AP Chapter 21 Immune System

Activities

1. Amplifies inflammatory response. 2. Activates complement.

Hypersensitivities

Immune responses to perceived (harmless) threat cause tissue damage. Different types distinguished by: their time course, whether antibodies or T cells involved. Antibodies cause immediate and subacute hypersensitivities. T cells cause delayed hypersensitivity.

Autoimmune Disease

Immune system loses ability to distinguish self from foreign. Production of autoantibodies and sensitized Tc cells that destroy body tissues. 1. multiple sclerosis, myasthenia gravis, graves disease, type 1 diabetes mellitus, systemic lupus erythematosus (SLE), rheumatoid arthritis.

Chemotaxis

Inflammatory chemicals act as chemotactic agents that promote positive chemotaxis of neutrophils toward injured area.

Incomplete Antigens (Haptens)

Involve molecules too small to be seen so are not immunogenic by themselves. Ex.) small peptides, nucleotides, some hormones. May become immunogenic if hapten attaches to body's own proteins. Combination of protein and hapten is then seen as foreign. Causes immune system to mount attack that is harmful to person because it attacks self-proteins as well as hapten. Ex.) poison ivy, animal dander, detergents, cosmetics.

Inflammation

Is triggered whenever body tissues are injured. Injuries can be due to trauma, heat, irritating chemicals, or infections by microorganisms.

Other Chemicals

Lipids in sebum and dermicidin in sweat are toxic to some bacteria.

Cellular Immunity

Lymphocytes (T cells) act against target cell. Directly - by killing infected cells. Indirectly - by releasing chemicals that enhance inflammatory response; or activated other lymphocytes or macrophages. Cellular immunity has cellular targets.

Antigen Receptor Diversity

Lymphocytes become immunocompetent BEFORE meeting the antigens they may encounter later. Genes, not antigens, determine which foreign substances the immune system will recognize. ~25,000 different genes codes for up to a billion different types of lymphocyte antigen receptors. Huge variety of receptors: gene segments are shuffled around, resulting in many combinations.

Enzymes

Lysozyme of saliva, respiratory mucus, and lacrimal fluid kills many microorganisms; enzymes in stomach kill many microorganisms.

Lyse By Complement Fixation And Activation

Main antibody defense against cellular antigens (bacteria, mismatched RBCs). When several antibodies are bound close together on same antigen, complement-binding sites on their stem regions are aligned. Alignment triggers complement fixation, which leads to cell lysis, as well as other complement functions.

Regulatory T Cells

Moderate immune response. Important in preventing autoimmune reactions. Research into using them to induce tolerance to transplanted tissue.

Neutrophils

Most abundant phagocytes, but die fighting.

Plasma Cells

Most clone cells. Antibody-secreting effector cells. Secrete specific antibodies at rate of 2000 molecules per second for 4 to 5 days, then die. Antibodies circulate in blood or lymph, binding to free antigens, marking them for destruction by innate or other adaptive mechanisms.

Diapedesis

Neutrophils flatten and squeeze between endothelial cells, moving into interstial spaces.

Phagocyte Mobilization

Neutrophils flood area first, macrophages follow. If inflammation is due to pathogens, complement is activated adaptive immunity elements arrive.

Natural Killer (NK) Cells

Nonphagocytic, large granular lymphocytes that police blood and lymph. Can kill cancer and virus-infected cells before adaptive immune system is activated. Attack cells that lack "self" cell-surface receptors. Kill by including apoptosis in cancer cells and virus-infected cells. Secrete potent chemicals that enhance inflammatory response.

Active Humoral Immunity

Occurs when B cells encounter antigens and produce specific antibodies against them. Two types of active humoral immunity: 1. Naturally acquired: formed in response to actual bacterial or viral infection. 2. Artificially acquired: formed in response to vaccine of dead or attenuated pathogens.

Passive Humoral Immunity

Occurs when ready made antibodies are introduced into body. B cells are not challenged by antigens. Immunological memory does not occur. Protection ends when antibodies degrade.

Basic Antibody Structure

Overall T- or Y-shaped antibody monomer consists of four looping polypeptide chains linked by disulfide bonds. Four chains consist of: 1.Two identical heavy (H) chains with hinge region at "middles" 2.Two identical light (L) chains. Variable (V) regions at one end of each arm combine to form two identical antigen-binding sites.

