and NK cells)

    Neutrophils are found in blood and are the main type of cell involved in swallowing bacteria by phagocytosis.

    Eosinophils attack larger parasites such as worms or fungus, which are too big for phagocytosis. Instead the eosinophils secrete enzymes to break up and digest the worm.

    Basophils &emdash; inflammation and allergies.

    Monocytes &emdash; leave the blood and mature into macrophages in the other tissues of the body.

    Macrophages &emdash; the largest phagocytes.

    B cells and T cells are the main cells of the immune system - see later lectures. B cells make antibodies and T cells perform various roles in cell based immunity.

    Natural killer cells (NK cells) destroy other cells of the body that have become infected with viruses.

    3. The Lymphatic System

    Lymphatic system consists of vessels, nodes and other tissues (bone marrow, thymus, spleen). Three main functions:

    1. Collects excess fluid from tissues &emdash; returns it to bloodstream

    2. Carries digested fats from intestine to the bloodstream.

    3. Origin of white blood cells and other immune cells. Lymphatic fluid contains lymphocytes, leucocytes, neutrophils, macrophages etc. but no red cells.

    Lymph nodes are found in the neck, armpits, groin. They filter out intruders and contain large numbers of white cells. Sometimes the system gets overwhelmed and the microorganisms collected in the lymph nodes start to multiply there. The lymph nodes then become swollen and tender - sore glands.

    Thymus and spleen are important in development of the immune system &emdash; later chapters. Stem cells in bone marrow give rise to all kinds of blood cells (red and white).



    V Inflammation and Fever

    1. Definition and Characteristics of Inflammation

    Inflammation is a response to tissue damage (including cuts, abrasions, burns, electrical burns, sunburn, radiation damage, chemical damage, and allergies). Characteristics are pain, redness, heat and swelling. First there is an injury of some kind, later you notice that it is red and swollen and the surrounding area gets warm and hurts. Usually it just goes away. If it gets worse and spreads this means possible infection.

    "Cardinal signs" of inflammation: rubor (redness), calor (heat), tumor (swelling), dolor (pain).

    2. The Acute Inflammatory Process

    Acute = short term. This is an important nonspecific defense and is stimulated by the presence of invading microorganisms and almost any kind of tissue damage.

    Three functions:

    Kill invading microbes

    Clear away debris and fragments of dead cells etc

    Repair damaged tissue

    Order of Events:

    First there is a brief constriction of the blood vessels.

    Then histamine is released by mast cells and basophils.

    Histamine causes the blood vessels in the area to dilate and become more permeable.

    Dilation causes more blood flow to the area, which accounts for the redness and heat. This brings in oxygen and nutrients to the damaged tissues.

    Increased permeability allows fluid from the blood to move out into the tissues, which accounts for the swelling (edema).

    Increased blood flow also brings in blood cells, especially white blood cells that are phagocytic and defend against invading microorganisms. Increased permeability of the blood vessels allows these cells to move out into the tissues.

    Macrophages arrive and release cytokinins to attract other phagocytes.

    Tumor necrosis factor alpha (TNFa) is released and causes more dilation and edema.

    Blood clotting factors etc are brought in by blood flow and blood clots form if necessary.

    Bradykinin (small peptide) is released and causes pain which is intensified by prostaglandins (regulatory molecules). It is believed that pain protects the area from further damage because it hurts to put pressure on it. Aspirin works by blocking prostaglandin synthesis.

    Note: Histamine is responsible for hay fever symptoms (red watery eyes, runny nose) and difficulty breathing of some allergies. Anti-histamines block histamine action by preventing it from binding to its receptors.

    Dead phagocytes and bacterial cells and damaged tissue cells and lymph accumulate and form pus. Some bacteria greatly stimulate the formation of pus because they kill phagocytes (by leukocidins) and it therefore takes longer to deal with them. These are known as pyogenic bacteria and include many cocci e.g. Streptococcus, Staphylococcus, gonococcus, meningococcus).

    If enough tissue damage happens to form a cavity filled by pus, this is called an abscess (includes boils and pimples).

    Inflammation usually helps but sometimes things go wrong:

    1) The system can be overwhelmed if the bacteria multiply at the site and spread. This gives a real infection.

    2) Sometimes inflammation itself causes damage.

    Inflammation due to infections in the brain may cause swelling and may injure the brain. E.g. cryptococcosis or meningitis.

    Sometimes live organisms can survive and multiply in a walled off abscess where they are protected from phagocytes.

    3. Repair and Regeneration

    Capillaries grow into the damaged area. Fibroblasts (connective tissue cells) replace the damaged tissue. In the best case, pus is cleared away, cells are replaced and the area returns to normal. If damage was extensive, there may be a scar left. Although not so elastic, it provides a protective patch and function can usually return to normal.

    Healing is faster in younger people, when there is good nutrition, and good circulation of the blood. Some medical conditions make healing more difficult, for example, diabetes.

    4. Chronic Inflammation

    Chronic inflammation occurs when neither host or invader gains a decisive victory. This happens when the phagocytes are unable to clear away the bacteria or other foreign substances adequately. So all kinds of cells, living and dead, accumulate at the site and finally form a clump or mass called a granuloma. Some organisms are especially likely to cause granulomas - M. leprae, M. tuberculosis, Treponema pallidum (syphilis). These even have special names; gumma (syphilis), leproma (leprosy) and tubercle (tuberculosis).

    5. Fever

    Fever = an elevated body temperature. Normal body temperature is 37o C or 98.6o F, although of course there is a natural range of maybe plus or minus about a degree Fahrenheit or half a degree Celsius.

