The Body Defenses (Immune System)

The Body Defenses (Immune System)

Immunity

  • Immunity: The body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells.
  • The immune system defends against pathogens, removes worn-out cells, and destroys abnormal or mutant cells.
  • Inappropriate immune responses lead to allergies or autoimmune responses.
  • Primary pathogens: bacteria and viruses.
    • Bacteria: Non-nucleated, single-celled microorganisms.
    • Viruses: Non-cellular, consisting of nucleic acid enclosed by a protein coat.
    • Virulent forms can cause disease (pathogenic).
  • The immune system uses blood leukocytes for defense.

Immune Responses

  • Immune responses are either innate and nonspecific or adaptive and specific.
  • They differ in timing and selectivity of the defense mechanism.
  • Innate, nonspecific responses work immediately upon exposure to a threatening agent.
    • They nonselectively defend against foreign invaders.
    • Provide a first line of defense, with rapid but limited responses.
  • Adaptive, or acquired, immunity specifically targets foreign material after prior exposure.
    • The body has a specific defense against the pathogen.
  • Neutrophils and macrophages are important in innate defense, along with several plasma proteins.
  • Phagocytic cells have receptors that recognize and bind to pathogenic markers.
  • Other chemicals are secreted by the phagocytes of the adaptive immune system.

Non-Specific Defenses

  • Defense against pathogens: harmful, disease-causing microorganisms.
  • Surface barriers and mucosa.
  • Mechanical barriers (physical obstruction).
  • Acidic skin/oral/stomach secretions (pH 3-5).
  • Lysozyme in saliva to destroy bacteria.
  • Mucus traps in the digestive and respiratory pathways.

Innate Immunity Defenses

  • Include inflammation, interferon, natural killer cells, and the complement system.
  • Inflammation: A nonspecific response to foreign invasion or tissue damage.
    • Neutrophils and macrophages, both phagocytic specialists, play a major role. Plasma proteins contribute to the nonspecific defense.
    • Inflammation attempts to:
      • Isolate, destroy, and inactivate the invaders.
      • Remove debris.
      • Prepare for subsequent healing and repair.

Inflammation Responses

  • A series of events.
  • Resident macrophages defend against invasive bacteria during the first hour.
  • Arterioles, serving the invaded area, dilate.
  • Histamine is released to increase capillary permeability in the area. Plasma proteins can leave the blood and enter the area.
  • Exudate released: fluid with clotting factors and antibodies from the bloodstream into tissue spaces.
  • The leakage of plasma proteins and fluid from the blood causes localized edema in the injured area.
    • The fluid accumulation causes swelling, redness, and increased temperature in the area.
    • The swelling causes pain.
  • Fibrin formation walls off the area from surrounding tissues.
  • Neutrophils or monocytes emigrate from the blood into the area.
    • They adhere to the inside surface of capillaries by margination.
    • They enter the interstitial spaces by diapedesis.
    • They are guided to the areas where they are needed by chemotaxis.

Phagocyte Mobilization

  • Leukocytosis:
    • Promote release of neutrophils from red marrow.
  • Margination:
    • Inflamed areas sprout cell adhesion molecules (CAMs) providing footholds for neutrophils to cling to the damaged area.
  • Diapedesis:
    • Neutrophils squeeze through capillary walls.
  • Chemotaxis:
    • Neutrophils follow a chemical gradient to the site of the injury.

Events in Inflammation

  • Within a few hours of the beginning of the inflammatory response, there is leukocyte proliferation.
    • Neutrophil numbers may increase four or five times.
    • Monocytes increase at a slower rate, forming macrophages.
  • Bacteria are marked for destruction by opsonins.
    • This allows phagocytes to distinguish among normal and foreign/abnormal cells.
    • The opsonins are antibodies and one of the activated proteins of the complement system.
  • Leukocytes destroy bacteria by phagocytosis.
  • There is mediation of the inflammatory response by phagocyte-secreted chemicals.
    • These chemicals include:
      • Nitric oxide (from macrophages).
      • Lactoferrin (from neutrophils).
      • Histamine (increasing capillary permeability).
      • Kinins (formed from kininogens).
      • Endogenous pyrogen (induces fever development).
      • Leukocyte endogenous mediator (decreases plasma iron).
      • Acute-phase proteins from the liver.