Antigenic Determinants

Parts of antigen that antibodies or lymphocyte receptors bind to. Most naturally occurring antigens have numerous antigenic determinants that: mobilize several different lymphocyte populations. Form different kinds of antibodies against them. Large, chemically simple molecules (such as plastics) have little or no immunogenicity.

Prevention of Rejection After Surgery

Patient treated with immunosuppressive therapy. Corticosteroid drugs to suppress inflammation. Antiproliferative drugs. Immunosuppressant drugs. Many have severe side effects.

Immunosuppressive Therapy Problems

Patient's immune system suppressed. Cannot protect from foreign agents. Bacterial and viral infections lead to death. Must balance drugs for graft survival by no toxicity. Use antibiotics to control infections. Best circumstances- rejection after 10 years in 50% of patients.

Fixed Macrophages

Permanent residents of some organs; examples: stellate macrophages (liver) and microglia (brain).

PLAN

Precipitation Lyse (by complement fixation) Agglutination Neutralization

IgA

Prevents pathogens from adhering to mucus membranes. Plentiful in breast milk.

Shortcoming: Must Be Primed By Initial Exposure To Specific Foreign Substance

Priming takes time.

Secondary Immune Response

Re-exposure to same antigen gives faster, more prolonged, more effective response. Sensitized memory cells provide immunological memory. Respond within hours, not days. Antibody levels peak in 2 to 3 days at much higher levels. Antibodies bind with greater affinity. Antibody level can remain high for weeks to months.

Leukocytosis

Release of neutrophils from bone marrow in response to leukocytosis-including factors from injured cells.

Neutralization

Simplest, but one of the most important defensive mechanism. Antibodies block specific sites on viruses or bacterial exotoxins. Prevent antigens from binding to receptors on tissue cells. Antigen-antibody complexes undergo phagocytosis.

Precipitation

Soluble molecules (instead of cells) are cross-linked into complexes. Complexes precipitate out of solution. Precipated complexes are easier for phagocytes to engulf.

Adaptive Immune System

Specific defensive system that eliminates almost any pathogen or abnormal cell in body.

Mucin

Sticky mucus that lines digestive and respiratory tract traps microorganisms.

Antigens

Substances that can mobilize adaptive defenses and provoke an immune response. Targets of all adaptive immune responses. Most are large, complex molecules not normally found in body (nonself).

Treatment of Autoimmune Diseases and Research

Suppress entire immune system: anti-inflammatory drugs, corticosteroids, blocking cytokine action, blocking co-stimulatory molecules. Activating regulatory T cells; inducing self-tolerance using vaccines; directing antibodies against self-reactive immune cells.

First Line Of Defense: Surface Barriers

Surface barriers are skin and mucous membranes, along with their secretions. Physical barrier to most microorganisms. Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins. Mucosae provide similar mechanical barriers.

Lymphocyte Development, Maturation, And Activation

T and B cells share common development and steps in their life cycles. 5 general steps: 1. origin; RBM 2. Maturation; immunocompetence (meaning recognize specific antigen by binding it using a unique receptor) self tolerance. 3. Seeding secondary lymphoid organs and circulation. Naive cells are exported to nodes so they may be exposed to an entigen. 4. Antigen encounter and activation. 5. Proliferation and differentiation. Replicates exacts copies called clones.

Cellular Immune Response

T cells provide defense against intracellular antigens. Some T cells directly kill cells; others release chemicals that regulate immune response. Two populations of T cells based on which glycoprotein surface receptors displayed.

Surface Barriers Breached By Nicks or Cuts Trigger...

The internal second line of defense that protects deeper tissues.

Once Pathogens Are Inside Body..

They grow and multiply - with destructive consequences. Damaging our cells or releasing toxins. Pathogens cause a host of illnesses, from colds and measles to fatal conditions like tuberculosis and malaria.

Purpose of Immune System

To recognize, disable and dispose of all intruders - and then to remember them, in case they return.

Helper T Cells

Used when acidified lysosomal enzymes to not work (tuberculosis) so..T cells trigger macrophage to produce respiratory burst, which kills pathogens resistant to lysosomal enzymes.

Innate Defenses

Uses the first and/ or second lines of defense to stop attacks by pathogens (disease-causing microorganisms)

Vasodilation And Increased Vascular Permeability

Vasodilation casues hyperemia- congestion with blood - which leads to redness and heat. Increased capillary permeability causes exudate- fluid containing clotting factors and antibodies - to leak into tissue. Results in edema (swelling) swelling pushes on nerve endings causing pain. Pain can also result from release of toxins from bacteria or released prostaglandins and kinins. Benefits of edema: surge of fluid in tissue sweeps foreign material into lymphatic vessels for processing in lymph nodes, delivers clotting proteins and complement to area. Clotting factors form fibrin mesh that acts as scaffold for repair.