    Not so long ago fever was regarde as bad. It is now recognized that an increase in body temperature speeds up phagocytosis and immune responses such as antibody synthesis, T cell activity and interferon action. Sometimes it inhibits the multiplication of bacteria or viruses [polio, cold viruses, herpes zoster, some fungi, Mycobacterium, Treponema pallidum]. Fever also causes macrophages to stop releasing iron, which bacteria need for growth.

    Artificial induction of fever has even been used to combat some fungal infections and some tumors, because some cancer cells are heat sensitive.

    Fever is caused by some endotoxins, some exotoxins, some viruses, also some substances secreted by host cells in response to invasion. Any substance that causes a fever is called a pyrogen.

    Is fever always good? Not if it gets too high (a temperature over about 40o is a cause for concern). Also, for some individuals with other medical problems, such as a heart problem, the increased metabolic activity that comes with fever may be dangerous.

    Obviously pyrogens taken accidentally in blood products, vaccines etc don't help at all. There is no point in having a fever for nothing. So some substances are labeled "non-pyrogenic" to indicate that there is nothing in the product that will cause a fever.



    VI Molecular Defenses - Interferon and Complement

    1. Interferon

    Interferons are small proteins that act as antiviral agents. Interferon itself does not have antiviral activity but it stimulates molecules that do. Because interferons are regulatory protein molecules, they vary from one species of animal to another. Human interferon will not protect chickens and vice versa.

    On the other hand, once interferons are produced, in response to infection by one kind of virus, they protect against viruses in general.

    Humans have three types of interferon: alpha, beta and gamma:

    Alpha-interferon (INFa) &emdash; made by leukocytes. Family of 20 or so subtypes.

    Beta-interferon (INFb) &emdash; made by fibroblasts.

    INFa and INFb are both induced by viruses. Interferons INFa and INFb are both secreted by infected cells. They stimulate neighboring cells to make anti-viral proteins. The result is that the infected cell is surrounded by cells that are resistant to virus infection. This limits spread of the infection.

    Anti-viral proteins work best against RNA viruses. This is because all RNA viruses must pass through a stage with double stranded RNA (dsRNA). RNA is normally single stranded and dsRNA is not found in normal cells. The dsRNA is a target for some of the anti-viral proteins. Other anti-viral proteins destroy virus mRNA and/or prevent its translation. Anti-viral proteins are made within 48 hours of infection - faster than antibodies.

    Gamma interferon &emdash; made by lymphocytes. Induced by viruses and other foreign antigens. Activates killing of infected cells and cancer cells.

    INFg is secreted by non-infected T cells and NK cells after detection of viruses, bacteria or tumor cells. It enhances the action of lymphocytes and macrophages in attacking infections and tumors.

    Greatest production of interferon happens with viruses that are not very virulent. Highly virulent viruses seem to kill cells before they can produce much interferon.

    Interferon is of less clinical value than originally hoped. Interferon is used for some severe virus infections and cancers, e.g. hairy cell leukemia or hepatitis C infection. However, patients usually relapse when treatment is stopped.

    Interferon is manufactured by genetic engineering &emdash; the human interferon genes are expressed in bacteria which then produce large amounts of interferon protein. Interferon is not very stable and must be given several times a week.

    Some viruses (e.g. adenoviruses) are resistant to the effects of interferon. Others (e.g. hepatitis B) avoid inducing interferon synthesis during infection.

    There are also toxic side effects when large, clinically effective doses are given. Toxic to kidneys, liver, heart and bone marrow.



    2. The Complement System

    Complement is a set of over 20 proteins that attack invading bacteria and also stimulate the immune system. These proteins are made in the liver and circulate in the blood in inactive forms. Although it may be activated by the immune system, complement is non-specific. It reacts the same way irrespective of which microorganism is invading the body. Complement attacks invaders long before the more specific immune system is mobilized.

    Functions:

    a) Stimulates phagocytosis.

    b) Directly destroys bacteria and enveloped viruses by punching holes in their membranes.

    c) Produces peptide fragments that act as signals to promote inflammation and the immune response.

    The complement system works by a cascade mechanism - when the first protein is activated, it activates the next, which activates the next, etc.

    Two main routes for complement activation exist. Both activate C3 which then activates other complement components (C5, C6, C7, C8, C9).

    The "classic pathway" is started by an antigen-antibody reaction. This triggers C1, which activates C4 which activates C2 which activates C3. For this to work, you must already have antibodies to the infectious agent.

    The alternative or properdin pathway does not require antibodies. Factor B activates factor D which activates factor P (= properdin) which activates C3. This scheme is triggered by proteins and polysaccharides that are characteristic of bacteria in general. So this pathway will act first, before the "classic pathway".

    Activation of complement components splits some of the C proteins into two halves, a and b (e.g. C3a and C3b).

    C4a, C3a and C5a promote inflammation.

    C3b promotes opsonization &emdash; the swallowing of bacteria coated with antibodies by macrophages.

    C5b plus C6, C7, C8, and C9 form a membrane attack complex that destroys bacterial membranes.

    Inherited defects may occur in various components of the complement system. These cause greater susceptibility towards bacterial infections. Complement is less important against viruses.

    Source - College of Science, Southern Illinois University


    [This Message was Edited on 08/06/2005]
  2. victoria

    victoria New Member

    Thanks Tansy, looks like a good reference!

    best,
    Victoria
  3. Rosiebud

    Rosiebud New Member

    I'm putting my name down so this will be added to my profile and I can read it when my brain is a bit clearer.

    love
    Rosie
  4. Tantallon

    Tantallon New Member

    Anything to understand the working of the body better is a bonus. Many thanks for posting it.
    Sue.