A&C: Understanding the Immune System

Humoral Immune Response Produces 5 Types of Immunoglobulins

IgG - most abundant in the blood (75% of all immunoglobulins in plasma); crosses placental barrier and protects newborns for several months; provides most natural and acquired immunity. IgA - found in exocrine secretions (saliva, tears, breast milk, urogenital tract); protects mucosal surfaces from invasion by pathogenic bacteria and viruses. IgM - responsible for primary immune response; forms antibodies to ABO blood antigens; stimulates complement system, leading to cell-mediated immunity. IgE - attaches to mast cells and basophils; triggers the release of histamine at the site and causes symptoms of allergic reactions; provides defense against parasites; IgE levels will be ↑ in persons with allergies or parasites. ↓ levels indicate ↑d risk for respiratory infections. IgD - found on the surface of B cells and helps regulate B cell function; important in antigen recognition.

Anatomy & Physiology of the Immune System

Immune system plays a vital role in preserving health *Normally functioning immune system: 1. Provides continuous surveillance. 2. Protects body from invading organisms. 3. Maintains homeostasis. 4. Discovers and disposes of abnormal cells.

Thymus

*An organ in the mediastinum. *Peak development in childhood—then begins to atrophy. *Aids in the maintenance of T lymphocytes. *70% to 80% lymphocytes are T cells.

Circulating antibodies contribute to immunity in 3 ways: Provide Immunity in Body Fluids

*Bind to, and coat their complementary antigen, making the antigen an easier target for destruction by macrophages and other cells. *Bind to antigens and prevent them from entering or damaging other cells. *Trigger destruction of antigens by stimulating other immune responses, such as the complement pathway.

Peripheral Lymphoid Organs: Spleen

*Located in the LUQ of the abdomen beneath the diaphragm. *Gathers and isolates worn-out erythrocytes, stores blood (lymphocytes) and 20% - 30% of platelets. *Filters and removes foreign materials, worn-out cells, and cellular debris.

Central Lymphoid Organs: Bone Marrow

*Major organ of the immune system *Hematopoiesis a process that forms the bone marrow's stem cells, which are the source of all blood cells, including: -RBCs -WBCs -Platelets -Lymphocytes (B and T cells of the immune system) -B cells mature and differentiate from stem cells in the bone marrow. Immune system and blood are closely related—their cells share a common origin in the bone marrow, and the immune system uses the blood stream to transport its components.

Types of Immunity: Acquired Passive Immunity

*Natural—transfer of antibodies from another host (naturally acquired antibodies). Provide temporary protection measured in weeks to months. Example: Transplacental passive immunization with transfer of IgG antibodies from maternal circulation across placenta to fetus; or transfer through breast milk. Artificial—immunity: is induced artificially when antibodies are given to a non-immune individual. *may be necessary if an individual is exposed to a serious infection to which the person has no immunity, or the person's own immune system is impaired or deficient. Antibodies come from: *pooled and purified blood products of immune people. Example: pooled human gamma globulin. Gamma globulin is a plasma protein containing immunoglobulins....provides short-term antibody protection to the patient. These immunoglobulins are broken down after while and eliminated from the body. Since the patient's body did not create them, there is no "memory" of an exposure to trigger the production of more antibodies. Immunity is temporary and is used in treatment of clinical emergencies such as rabies exposure, tetanus, snake bite, exposure of hepatitis B. Hepatitis B immune globulin (HBIG) is given to persons exposed to Hep B virus (HBV) who have not been vaccinated; should be given within 24 hours after exposure.

Cytokines

*Proteins produced by WBCs and lymphocytes when an antigen is detected.....over 100 different types. *Interact with cells of the immune system to regulate the body's response to disease and infection—act as messengers between cells (T, B, monocytes, neutrophils) and instruct them to alter their proliferation, differentiation, secretion, or activity. So, cytokines regulate the inflammatory response, mediate immunity, and stimulate hematopoesis. Cytokines Role: Initiate chemotaxis—the movement WBCs to an area of inflammation. Chemotactic Cytokines are produced locally at the site of injury and are responsible for moving neutrophils and monocytes to the area. Mediate the normal inflammatory response and contribute to the manifestations seen with inflammation (such as fever).

Peripheral Lymphoid Organs: Accessory Organs

*Tonsils *Adenoids *Appendix *Peyer's patches Remove foreign debris in much the same manner as lymph nodes.