Tissue Repair

  • The inflammatory process repairs tissues.
    • The repair varies.
      • Cell division replaces lost cells, replacing the injured area with the same kind of cells.
      • Scar tissue replaces nonregenerative tissues such as nerve and muscle.
  • Salicylates and glucocorticoid drugs suppress the inflammatory response.
    • Salicylates decrease histamine release. They also reduce fever by inhibiting the production of prostaglandins.
    • Glucocorticoids suppress most aspects of the inflammatory response.

Interferon

  • Interferon transiently inhibits the multiplication of viruses in most cells. It interferes with viral replication.
    • It triggers the production of virus-blocking enzymes by potential host cells. The enzymes remain inactive unless cells are attacked by viruses.
    • Interferon is released nonspecifically from any cell infected by a virus. It can induce immunity against many different viruses in many other cells.
    • Interferon (IFNs) stops viruses from replicating by stopping protein replication in cells; it is not virus-specific.
      • Gamma (immune) interferon (lymphocytes).
      • Alpha interferon (other leukocytes).
      • Beta interferon (fibroblasts).
    • It can bind to and forewarn neighboring cells to viral attack. Interferon slows cell division and has anticancer effects.
  • Natural killer cells destroy virus-infected cells and cancer cells on first exposure to them.
    • They lyse cell membranes upon first exposure to these cells. NK cells provide an immediate, nonspecific defense.

Complement

  • Punches holes (lysis) in microorganisms (bacteria).
  • The complement system consists of plasma proteins produced by the liver.
    • This is a nonspecific response.
    • It is activated by exposure to particular carbohydrate chains on the surface of microbes and to antibodies produced by specific foreign invaders.
    • The powerful complement cascade reinforces other general inflammatory tactics.
      • C1 of this cascade activates C2 and so forth. C5 through C9 assemble into the membrane attack complex. This attacks the surface membrane of microorganisms.
    • Complement proteins have additional functions such as serving as chemotaxins and acting as opsonins.

Complement System

  • Complement system (complement):
    • 20 plasma proteins that circulate inactive.
    • C1-C9, B, D, and P.
    • Destroy foreign substances in the body by amplifying the inflammation process.
    • Kill bacteria by lysis.

Fever

  • Fever, the final non-specific defense.
  • An abnormally high temperature.
    • The internal temperature thermostat can be reset (from 98.6 degrees Fahrenheit) using chemicals called pyrogens.
    • Secreted by leukocytes and macrophages upon exposure to bacteria.

Benefits of Fever

  • Increased temperature kills bacteria, as they are unable to thermoregulate.
  • Bacteria require iron and zinc to multiply, which are sequestered by the liver and spleen during fevers.
  • Fever also speeds repair (by lowering the EA of enzyme activity).

Adaptive Immune Responses

  • Adaptive immune responses are antibody-mediated (humoral) immunity and cell-mediated immunity.
  • B cells differentiate and mature in the bone marrow.
  • The thymus gland processes T cells that migrate from the bone marrow.
  • B and T cells take up residence in lymphocyte colonies where they produce new B and T cells and occupy different lymphoid tissues.
  • Thymosin is a hormone that maintains T cell lineage.
  • An antigen induces an immune response against itself.
    • Their presence allows B and T cells to distinguish between foreign invaders (antigenic) and normal cells.

Aspects of the Adaptive Immune System

  • It is antigen-specific.
    • Reaction against particular antigens that initiate the immune response.
  • It is systemic.
    • Occurring throughout the body, rather than locally.
  • It has a memory.
    • Reacting stronger and faster the second time a pathogen is encountered.

