CELLS AND TISSUES OF THE IMMUNE SYSTEM 1.

Positive outcomes of an immune response :

• Innate immunity: protection predetermined at birth
• Acquired immunity: recovery from infection, protection from reinfection.
• Tolerance to 'self:' your immune system is trained not to react to your own cells and tissues.

Negative outcomes of an immune response

• Autoimmunity (loss of tolerance to self induced by chemicals or infection)
• Anergy (opposite of energy): a lack of responsiveness. A feature of immunodeficiencies. An example of anergy seen in HIV disease is a lack of responsiveness to "recall antigens" such as tuberculin used in the TB skin test
• Rejection: grafts and transplants recognized as non-self and attacked by the immune system
• Hypersensitivity/allergy ( an exagerrated immune response to a foreign substance)

NONSPECIFIC IMMUNE DEFENSES

The body has a variety of non-specific defenses that help resist foreign bodies and disease-causing agents (pathogens) before they enter the body. Unlike specific immune mechanisms, nonspecific defenses are not heightened upon subsequent encounters with an antigen.

Factors that can influence the overall function of the immune system include:

• Age: young infants, children and the elderly are often more susceptible to diseases.
• Race: The CKR-5 mutation associated with resistance to macrophage-tropic strains of HIV-1 subtype B appears to be more common in Caucasians.
• Gender: Kaposi's sarcoma is frequently seen in males with AIDS, yet is seen very rarely in women
• Genetic factors: sickle cell trait is a genetically inherited disorder whereby a person possesses an abnormal copy of the hemoglobin gene. Sickle cell trait is thought to have evolved as a means of natural resistence to the malaria parasite which invades red blood cells and uses hemoglobin as a nutrient source.
• Nutritional status: has a major impact on the functions of the immune system. Metabolic changes in AIDS contribute to wasting syndrome.

First line of defense: skin and mucus membranes.

Physical/Mechanical barriers

• Intact skin protects against invasion by most invaders. Three major layers of the skin are:

• Epidermis- outer layers of dead cells, waterproof inner layer with oil and sweat glands
• Dermis-structural support: has a blood supply with immune cells and nerve endings for detection of pain and heat
• Subcutaneous-fat for insulation and shock absorption
• Lacrimal (tear) glands, eyebrows, eyelids and lashes protect eyes
• Saliva: provides a natural cleansing action of teeth and gums.
• Mucus:traps microbes and particles in the respiratory tract and the gut which can be expelled by coughing or expelled in feces, respectively.
• Cilia: the sweeping action of cilia in the upper airways moves mucus and particles up toward the throat (this action inhibited by smoking which weakens defenses against chest infections).
• Alcoholics are predisposed to pneumonia. When alcoholics are "sleeping off a drunk" their epiglottis ( a flap of tissue that stops food and fluid from entering the lungs) fails to close properly. Fluids and bacteria can enter the lungs. The macrophages in the lungs of alcoholics also do not function efficiently to destroy microbes.
• Peristalsis: rhythmic movements of the gut and urinary tract prevent build up of toxic waste products and microbes.
• Reflexes such as coughing and sneezing help expel invaders. Unfortunately, they can also help transmit them to others! (Of course, HIV is not an airborne infection!).

Chemical barriers

• Sebum (oil) inhibits some pathogens
• Lysozyme: antibacterial enzyme in tears, saliva, sweat, nasal secretions. Lysozyme is not effective against viruses.
• A protein known as "SLPI" may be inhibitory to HIV in saliva
• Strong acidity of gastric juice kills most organisms passing through the stomach. The acidity of the skin, urine and vagina is also protective.
• Normal flora and their products such as lactic acid and hydrogen peroxide out-compete pathogens. Normal flora are microorganisms that are naturally present in or on our bodies. These organisms can produce substances that benefit us and do not normally cause disease. However, disruptions of normal flora can occur when the immune system is damaged or when taking certain medications which can result in opportunistic infections.

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Second line of defense

If the skin and mucus membrane barriers are penetrated another set of nonspecific mechanisms that don't "ask" the identity of the invader swing into action immediately. The second line of defense includes the following cells and mechanisms which will each be outlined in more detail below:

• Phagocytic cells
• Natural killer cells
• The inflammatory response
• The fever response
• The complement system

Phagocytic cells; "The clean up crew."

These are several types of white blood cells (WBCs) that literally "eat" particulate matter, dead cells and microbes by a process called phagocytosis. An accumulation of white cells, cell debris and microbes forms the gooey substance more popularly known as 'PUS.' The major types of phagocytic cells are:

• Neutrophils

These are the most common type of WBCs (60-70% all WBCs) that chomp up bugs. They are attracted to sites of injury, inflammation and infection and are often the first WBCs at the 'scene of a crime'. They are also short-lived; their life span is around seven hours!

Neutrophils are one of several types of WBCs called granulocytes; they carry two types of granules in their cytoplasm. Type A granules stain purple and contain enzymes such as lysozyme which help digest microbes. Type B granules stain pink and contain enzymes which help the cell move through tissue, and a substance called lactoferrin which is toxic to bacteria and fungi. Microbes are also killed by the formation of reactive oxygen compounds called free radicals within the vesicles of neutrophils.

Neutrophils attach to blood vessel walls in a process called margination. The cells then move into surrounding tissue and gobble up microbes. The granules fuse with the vesicles containing microbes and release their contents, killing both the bug and the neutrophil.

• Macrophages.