Free Macrophages

Wander through tissue spaces; example: alveolar macrophages.

Humoral Immune Response

When B cell encounters target antigen. Antibodies for that antigen are then produced.

Phagocytes

White blood cells that ingest and digeset (eat) foreign invaders. Some pathogens are not killed with acidified lysosomal enzymes. They need help so they use their helper T cells.

Macrophages

Widely distributed in connective tissues and lymphoid organs. Present antigens to T cells, which not only activates T cell, but also further activates macrophage. Activate macrophage becomes phagocytic killer. Also triggers additional defenses.

Developmental Aspects

With age, immune system begins to wane. Greater susceptibility to immunodeficiency and autoimmune diseases. Greater incidence of cancer. Do not know why immune system fails but may be due to atrophy of thymus and decreased production of naive T and B cells.

Innate And Adaptive Defenses Are Intertwined

1. Both release and recognize many of the same defensive molecules 2. Innate defenses do have specific pathways for certain substances 3. Innate responses release proteins that alert cells of adaptive system to foreign molecules.

Two Populations of T Cells:

1. CD4 cells - usually become helper T cells (Th). - Some CD4 become regulatory T cells (Tr) - also become memory T cells 2. CD8 cells - become cytotoxic T cells (Tc)

Two Main Branches of Adaptive System

1. Humoral (antibody-mediated) immunity 2. Cellular (cell-mediated) immunity. T cells

Stages of Inflammation

1. Inflammatory chemical release 2. Vasodilation and increased vascular permeability. 3. Phagocyte mobilization.

Most Important Microbial Proteins

1. Interferons 2. Complement proteins

Steps for Phagocyte Mobilization

1. Leukocytosis 2. Margination 3. Diapedesis 4. Chemotaxis

Respiratory System Also Has Modifications To Stop Pathogens

1. Mucus-coated hairs in nose trap inhaled particles. 2. Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus toward mouth.

Two Types of Passive Humoral Immunity:

1. Naturally acquired: antibodies delivered to fetus via placenta or to infant through milk. 2. Artificially acquired: injection of serum, such as gamma globulin.

Innate System Necessary If Microorganisms Invade Deeper Tissues; Includes:

1. Phagocytes 2. Natural killer (NK) cells. 3. Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals) 4. Antimicrobial proteins (interferons and complement proteins) 5. Fever.

Benefits of Inflammation

1. Prevents spread of damaging agents 2. Disposes of cell debris and pathogens 3. Alerts adaptive immune system 4. Sets the stage for repair.

Phagocytosis

1. Process starts when phagocyte recognizes and adheres to pathogen's carbohydrate "signature". Some microorganisms have external capsules that hide their surface carbohydrates, helping them evade phagocytosis. 2. Cytoplasmic extensions (pseudopods) bind to and engulf particle in vesicle called phagosome. 3. Phagosome fuses with lysosome, forming phagolysosome. 4. Phagolysosome is acidified, and lysosomal enzymes digest particles. 5. Indigestible and residual waste is exocytosed from phagocyte.

4 Cardinal Signs of Acute Inflammation

1. Redness 2. Heat 3. Swelling 4. Pain Sometimes a fifth sign, impairment of function, is seen if movement or use of area is hampered.

Adaptive (specific) Defense System

1. Third line of defense: attacks specific foreign substances (takes longer to react than innate). (humoral immunity: B cells, Cellular immunity, T cells)

Characteristics of Adaptive Immunity

1. it is specific: recognizes and targets specific antigens. 2. it is systemic: not restricted to intial site. 3. it has memory: mounts an even stronger attack to "known" antigens (second and subsequent exposures)

As Attach Continues, Monocytes Arrive Later

12 hours after leaving bloodstream, they are transformed into macrophages. These "later-arrivers" replace dying neutrophils and remain for cleanup prior to repair.

Adaptive Immune System

3 crucial types of cells: 1. Two types of lymphocytes: - B Cells: humoral immunity - T Cells: cellular immunity 2. Antigen-presenting cells (APCs): - do not respond to specific antigens - play essential auxiliary roles in immunity.

IgG

75-85% of antibodies in plasma, most common circulating in blood. Crosses placental barrier.