Functions of Complement

-Directly kills bacteria & neutralizes viruses. -Chemotaxis—attracts macrophages & neutrophils to a trouble spot. -Coats & attaches to bacteria which enhances the phagocytic action of neutrophils and macrophages. -Promotes antibody formation and enhances their effectiveness. -Helps the body eliminate immune complexes. Activated plasma complement system bridges humoral and cell-mediated immunity

Example-->Exposure to Rhinovirus

1) First time exposure, cold-like symptoms are at their peak for the first 4 - 5 days. Primary immune response takes up to10 days to produce sufficient antibodies to eliminate the virus and the symptoms that accompany it—the level of antibodies in the blood is lower with the primary immune response. IgM antibody forms, and IgG to a lesser extent. It may take 7-10 days for cold symptoms to disappear. 2) Second exposure to same virus activates memory B cells-->the production of antibodies specific to that antigen is quicker and greater with the secondary response. It occurs 1 -3 days after viral invasion and results in mild or no cold symptoms. IgG antibody has become more powerful and is responsible for secondary immune response. No symptoms if re-exposed to the same virus. IgM or IgG antibodies (immunoglobulins) react with the antigen and form an antigen-antibody complex-->this complex activates the complement system-->3rd line of defense The complement system consists of more than 30 proteins that act in a sequence: One protein activates another and so on. This sequence is called the complement cascade.

What Happens in Inflammation?

1) Inflammatory response: To an antigen involves vascular and cellular changes that eliminate dead tissue, microorganisms, toxins, and inert foreign matter. This nonspecific immune response is a normal process that facilitates tissue repair through the following steps--> A. Soon after microorganisms invade damaged tissue, there is a vascular response... with cell injury ↓ arterioles briefly undergo vasoconstriction ↓ this stimulates basophils to leave the blood and accumulate at the site of damage. These cells do not ingest foreign cells or bacteria and represent 1% or less of the total WBC Vascular Response ↓ Upon arrival, basophils release inflammatory mediators from their cytoplasmic granules: histamines, heparin, bradykinins, prostaglandins serotonin ↓ These substances promote vasodilation which ↑s blood flow to the area (hyperemia) ↓ Hyperemia ↑s filtration pressure resulting in ↑ capillary permeability ↓ Fluid, protein, and cells escape into interstitial spaces and into affected tissues = swelling ↓ Pain results from swelling which puts pressure on nerve endings-->histamine & prostaglandins also stimulate nerve endings causing pain; there may be a temporary loss of function if a limb is involved 2) Cellular Response granulocytes, predominantly Neutrophils, migrate to the invasion site--> basophils arrived earlier during vascular response— but, limited phagocytosis activity. Eosinophils now arrive and release chemical mediators to control the effects of histamine and serotonin. Eosinophils also have phagocytic properties and will ↑ in number if the inflammatory reaction is caused by allergic conditions or parasitic infections. Neutrophils (most abundant type of WBC) are the first to arrive during cellular response—usually within 6-12 hours ↓ Engulf bacteria, other foreign material, damaged cells ↓ Fever results from phagocytic release of pyrogens from bacterial cells, as well as the release of cytokines, which cause an elevation in the hypothalamic set point ↓ Neutrophils have short life span (24-48 hours), then dead neutrophils, digested bacteria, and cell debris accumulate (pus) To keep up with the demand for neutrophils, bone marrow releases more neutrophils into circulation ↓ Elevated WBC ↓ As demand for neutrophils ↑s, bone marrow cannot keep up ↓ So, bone marrow releases immature forms of neutrophils into circulation (called BANDS) Monocytes are the second type of phagocytic cells to migrate from circulating blood ↓ Attracted to site by chemotaxis and usually arrive at the site in 3-7 days ↓ Upon entering the tissue, monocytes transform into macrophages (red arrows) Macrophages recognize and phagocytize foreign material, remove old or damaged cells from circulation, clean area before healing can occur. ↓ Once digestion is complete, macrophages expel digestive debris, including lysozymes, prostaglandins, complement components, interferon-->which continue to mediate the immune response After the macrophage processes the antigen and expels the debris, it presents the antigen to antigen-specific lymphocytes-->their role is related to humoral and cell-mediated immunity.