Macrophages live up to their name: they are the "big eaters" of the immune system and the most efficient phagocytes. They are a type of agranuolocyte; that is, they lack specific granules in their cytoplasm. They are about three times larger than a red blood cell. Macrophages tend to follow neutrophils to assist in a clean up. In order to clean up efficiently macrophages must be activated. Activation results from chemical factors released by lymphocytes during an immune response. Macrophages also possess receptors on their surfaces which recognize immune system proteins called antibodies. Antibodies act like a red flag and help mark microbes for destruction by macrophages. Macrophages also play a critical role in presenting antigens to lymphocytes during an immune response (See a discussion of antigen-presenting cells under the section on specific immune responses).

All macrophages are derived from monocytes which in turn arise from a common stem cell in the bone marrow. At the proper signal, monocytes leave the bloodstream and migrate through the lining of small blood vessels. In connective tissue they mature into macrophages, which typically have a lifespan of about 2 months.

Tissue (resident) macrophages are present in certain regions of the body were given specific names before it was realized that they all have a common origin, appearance and function. Resident macrophages and their locations include:

• Langerhans cells (also called Dendritic cells for their finger-like processes): skin and mucus membranes including oral cavity and vagina.
• Dust cells: lung
• Kupffer cells: Liver

Although different in appearance the following cells are also derived from monocytes:

• Microglia:brain
• Osteoclasts: bone

Macrophages are known to be early targets of HIV infection

Macrophages carry two markers on their surfaces called CD4 and CKR-5 which HIV uses to gain entry into these cells. Strains of HIV that infect macrophages are called M-tropic. One of the first cells thought to be infected by HIV is the Langerhans (dendritic) cell underneath the skin and mucus membranes where they can reach as many as 800 per mm.2 These cells are thought to be abundant in the vaginal lining which may explain in part why male-to-female transmission of HIV is so efficient. Langerhan's cells act like "string mops" picking up microbes in the skin and migrating to lymph nodes where they present antigens to lymphocytes.

• Eosinophils

These cells normally make up a small percentage of WBCs and are another type of granulocyte. Eosinophils are attracted to the site of allergic reaction, inflammation, or parasitic worm infection and tend to increase in numbers in these situations. Eosinophils also eat up complexes of antibodies and bugs.

Other WBCs involved in nonspecific immunity:

• Natural Killer cells

NK cells are a form of WBCs called a lymphocyte. They can destroy some tumor cells and virally-infected cells that have been flagged by antibodies. Unlike T lymphocytes, NK cells destroy their targets nonspecifically and do not need to be "told what to do."

NK cells release chemicals called perforins which punch a hole into the target cell. Other chemicals called fragmentins pass into the target cell and trigger apoptosis (programmed cell death). NK cells also release a chemical called gamma-interferon which activates macrophages to kill microbes.

Complement proteins

A group of at least 20 serum proteins that activate one another in sequence to destroy invaders. Complement proteins interact to form a membrane attack complex (MAC) that punch holes in the surface of invading microbes and cause the cell to rupture. A key component of the complement system is the protein C3. Deficiencies of this protein predisposes a person to recurring bacterial infections.

Inflammatory response

A nonspecific response to cell damage marked by: redness, pain, heat, swelling and sometimes loss of function.

Increased blood vessel permeability (leakiness) produces redness, heat and swelling. This is caused by chemicals released by damaged or activated cells including histamines, prostaglandins and kinins. This process allows phagocytes and blood-clotting elements called platelets to access the damaged area. Clots wall off infection and help prevent spread of microbes.

Fever response

An abnormally high body temperature in response to infection. Body temperature (normally 37 C) is regulated by the hypothalamus in the brain. When bacteria are ingested by phagocytes the latter release a chemical called interleukin 1 . IL-1 causes the hypothalamus to release prostaglandins that reset the hypothalamic thermostat at higher temperatures causing fever. Fever makes you feel sick and forces you to rest. High persistent fevers can become life-threatening.

The average adult has about 5 liters of blood (think of 2 and a half two liters bottles of coca cola if you want to compare volumes!) Blood consists of red blood cells, white blood cells and cellular fragments called platelets-suspended in a fluid component known as plasma. All blood cells arise from a common stem cell which accounts for about 0.1% of the nucleated cell population of bone marrow. The stem cells undergo numerous cell divisions and pass through several intermediate stages before becoming mature blood cells. The whole process is controlled by various growth factors which act to regulate the type of cells formed and their rate of production. Stem cells are programmed to die by apoptosis (a-pop-TOE-sis) unless they receive signals from appropriate growth factors. It may be possible to help restore the immune function of people with HIV by isolating and expanding populations of healthy bone marrow stem cells.

An adult male usually has about 5 million RBCs per mm3 of blood and females 4.5 million/mm3 . Adults possess far fewer WBCs than RBCs, usually between 6,500 and 10,000 WBCs/mm3 of blood. We are primarily concerned with the elements of the blood that function in immune defense. Cells of the immune system are white blood cells (leukocytes). The plasma also contains antibody molecules, clotting proteins and complement proteins.

The Lymphatic system

Throughout the circulatory system some plasma filters out of blood capillaries and into spaces between tissue cells. The fluid between and around tissues is called interstitial fluid. Microscopic vessels surrounding tissue cells are called lymph capillaries. Once interstitial fluid enters lymph capillaries it is known as lymph. The capillaries are also leaky and readily pick up microbes or their products. Lymph drains into larger vessels called lymphatics which contain valves that prevent backflow of fluid. Lymph containing filtered proteins and fluid, enters a duct and returns to the venous blood just before entering the right atrium of the heart. Lymph flows through various lymph nodes en route. The lymph nodes are like mini-battle grounds that attempt to block the spread of infection. Microbes are trapped by dendritic macrophages in the nodes and encounter B and T cells. These B and T cells will multiply in reponse and some will become memory cells.