THE IMMUNE SYSTEM Human phagocyte engulfing a yeast cell. Chapter 43

All animals have some form of immunity (resistance to disease). Relies on ability of animal’s immune system to identify “foreign” antigens. Antigen - any molecule that elicits an immune response (usually a carbohydrate or protein) Immunity is essential to an animal’s survival. Phagocytes of a starfish larva surround & attack an invading thorn.

Innate immunity is inborn. rapid nonspecific Adaptive immunity develops after birth. slow (first encounter) highly specific has memory (rapid response in subsequent encounters) Invertebrates possess innate immunity. Vertebrates possess innate & adaptive immunity.

A. Innate Defenses of Humans Consist of physical barriers, phagocytes, inflammation & antimicrobial proteins. 1. Physical Barriers Body’s first line of defense; prevent microbes from entering body. skin & mucus membranes antimicrobial secretions nose hairs & respiratory cilia earwax Mucus membranes line all body cavities that open to the exterior: digestive, respiratory, urinary & reproductive tracts. As long as skin & mucus membranes remain intact, they are an effective physical barrier. Skin & mucus membranes produce several antimicrobial secretions: acids - kill bacteria directly or inhibit their growth (skin & vaginal secretions are acidic; HCl in stomach) lysozyme - enzyme found in saliva & tears; kills bacteria. Mucus - traps microorganisms (respiratory mucosa); respiratory cilia move mucus out of respiratory tract.

2. Phagocytes White blood cells that engulf & digest microbes managing to penetrate the skin & mucus membranes. macrophages - large cells derived from monocytes; engulf bacteria & cellular debris. free macrophages move through tissues fixed macrophages are anchored in a particular organ. Monocyte - type of WBC found in bloodstream. Monocytes that leave the bloodstream & enter tissues enlarge and develop into macrophages. Macrophages can consume up to 100 bacteria before they die.

neutrophils - most abundant WBC; engulf bacteria & cellular debris. eosinophils - destroy parasitic worms (tapeworms, flukes, pinworms, hookworms). Dead phagocytes are a component of pus. Neutrophils live only a few days; die after consuming about 20 bacteria.

3. Inflammation Localized response to tissue injury; creates an environment hostile to microbes. Tissue injury causes release of chemical mediators (histamine, complement, etc.) that: dilate local arterioles - increases blood flow to the area causing the heat & redness associated with inflammation. increase capillary permeability - capillaries leak fluid into surrounding tissues causing the pain & swelling associated with inflammation. Leaked fluid brings oxygen, nutrients & clotting proteins into area. The clotting proteins function to wall off the area, preventing spread of infection. attract WBCs to the area. stimulate production of white blood cells. Histamine is the chemical responsible for dilating arterioles & increasing capillary permeability. Complement - enhances phagocytosis & intensifies the inflammatory response.

4. Antimicrobial Proteins Produced & released in response to microbial invasion. defensins - released by neutrophils; lyse bacteria. complement system - group of ~ 20 plasma proteins; enhance phagocytosis, intensify inflammation & lyse bacteria.  Complement system is activated when some of its proteins bind directly to surface of bacterium or to antibodies attached to the bacterial surface. Some activated complement proteins coat bacterial surfaces (enhances phagocytosis). Some stimulate histamine release (intensifies inflammation). Some  &  combine, forming a MAC (membrane attack complex) that is inserted in the bacterial membrane.  Cell contents leak out of MACs, killing the bacterial cell. MAC (membrane attack complex)

cytokines - proteins synthesized in certain activated cells; stimulate or inhibit the activity of other cells. interferons - released by virus-infected cells; protect adjacent uninfected cells from infection & activate macrophages. interleukins - stimulate WBC production. pyrogens - released by WBCs & macrophages; causes fever (resets body’s thermostat in hypothalamus).

B. Adaptive Defenses of Humans Consist of macrophages, B lymphocytes (B cells), and T lymphocytes (T cells). Interact with components of innate defenses.

Adaptive immunity distinguishes self from nonself. Molecules called the Major Histocompatibility Complex (MHC) identify a cell as “self”. Anything with something different is identified as “foreign”. Foreign invaders are vigorously attacked. The system “REMEMBERS”. Each individual develops a tremendous diversity of T cells. For example, some are programmed to respond to the chicken pox virus, while others are programmed to respond the the pneumonia bacterium. There are enough T cells to respond to any kind of antigen we would ever encounter. Some will be activated over the course of our lifetime, while others will not.