Types of Cytokines

1) Interleukins—produced by lymphocytes and enable cells of immune system to communicate and coordinate immune response. Stimulate chemical factors that begin the inflammatory response. 2) Interferons—proteins produced by T cells when the invading organism is a virus. Enhance the activity of macrophages, NK cells, and cytotoxic T cells; attack certain tumor cells and viruses. 3) Tumor Necrosis Factor (TNF)—produced by granulocytes, lymphocytes, and other cells. Stimulates the initial inflammatory response, specifically macrophages and granulocytes. 4) Colony-Stimulating Factors (CSFs)— promote the production of WBCs. 3 main types: a) Granulocyte CSFs b) Granulocyte-macrophage CSFs c) Macrophage CSF

Abnormal Functioning of the Immune System

1. Immune hyperactivity leads to allergic states. 2. Immunodeficiency causes exaggerated vulnerability to infections (HIV). Physiologic effects can be devastating (mild cold or viruses can kill). 3. Misdirected immune response results in autoimmune disorders (lupus, rheumatoid arthritis). 4. Failure of surveillance allows uncontrolled growth of tumor cells.

Specialized Cells of the Immune System: Lymphocytes B and T cells

1. Immunocompetent B cells circulate in the blood and lymphatic system performing immune surveillance. On the surface of each B cell are receptors that enable the cells to recognize antigens. These receptors are very specialized - each match only one specific type of antigen. When B cells encounter their specific antigen, they attach to it--> When attached, B cells are stimulated to proliferate, differentiate, and mature into either plasma cells or memory B cells. However, to become fully activated, they need help from T helper cells. 2. Some T cells help regulate the complex workings of the overall immune response, while others are cytotoxic and directly contact infected cells and destroy them.

Immune System

A complex defense system of the body designed to recognize, respond to, and eliminate antigens. This system preserves the internal environment damaged cells and by performing surveillance. To perform these functions efficiently, the immune system uses--> THREE BASIC DEFENSE STRATEGIES

Cell-Mediated Immunity

A delayed response effective against virus, slow growing bacteria, fungus, transplanted cells, and cancer cells--> This type of immunity provides protection to certain infectious agents that have an intracellular habitat. Here, the antigen is presented to T cells. Cell-Mediated Immunnity does not involve antibodies or complement, but rather involves activation of T lymphocytes, NK cells, leukocytes, and proteins: 1) T Helper cells 2) T Cytotoxic cells 3) T Suppressor cells 4) Natural killer cells 5) Macrophages 6) Dendritic cells 7) Activation of cytokines During the cellular response, several processes occur: -Phagocytosis and killing of intracellular pathogens. *Direct cell killing by cytotoxic T cells. *Direct cell killing by NK cells. These responses are important for destroying intracellular bacteria, eliminating viral infections and destroying tumor cells.

3 Types of T Cells

A) T Helper cells activate many immune cells, including B cells and other T cells: Regulate humoral and cell-mediated immunity. 1. Helper T Cell 2. B Cell 3. Plasma Cell 4. Secreted Antibodies B) T Cytotoxic cells attack antigens on cell membrane of foreign pathogens, release substances that destroy the pathogen— These cells are antigen specific and can be sensitized by exposure to the antigen. Often referred to as "killer T cells" because they directly kill virally infected cells, tumors, or foreign grafts. Some T Cytotoxic cells are sensitized by repeated exposure to a specific antigen and therefore do not attack—called Memory T cells.....on re-exposure to the same antigen, they rapidly initiate the immune response within cells. C) T suppressor cells tell the immune system when the battle with the infectious pathogen is over and to stop fighting.

B Cells

Achieve immunocompetence (ability to recognize a specific antigen) in bone marrow.

Types of Immunity: Adaptive (Acquired) Immunity

Acquired through contact with specific pathogens during our lifetime. It is called "adaptive" because it prepares the body's immune system for future challenges. Includes two types: 1. Active immunity—the result of an immune system response when exposed to a pathogenic organism. The person's own immune system produces antibodies against the invader. 2. Passive immunity—provided by antibodies that have not been produced by the person's own immune system-->no immune response occurs.