Two Systems of Adaptive Immunity

  • Humoral, antibody-mediated immunity.
    • Antibodies in the body fluids, produced by lymphocytes, bind to antigens and mark them for destruction by phagocytes.
  • Cellular, cell-mediated immunity.
    • Lymphocytes defend themselves directly.
      • Directly: lysing foreign cells.
      • Indirectly: release of chemical mediators.

Antigen

  • Any foreign substance in the body that mobilizes an immune response.
  • They are the target of the immune system.
  • Often large, complex molecules.
  • Termed: NONSELF.

Complete Antigens and Haptens

  • Complete antigen:
    • Immunogenicity: stimulates proliferation of specific lymphocytes and antibodies.
    • Reactivity: have the ability to react to the activated lymphocytes and antibodies.
  • Hapten:
    • Small molecules (hormones, peptides, etc.) causing an allergic reaction.
    • Mount an attack once linked to the body's defenses.

Types of Acquired Immunity

  • Includes naturally acquired active and passive immunity, and artificially acquired active and passive immunity.

Antibodies

  • Immunoglobulins (Igs) constitute the gamma globulins of blood proteins.
  • Activated by B-cells or plasma cells, binding to specific antigens.
  • Grouped into five classes, differing in structure and function.

Antibody Structure

  • All have in common:
    • Four polypeptide chains connected by disulfide bonds
    • Two heavy chains, two light chains composing an antibody monomer.
    • Each of the four chains have a variable (V) region at one end and a larger constant (C) region at the other end.

Antibody Structure: V and C Regions

  • V region: antigen-binding site shaped to fit a specific antigenic determinant.
    • Each monomer has two binding sites.
  • C region: form stem, the effector region.
    • Dictates cells and chemicals the antibody can bind to.
    • How the antibody class will function in antigen elimination.

Classes of Antibodies

  • Five classes, based on the C region.
    • IgM: pentamer.
    • IgA: dimer.
    • IgD: monomer.
    • IgG: monomer.
    • IgE: monomer.

Antibodies: PLAN

  • The acronym PLAN represents the functions of antibodies:
    • Precipitation
    • Lysis
    • Agglutination
    • Neutralization

Activated B-Cell Clones

  • Multiply and differentiate into plasma cells or memory cells.
    • Most are transformed into plasma cells.
      • They produce and secrete IgG antibodies.
      • Each antibody combines with an antigen, marking it for destruction.
    • During the initial contact with a microbial antigen, the antibody response is delayed.
      • Plasma cells are formed.
      • It reaches its peak in a couple of weeks during the primary response.
      • After this peak, the antibody concentration decreases.
    • A small percentage of the B lymphocytes become memory cells.
      • They remain dormant and expand a specific clone.
      • Upon re-exposure to the same antigen, they are more ready for immediate action than the original lymphocytes of the clone.
      • This secondary response is quicker, more potent, and longer-lasting.
      • This can be induced by disease or vaccination.

Immunological Memory

  • Cell proliferation and response to the primary immune response (first exposure).
    • Lag time of 3-6 days (proliferation and differentiation of plasma cells).
  • Secondary immune response: faster, longer, more effective, as the immune system is primed for the antigen.
    • There is an increased titer level in the blood for antibodies.

Lymphocytes and Antigen-Presenting Cells

  • Lymphocytes respond only to antigens presented to them by antigen-presenting cells.
    • Macrophages can be antigen-presenting cells. They cluster around an appropriate B-cell clone, making the introduction.
    • Phagocytosis occurs, processing the raw antigen intracellularly and presenting the processed antigen, exposing it to the outer surface of the macrophage's plasma membrane.
    • As a macrophage engulfs and ingests a microbe, it ingests it into antigenic peptides. Each binds to an MHC molecule.
    • The MHC transports the bound antigen to the cell surface, presenting it to passing lymphocytes.
    • Antigen-presenting macrophages secrete interleukin. This chemical mediator enhances the differentiation and proliferation of the now-activated B cell clone. Dendritic cells are antigen-presenting cells. Helper T cells help B cells.