All WBCs are produced in bone marrow. Monocytes enter bloodstream, then exit & enlarge to form macrophages. Most lymphocytes enter bloodstream & travel to thymus gland (develop into T cells). In thymus, each T cell is genetically programmed to respond to one specific kind of “foreign” antigen. Each individual develops a tremendous diversity of T cells. For example, some are programmed to respond to the chicken pox virus, while others are programmed to respond the the pneumonia bacterium. There are enough T cells to respond to any kind of antigen we would ever encounter. Some will be activated over the course of our lifetime, while others will not. T cell antigen receptors

Some lymphocytes remain in bone marrow (develop into B cells). In bone marrow, each B cell is genetically programmed to respond to one specific kind of “foreign” antigen. B cell antigen receptors (antibodies) Each individual develops a tremendous diversity of B cells. For example, some are programmed to respond to the chicken pox virus, while others are programmed to respond the the pneumonia bacterium. There are enough B cells to respond to any kind of antigen we would ever encounter. Some will be activated over the course of our lifetime, while others will not. Once programmed, B & T cells migrate to lymphoid tissues.

1. Macrophages Function in adaptive immunity as antigen-presenting cells (APCs). Macrophage ingests bacterium. Displays “foreign” antigen on its MHC “self” protein. MHC - major histocompatibility complex (self antigen). “Free” foreign antigens are not recognized by helper T cells. Helper T cells are activated only if the “foreign” antigen is complexed with an MHC protein. Note: it is the MHC protein profile that is “typed” to determine compatibility in organ transplantation. Certain helper T cells recognize & bind to antigen-MHC protein complex. Activated helper-T cells secrete interleukin-2.

2. B Lymphocytes (B cells) B cells are responsible for humoral immunity (antibodies are used to fight bacteria & viruses in body fluids). B cells are activated when:  they recognize & bind to a foreign antigen, AND  are exposed to interleukin-2 Interleukin-2 is produced by helper T cells that were activated when exposed to the same antigen. Most B cells must also bind to the activated T cell to become fully activated themselves.

Interleukin-2 (from activated helper T cell) Activated B cell divides rapidly, producing clones (groups of identical cells). Most of these cells develop into plasma cells.

Plasma cells secrete antibodies that circulate in blood or lymph. Antibodies bind to the same foreign antigen that triggered their production. Each plasma cell produces ~2000 antibodies/second for 4-5 days, then dies. Polyclonal antibody response refers to the different types of antibodies that are secreted in response to the different antigens on a foreign cell’s surface. In this case, this bacterium possesses 3 different antigens that activated 3 different groups of B cells, resulting in the formation of 3 different antibodies. There are 5 major classes of antibodies - determined by location in body & function (Table 39.1). IgA, IgD, IgE, IgG, IgM (plasma cell) (plasma cell) Antibodies mark antigens for destruction by macrophages or complement.

Vaccinations produce memory B cells. Memory B cells remain dormant in body fluids; function in the secondary immune response. Primary immune response - occurs when B cells are first exposed to a particular antigen; antibody levels rise slowly & decline rapidly. Secondary immune response - occurs when memory B cells encounter the same antigen in the future; antibody levels rise rapidly & remain high for a long period. Vaccinations produce memory B cells. Person usually feels ill during a primary immune response because it takes a few days for them to produce enough antibodies to destroy the foreign antigen. However, during a secondary immune response, a person may not even be aware of the infection. Antibodies are produced rapidly enough to destroy the foreign antigen before it can exert its effect. Vaccinations trick your immune system into thinking it has been invaded by a particular antigen. Your immune system responds to this “fake” antigen by producing memory cells that will protect you against future invasions of the antigen.

3. T lymphocytes (T cells) T cells are responsible for cell-mediated immunity (T cells destroy body cells infected with bacteria & viruses). Types of T cells helper T cells (CD4 / T4 cells) activated by antigen presenting cells (macrophages or B cells displaying foreign antigens) produce cytokines (interleukins, interferons & tumor necrosis factor) Tumor necrosis factor - slows tumor growth & helps activate T cells, phagocytes & eosinophils.