Neutrophils, Monocytes, Macrophages

Are types of WBCs (leukocytes). a) Monocytes are circulating precursors to Macrophages...when they enter various organs or tissues, they transform into Macrophages. b)Macrophages-responsible for phagocytosis of inflammatory debris— capture, process, and present the antigen to the lymphocytes-->this triggers the immune response. Neutrophils, monocytes, and macrophages are critical effectors and regulators of inflammation, and important components of the innate or natural immune response. This response acts within hours of a pathogen's appearance in the body. Innate defenses are nonspecific - they recognize and respond to any pathogen in a generic way. They include your first and second lines of defense against pathogens.

Immunity

Body's capacity to resist invading organisms and toxins, thus preventing tissue and organ damage. It is an inherited, acquired, or induced resistance to infection by a specific pathogen.

Peripheral Lymphoid Organs: Afferent Lymphatic Vessels

Carry lymph and bacteria into the subcapsular sinus of the node. Then it flows through cortical sinuses and medullary sinuses. Phagocytic cells in the deep cortex and medullary sinuses attack the antigen.

Organs and Tissues of the Immune System

Central Lymphoid Organs BONE MARROW AND THYMUS: Both play a role in developing the primary cells of the immune system: -B Cells and T Cells

Immune System Anatomy: Specialized Structures

Central Lymphoid Organs: *Bone marrow *Thymus Peripheral Lymphoid Organs: *Lymph nodes *Spleen *Tonsils *Adenoids *Appendix Also consists of specialized cells: *Lymphocytes: -B cells -T cells -Natural killer cells *Leukocytes -Neutrophils -Macrophages -Dendritic cells

Dendritic Cells

Found in: skin, nose, lungs, stomach, and intestines; also found in the blood in an immature form. Capture antigens and transport them to their specific T cells making dendritic cells important in the development of cell- mediated memory. Help stimulate B cell memory, to a lesser extent. Essential for the establishment and maintenance of immune tolerance—the ability of the immune system to tolerate all "self antigens" while retaining the ability to mount an immune response to "non-self antigens." If immune tolerance fails, a person will develop an autoimmune disease. Have a critical role in acquired (also called adaptive) immunity—especially cell-mediated immune response. Acquired immune response occurs with the third line of defense and involves the invasion of the body with an antigen, and the development of antibodies and sensitized lymphocytes. Therefore, dendritic cells are essential for long-term immunity.

Three Basic Defense Strategies: 2nd Line of Defense

General host defenses: a. Inflammation—the first response against an antigen—causes heat, redness, swelling, pain; occurs in response to physical and chemical agents, temperature extremes, and pathogens. *This response neutralizes and dilutes the inflammatory agent, moves necrotic materials, and establishes an environment for healing and repair.

Infection

Is caused by invasion of cells and tissues by a pathogen (bacteria, fungi, virus) An infection is present when the invading agent is living, growing, and multiplying in tissues. Is is able to overcome the body's normal defenses. With and infection, you will see greater systemic manifestations.

Inflammation

Is the part of the normal healing process when cells are injured. It can be caused by pathogens, BUT can also be caused by non-living agents, such as: -heat -radiation -allergies -trauma It is a defensive function intended to neutralize, control or eliminate the offending agent to prepare the site for repair.

Memory B Cells

Memory B cells are activated with B cells' initial exposure to an antigen, and are encoded with the "memory" of the battle. They remain in the circulatory system for long periods of time, possibly a whole lifetime. If re-exposed to the same antigen, these cells will "remember" how to get rid of it and will respond quickly with large amounts of a specific antibody. This is called the "secondary immune response" and provides a high level of protection against re-exposure to specific antigens, as well as lasting immunity.

T Cells

Migrate to the thymus gland, where they become immunocompetent.

Types of Immunity: Acquired Active Immunity:

Natural exposure—natural contact with an antigen through infection. *person is infected by the disease once and then antibodies are produced that grant future immunity. Examples: recovery from childhood diseases: chicken pox, measles. Long-term immunity—often life-time. Artificial exposure-->immunization with an antigen - live or killed vaccines: After receiving an immunization composed of a harmless version of a disease, the immune system is triggered to develop appropriate antibodies, giving immunity. -Bacteria exotoxins, such as those produced by diphtheria and tetanus, can be successfully detoxified without destroying the major antigenic determinants on the protein molecule (detoxified antigenic materials are called toxoids). -Killed vaccines of viruses and bacteria provide safe antigen for immunization: Pertussis, Typhoid. -Attenuated live vaccines—living organisms that have been modified so they are nonvirulent: MMR, live polio vaccine-->This should never be given to a person with immunodeficiency.