Fever

Abnormally high body temperature that is systemic response to invading microorganisms. Leukocytes and macrophages exposed to foreign substances secrete pyrogens. Pyrogens act on body's thermostat in hypothalamus, raising body temperature. Benefits of moderate fever: 1. Causes liver and spleen to sequester iron and zinc (needed by microorganisms) 2. Increases metabolic rate, which increases rate of repair.

Acid

Acidity of skin and some mucous secretions inhibits growth; called acid mantle.

Hodgkin's Disease

Acquired immunodeficiency. Cancer of B cells. Leads to immunodeficiency by depressing lymph node cells.

Helper T Cells

Activate B cells, other T cells, macrophages. Direct adaptive immune response.

Helper, Cytotoxic, Regulatory T Cells Are ...

Activated T cells.

IgE

Active in some allergies and parasitic infections (extracellular pathogens, like helminthes). Causes mast cells and basophils to release histamine.

Immediate Hypersensitiity

Acute (type I) hypersensitivities (allergies) begin in seconds after contact with allergen. Allergic reactions local or systemic. Local- mast cells of skin and respiratory and gastrointestinal mucosa. Systemic response is anaphylactic shock (bee sting).

Self-Antigens

All cells are covered with variety of proteins located on surface that are not antigenic to self, but may be antigenic to others in transfusions or grafts. One set of important self-proteins are group of glycoproteins called MHC proteins.

Antibodies

Also called immunoglobulins (Igs) are proteins secreted by plasma cells. Make up gamma globulin portion of blood. Capable of binding specifically with antigen detected by B cells. Grouped into one of five Ig classes: 1. IgM 2. IgA 3. IgD 4. IgG 5. IgE

Agglutination

Antibodies can bind same determinant on two different antigens at the same time. Each antibody has two arms, each containing a variable region capable of binding to one antigen. Allows for antigen-antibody complexes to become cross-linked into large lattice-like clumps. Process referred to as agglutination. Ex.) clumping of mismatched blood cells.

Antibody Targets And Functions

Antibodies do not destroy antigens; they inactivate and tag them. Form antigen-antibody (immune) complexes. Defensive mechanisms used by antibodies.

Humoral Immunity

Antibodies, produced by lymphocytes (B cells), circulate freely in body fluids. Bind temporarily to target cell. Temporarily inactivate. Mark for destruction by "phagocytes or complement". Humoral immunity has extracellular targets.

Summary of Antibody Actions

Antigen-antibody complexes do not destroy antigens; they prepare them for destruction by innate defenses. Antibodies go after extracellular pathogens; they do not invade solid tissue unless lesion is present.

Defensins

Antimicrobial peptides that inhibit microbial growth.

Pathogens

Bacteria, parasites, fungi, viruses, cancer cells which seek any means possible to broach our bodies' defenses. They enter through wounds, or through the mouth as we swallow, or even when we breathe in.

Naive T cells are ...

CD4 or CD8 cells.

Characteristics of Antigens

Can be a complete antigen or hapten (incomplete). Contain antigentic determinants. Can be a self-antigen. Antigens can be complete or incomplete.

Some Bacteria, Such As Tuberculosis Bacilli, Resist Digestion By Macrophages And Remain Alive Inside

Can form tumor-like growths called granulomas- area of infected macrophages surrounded by uninfected macrophages and outer capsule. Bacteria may remain inactive forever, or if person's immunity decreases, may break free, become activate and cause disease.

Plasma B Cells

Can switch from making one class of antibodies to another. IgM is released during primary response, but plasma cell can switch to IgG for secondary response. Almost all secondary responses are IgG.

Acquired Immune Deficiency Syndrome (AIDS)

Caused by human immunodeficiency virus (HIV) transmitted via body fluids- blood, semen, and vaginal secretions. HIV enters the body via- blood transfusions; blood-contaminated needles; sexual intercourse and oral sex; mother to fetus.

Primary Immune Response

Cell proliferation and differentiation upon exposure to antigen for the first time. Lag period: 3 to 6 days. Peak levels of plasma antibody are reached in 10 days. Antibody levels then decline.

Cytokines

Chemical messengers of immune system. Mediate cell development, differentiation, and responses in immune system. Include interferons and interleukins.