T Lymphocytes

  • T lymphocytes carry out cell-mediated immunity.
    • They do not secrete antibodies. They bind directly to targets.
    • T type killer cells release chemicals that destroy these targeted cells.
    • T cells are clonal and antigen-specific. They acquire receptors for this specificity in the thymus.
    • T cells are activated for foreign attack only when on the surface of a cell that carries foreign and self-antigens. Both must be on a cell's surface for T cell binding.
    • T cells learn to recognize foreign antigens only in combination with a person's own tissue antigens. There is a dual antigen requirement.
    • A few days are required before T cells are activated to launch a cell-mediated attack.

Types of T Cells

  • The two types of T cells are cytotoxic and helper.
    • Helper cells are the most numerous T cells.
    • Cytotoxic T cells secrete chemicals that destroy target cells. Most frequently they destroy cells infected with viruses.
      • There is a clone of these cells specific for a particular virus. These T cells bind to the viral antigens and self-antigens on the surfaces of the viral-infected cells.
      • The cytotoxic T cells release chemicals that destroy the attacked cell before the virus can enter the nucleus and start to replicate.
      • Cytotoxic T cells also destroy targeted cells by releasing perforins. The exception to this is nerve cells.
      • Viruses are released from the destroyed cells, and they are destroyed in the extracellular fluid by phagocytic cells.
      • Cell division replaces the lost body cells with healthy cells.

Helper T Cells and Cytokines

  • Helper T cells secrete chemicals that amplify the activity of other immune cells.
    • Cytokines are chemicals (with the exception of antibodies) secreted by helper T cells. They spur other immune cells to help ward off the invader.
    • Examples of cytokines include the B-cell growth factor, interleukin 2, chemotaxins, and macrophage-migration inhibition factor.
    • There are two subsets of helper T cells that augment different patterns of immune responses by secreting different types of cytokines.

Tolerance of Self-Antigens

  • The immune system is normally tolerant of self-antigens.

    • Tolerance refers to preventing the immune system from attacking the person's own tissues. There are at least five different mechanisms:

      • By clonal deletion, there is a triggering of the apoptosis of immature cells that would react with the body's own proteins.
      • By clonal anergy, a lymphocyte must receive two specific signals at the same time for activation. A single signal from a self-antigen turns off a compatible T cell, rendering the cell unresponsive to further exposure to the antigen.
      • By receptor editing, a B cell with a receptor for one of the body's own antigens changes its receptor to a nonself version if it encounters a self-antigen.
      • B antigen sequestering self molecules are hidden from the immune system.
      • A few tissues have immune privilege.

MHC Molecules

  • MHC molecules mark cells as SELF. These self-antigens are plasma membrane glycoproteins.
    • They vary from one person to another.
    • Their natural function is to direct the responses of T cells.
    • MHC molecules (Major Histocompatibility Complex) on cells block T cell binding.
    • Cytotoxic T cells do not bind to MHC self-antigens in the absence of a foreign antigen. Therefore, normal body cells are protected from lethal immune attack.
    • T cells become active only when they match a given MHC-foreign peptide combination.
      • Class I: found on all cells
      • Class II: only certain cells acting in immune response
      • Cytotoxic T cells can respond to foreign antigens only in association with class 1 MHC glycoproteins.
      • Class II MHC glycoproteins recognized by helper T cells are confined to the surface of a few special types of immune cells.
    • T cells do bind with MHC antigens present on the surface of transplanted cells, accounting for their rejection.

Immune Surveillance

  • By immune surveillance, the T cell system recognizes and destroys newly arisen, potentially cancerous tumor cells.
    • A tumor consists of a clone of cells identical to the original mutated cell. A benign tumor does not infiltrate surrounding tissues.
    • Malignant tumors are invasive and cancerous. Their cells tend to metastasize. If these cells spread throughout the body, they cannot be removed surgically.
    • Untreated cancer is eventually fatal.
    • Most genetic mutations do not lead to cancer.

Immune Surveillance Mechanisms

  • Immune surveillance depends on the interplay of cytotoxic T cells, NK cells, and macrophages plus interferon. They attack and destroy cancer cells.