Types of Immunity: Innate (Natural) Immunity

Present at birth and does not have to be learned through exposure to an invader. Characterized by an immediate, non-specific response. Includes two types: 1. Humoral innate immunity involves substances found in body fluids. Includes: complement system, cytokines. 2. Cellular innate immunity identifies and eliminates pathogens that might cause infection. Includes: 1) NK cells 2) Mast cells 3) Eosinophils 4) Basophils 5) Phagocytic cells (macrophages, neutrophils, dendritic cells) The innate response functions continuously in a normal host without exposure to any virus-->everybody has this "built-in" innate immunity.

Plasma Cells

Produce antibodies (also called immunoglobulins). This is the "primary immune response.

Three Basic Defense Strategies: 1st line of defense

Protective surface phenomena: a. Intact and healing skin and mucous membranes. b. Skin desquamation (normal cell turnover) and low pH impede bacteria. c. Seromucous surfaces—conjunctiva of the eye, oral mucous membranes—protected by antibacterial substances, such as enzyme lysozyme; also found in tears, saliva, nasal secretions. d. Respiratory system—nostrils filter foreign material, nasal secretions contain naturally occurring immunoglobulin; mucous layer that lines the respiratory tract is sloughed off and replaced continuously, ciliary action traps and expels inhaled particles (cough reflex). e. GI system—saliva, swallowing, peristalsis, and defecation mechanically remove bacteria; low pH of gastric secretions; resident bacteria prevent colonization of other microorganisms. f. Urinary system is sterile except for the distal end of the urethra and the urinary meatus—urine flow, low pH, an immunoglobulin, and the bactericidal effects of prostatic fluid in men impede bacteria colonization; also sphincter muscles inhibit bacterial migration.

Three Basic Defense Strategies: 3rd Line of Defense

Specific Immune Responses: a. Humoral Immunity—"kicks-in" when bacteria or foreign material circulate in body fluids (blood, lymph, tissue fluids, interstitial fluids). An invasive antigen causes B cells (specialized lymphocytes) to divide and differentiate into plasma cells that produce and secrete antigen-specific antibodies (immunoglobulins). After the body's initial exposure to an antigen, a time lag occurs during which little or no antibody can be detected. During this time, B cells, neutrophils and macrophages are processing the antigen. Macrophages prepare to present it to a specialized lymphocyte--> 1) Primary Antibody Response: Occurs 4 - 10 days after first-time antigen exposure—immunoglobulin levels ↑, then quickly dissipate, and IgM antibodies form. IgM: *First type of antibody formed *Confined to intravascular space As immune response progresses-->IgG immunoglobulin is produced and can move from intravascular to extravascular spaces. 2) Secondary Antibody Response: Occurs when the individual is exposed to the same antigen a second time. Memory B Cells remember the first exposure and now manufacture antibodies more rapidly than with first exposure (occurs in 1 - 3 days). IgG is the main antibody found in secondary response. Elevated levels of antibodies persist for months and then fall slowly—this secondary immune response is faster, more intense, and more persistent, and it amplifies with each subsequent exposure to the same antigen.

Peripheral Lymphoid Organs: Lymph Nodes

Two important functions: 1. Filter, remove and destroy antigens circulating in the blood and lymph. 2. Provide specific immune responses such as protection and continuous surveillance (contain B, T and other immune cells). Lymph nodes are divided into 3 compartments: a. Superficial cortex—made up of predominantly B cells. b. Deep cortex—consists mostly of T cells. c. Medulla—contains numerous plasma cells that actively secrete immunoglobulins (antibodies) during an immune response. Cleansed lymph leaves the node through Efferent lymph vessels *These vessels drain into specific lymph node chains, which in turn--> *Drain into large lymph vessels that empty into the subclavian vein of the vascular system. Lymph usually travels through more than one lymph node because numerous nodes line the lymphatic channels that drain a particular region. For Example: *Axillary nodes filter drainage from the arms. *Femoral nodes filter drainage from the legs. This arrangement prevents organisms that enter peripheral body areas from migrating, unchallenged to central areas.

Natural Killer (NK) Cells

not T or B cells, but are large lymphocytes with numerous granules in the cytoplasm—involved in recognition and killing of virus infected cells, tumor cells, and transplanted grafts.