Activated helper T cells activate cytotoxic T cells & B cells Activated helper T cells activate cytotoxic T cells & B cells. Thus, they are essential to both cellular & humoral immunity.

cytotoxic T cells (CD8 / T8 cells) activated by interleukin-2 bind to body cells displaying foreign antigens (virus- or bacteria-infected cells, cancer cells, transplanted or transfused cells) release perforin (causes cell lysis) Cytotoxic T cells are also known as killer T cells. These are the only T cells that can directly attack & kill other cells. Body cells displaying foreign antigens include virus-infected cells, bacteria-infected cells, cancer cells & foreign cells (introduced into body by blood transfusions or organ transplants).

C. Rh Incompatibility During Pregnancy Rh antigen is one of many “self” antigens found on the surface of red blood cells. Individuals whose RBCs possess Rh antigen are Rh+ Individuals whose RBCs do not have Rh antigen are Rh- Rh- individual produces Rh antibodies only if exposed to the Rh antigen. An Rh- individual could be exposed to Rh antigen if they were transfused accidentally with Rh+ blood (ex. A+ instead of A-).

The Rh antigen causes problems during pregnancy when an Rh- woman carries an Rh+ fetus. Woman’s first pregnancy with an Rh+ fetus usually does not present a problem. Since the maternal & fetal bloodstreams are separate, their blood does not mix, so woman is not exposed to the Rh antigen. However, during the birthing process some of the baby’s blood will enter the mother’s bloodstream. Her immune system will immediately begin producing Rh antibodies. However, the Rh antibodies have nothing to attack (the baby has already been born). When woman becomes pregnant with another Rh+ fetus, her Rh antibodies pass through the placenta & target the fetus’s RBCs for destruction. Dying fetal RBCs release bilirubin, which accumulates & damages the brain. We currently avoid this potential problem by identifying Rh- women and testing to see if they are carrying an Rh+ fetus. If this is the case, she is given an injection of RhoGAM which prevents her immune system from making Rh antibodies.

Newborns have temporary immunity (passive immunity): some antibodies (IgG) pass from mother to fetus through placenta. some antibodies (IgA) pass from mother to infant through breast milk. Newborns begin producing their own antibodies (active immunity) by 6 months. Passive immunity - individual receives antibodies produced by another individual. Active immunity - individual makes their own antibodies.

D. Immune System Malfunction 1. Immunodeficiency Disorders Result from breakdown of the immune system. HIV (human immunodeficiency virus) acquired through infection virus initially attacks helper T cells Person can acquire HIV through a blood transfusion or by having unprotected sex or sharing syringes with an infected individual. Person cannot acquire HIV from doorknobs, toilet seats, kissing, holding hands or mosquito bites.

virus subsequently attacks cytotoxic T cells & macrophages (triggers apoptosis) AIDS - acquired immune deficiency syndrome AIDS was first identified in this country in 1981 among homosexual men & intravenous drug users. Kaposi’s sarcoma - cancerlike condition of the blood vessels (appears as purple lesions on skin). Pneumocystis pneumonia - a rare type of pneumonia caused by a protozoan (Pneumocystis crinii). opportunistic infections of AIDS develop (Kaposi’s sarcoma, Pneumocystis pneumonia)

SCID (severe combined immune deficiency) inherited B & T cells are nonfunctional individuals have little or no protection against pathogens treatments include bone marrow transplant & gene therapy

2. Autoimmune Disorders Occur when the immune system attacks “self” antigens. Type I (juvenile) diabetes mellitus - antibodies target beta cells in pancreas. Rheumatoid arthritis - antibodies target cells lining joints. Myasthenia gravis - antibodies target neurotransmitter receptors on skeletal muscle cells. Grave’s disease - antibodies target thyroid gland.

3. Allergies Occur when immune system is overly sensitive & responds to a normally harmless substance (allergen). Common allergens: foods, dust mites, drugs (penicillin), pollen, fur, insect venom.

Initial exposure: allergen activates overly sensitive B cells B cells produce clone of plasma cells that release IgE antibodies IgE antibodies attach to mast cells Mast cells contain granules filled with inflammatory chemicals such as histamine & heparin.

Subsequent exposure: if allergen ever encountered again, will attach to IgE antibodies on mast cells mast cells release inflammatory chemicals (histamine) - cause allergy symptoms anaphylactic shock may occur Anaphylactic shock occurs if mast cells release inflammatory chemicals throughout the body. Most often results from an allergy to penicillin or insect stings. Injection of adrenaline is given to prevent a person in anaphylactic shock from dying.