    • NK cells are the first line of defense against cancer.
    • Cytotoxic T cells probably defend against virus-induced cancers.
    • Macrophages clear away the remains of dead cells and engulf and destroy cancer cells intracellularly.
    • Some cancer cells can avoid these immune mechanisms.
      • Some cancer cells have counter-productive blocking antibodies that interfere with T cell function.

  • The immune system is regulated by the endocrine and nervous systems by negative feedback loops.

    • For example, cortisol mobilizes the body's store of metabolic fuel. Lymphocytes and macrophages are responsive to blood-borne signals.

Immune Deficiency Diseases

  • Abnormal functioning of the immune system can lead to immune diseases.
    • Immune deficiency diseases result from insufficient immune responses. The immune system does not respond adequately to foreign invasion.
      • For example, in severe combined immunodeficiency, both B and T cells are lacking.
      • In HIV, a virus invades and incapacitates helper T cells.
    • Inappropriate adaptive immune attacks cause reactions that harm the body. They include autoimmune responses, in which the immune system turns against the body. Another example is immune complex diseases, which damage tissues by violent reactions.
    • The third example is allergies.

Autoimmune Diseases

  • Autoimmune diseases arise from a loss of tolerance of self-antigens. There are several causes:
    • Lymphocyte programming ineffective:
      • T and B cells during the programming phase in the thymus and bone marrow escape rather than be destroyed (occurs in multiple sclerosis).
    • New self-antigens appear:
      • By gene mutation or hapten attachment as a result of infectious damage.
    • Foreign antigens resemble self-antigens:
      • Similar determinants of foreign and self cross-react (e.g., rheumatic fever).

Types of Autoimmune Diseases

  • Multiple sclerosis: white matter of the brain and spinal cord.
  • Myasthenia gravis: impairs neuromuscular junctions.
  • Grave's disease: excess thyroxine.
  • Type I (juvenile) diabetes mellitus: beta cells, losing insulin and the use of carbohydrates.
  • Systemic lupus erythematosus (SLE): kidney, heart, lungs, skin.
  • Glomerulonephritis: renal function.
  • Rheumatoid arthritis (RA): joints.

Hypersensitivities (Allergies)

  • Hypersensitivities (i.e., allergies):

    • Fighting a perceived threat: allergen.

    • Three different types of hypersensitivities:

      • Immediate
        • Begin in seconds, lasts for about ½ an hour
      • Subacute
        • Begin in 1 - 3 hours, lasts for 10 - 15 hours
      • Delayed
        • Begin in 1 - 3 days

Immediate Allergy

  • Anaphylaxis:
    • First exposure sensitizes the person, without symptoms.
    • Produce huge amounts of antibody (IgE) and attach to mast cells and basophils.
    • Second encounter: flood of histamine and inflammatory chemicals (e.g., chemotactic and prostaglandins).
  • Atopy:
    • Spontaneous allergy without previous exposure (10%).

Anaphylaxis: Local vs. Systemic

  • May be local or systemic:
    • Local:
      • Runny nose, hives, watery eyes, etc.
      • Antihistamine OTC (over the counter) medicine is used to counteract effects.
    • Systemic:
      • Anaphylactic shock - basophils and mast cells are recruited throughout the body.
      • Constrict bronchioles, possible circulatory collapse.

Subacute Allergy

  • Caused by antibodies (IgG, IgM, not IgE).
    • Cytotoxic: Binding of antibodies stimulates phagocytosis (e.g., mismatched blood transfusions).
    • Immune complex: Cannot clear the antibody-antigen complex from an area. Intense inflammation occurs, severely damaging tissues (e.g., systemic lupus, farmer's lung).

Delayed Hypersensitivity

  • Essentially, this is a cell-mediated hypersensitivity, including both cytotoxic and hypersensitive T-cells.
    • Depends on cytokine activated macrophages and non-specific killing.
    • Contact dermatitis (e.g., poison ivy or poison oak, cosmetics, heavy metals).
    • Has protective functions:
      • Against pathogens, resistance to cancer, rejection of foreign grafts or transplanted organs.