Inflammatory Chemical Release

Chemicals are released into ECF by injured tissues, immune cells, or blood proteins. Example: histamine released by mast cells in key inflammatory chemical. 11 types of TLRs (toll like receptor's) recognize specific classes of infecting microbes. Other inflammatory mediators besides histamine: 1. kinins, prostaglandins (PGs), and complement. All cause vasodilation of local arterioles. All make capillaries leaky. Many attract leukocytes to area. Some have other inflammatory roles, such as triggering pain receptors, or prompting release of more inflammatory chemicals.

Memory Cells

Clone cells that do not become plasma cells. Provide immunological memory. Mount an immediate response to future exposures to same antigen.

MHC Proteins

Coded by genes of major histocompatibility complex (MHC) and unique to each individual. Contain groove that can hold a piece of self-antigen or foreign antigen. T cells respond only to processed fragments of antigens displayed on surfaces of cells. Two types of MHC proteins important to T cell activation: 1. Class I MHC proteins - displayed by all cells except RBC's. 2. Class II MHC proteins- displayed by APCs (dendritic cells, macrophages, and B cells).

Abscess

Collagen fibers are laid down, walling off sac pus; may need to be surgically drained.

Complement

Complement system consists of ~20 blood proteins that circulate in blood in inactive form. Provides major mechanism for destroying foreign substances. Activation enhances inflammation and also directly destroys bacteria. Enhances both innate and adaptive defenses.

Immunodeficiencies

Congenital or acquired conditions that impair function or production of immune cells or molecules such as complement or antibodies.

Innate (nonspecific) Defense System

Constitutes first and second lines of defense. 1. First line of defense: external body membranes (skin and mucosae) 2. Second line of defense: antimicrobial proteins, phagocytes, and 'other cells' (inhibit spread of invaders), inflammation.

Pus

Creamy yellow mixture of dead neutrophils, tissue/cells, and living/dead pathogens.

Cytotoxic T Cells

Destroy cells harboring foreign antigens. Also become memory T cells. Target virus-infected cells, cells with intracellular bacteria or parasites, cancer cells, foreign cells. Releases perforins an granzymes by exocytosis.

HIV

Destroys Th cells which depresses cellular immunity. Cripples immune system by interfering with activity of helper T cells. Characterized by severe weight loss, night sweats, and swollen lymph nodes. Opportunistic infections occur, including pneumocystis pneumonia and Kaposi's sarcoma.

Macrophages

Develop from monocytes and are chief phagocytic cells; most robust phagocytic cell.

B Lymphocytes

Do no activate naive T cells. Present antigens to helper T cell to assist their own activation.

Margination

Endothelial cells of capillaries in inflamed area project cell adhesion molecules (CAMs) into vessel lumen that grab onto passing neutrophils, causing them to slow and roll along, clinging to vessel wall.

Antigen-Presenting Cells (APCs)

Engulf antigens and present fragments of antigens T cells for recognition. Major types: 1. dendritic cells 2. macrophages 3. B cells.

Antimicrobial Proteins

Enhance innate defense by: 1. Attacking microorganisms directly, or 2. Hindering microorganisms's ability to reproduce.

Interferons (IFN)

Family of immune modulating proteins. Cells infected with viruses can secrete IFNs that "warn" healthy neighboring cells. IFNs activate NK cells and macrophages, so they indirectly fight cancer. Artificial IFNs are used to treat disorders such as hepatitis C, genital warts, and multiple sclerosis.

Dendritic Cells

Found in connective tissues and epidermis. Act as mobile sentinels of boundary tissues. Phagocytize pathogens that enter tissues, then enter lymphatics to present antigens to T cells in lymph node. Key link between innate and adaptive immunity.

Organ Transplants

Four varieties: 1. Autografts: from one body site to another in same person. 2. Isografts: between identical twins. 3. Allografts: between individuals who are not identical twins. Most common. 4. Xenografts: from another animal species.

Immune System

Functional system rather than organ system. Provides resistance to disease. Made up of 2 intrinsic systems: 1. Innate (nonspecific) defense system 2. Adaptive (specific) defense system.

Severe Combined Immunodeficiency Syndrome (SCID)

Genetic defect. Marked deficit in B and T cells. Fatal if untreated; treated with bone marrow transplants.

Complete Antigens

Have two important functional properties: 1. Immunogenicity: ability to stimulate proliferation of specific lymphocytes. 2. Reactivity: ability to react with activated lymphocytes and antibodies released by immunogenic reactions. Ex.) foreign proteins, polysaccharides, lipids, and nucleic acids; seen on many foreign invaders such as pollen and microorganisms.