Chapter 22: Immunity

• Chapter 22 focuses on Immunity

Primary Locations of the Immune System

• Includes adenoids, tonsils, thymus, bone marrow, bronchus-associated lymphoid tissue, axillary lymph nodes, intestine, spleen, Peyer's patches, inguinal lymph nodes, and the appendix.

Innate vs. Adaptive Immunity

• Two types of immunity differ based on cells involved, specificity of cell response, mechanisms of eliminating harmful substances, and amount of time for response.

Innate Immunity

• Innate defenses respond rapidly and include species resistance, mechanical/chemical barriers, natural killer cells, inflammation, phagocytosis, and fever
• Innate immunity is present at birth and protects against a variety of different substances (nonspecific)
• No prior exposure to a substance is necessary for the innate immune system to work
• Barriers include skin and mucosal membranes, nonspecific cellular and molecular internal defenses
• Responds immediately to potentially harmful agents.

Adaptive Immunity

• Adaptive immunity is acquired or specific immunity
• Responds to specific antigens and Involves specific T- and B-lymphocytes
• A particular cell responds to one specific foreign substance but not another
• Takes several days to be effective
• Innate and adaptive immunities work together in body defense
• Adaptive immunity consists of specific defenses that develop slowly and are carried out by lymphocytes that recognize a specific invader.

Immune System Defense Strategies

• Defense strategies are divided into three categories; First, second, and third line of defense
• The first and second lines of defense are specific to the innate immune system
• The adaptive immune system possesses the third line of defense strategies

First Line of Defense: Mechanical Barriers

• Unbroken skin and mucous membranes of the body create mechanical barriers that prevent the entry of certain pathogens
• Includes hair, mucus, and sweat and represents the first line of defense.
• The rest of the innate defenses are part of the second line of defense.

Second Line of Defense: Chemical Barriers

• Chemical barriers, such as the highly acidic environment provided by gastric juice or lysozyme in tears, kill many pathogens.
• Interferons are hormone-like peptides that serve as antiviral substances, produced by cells when they are infected with viruses, and induce nearby cells to produce antiviral enzymes that protect them from infection; may also stimulate phagocytosis.
• Activation of complement stimulates inflammation, attracts phagocytes, and enhances phagocytosis.

Natural Killer (NK) Cells

• NK cells are a type of lymphocyte that defends the body against various viruses and cancer cells by secreting cytolytic substances called perforins
• Also secrete chemicals that enhance inflammation.

Inflammation

• Inflammation is characterized by redness, swelling, heat, and pain
• Major actions include: dilation of blood vessels, increase in blood volume in affected areas, and invasion of white blood cells into the affected area.

Phagocytosis

• The most active phagocytes are neutrophils and monocytes; these leave the bloodstream at areas of injury by diapedesis
• They are attracted to the injured area by chemotaxis
• Neutrophils engulf smaller particles; monocytes attack larger ones
• Monocytes give rise to macrophages, which become fixed in various tissues
• Phagocytosis also removes foreign particles from the lymph.

Fever

• Fever offers powerful protection against infection by interfering with the proper conditions that promote bacterial growth
• During fever, the amount of iron in the blood is reduced, therefore fewer nutrients are available to support the growth of pathogens.
• Phagocytic cells attack with greater vigor when the temperature rises.

Phagocytic Cells

• Neutrophils, macrophages, and dendritic cells are phagocytic.
• Infectious agents are engulfed, and phagolysosomes destroy the agent, leaving residue that is exocytosed.

Apoptosis-Initiating Cells: NK Cell

• NK cells release perforin and granzyme
• Perforin forms a transmembrane pore, and granzymes enter the pore, causing apoptosis of the unhealthy or unwanted cell.

Immune System Defense Summary

• First line of defense are mechanical barriers such as skin and mucous membranes
• Second line of defense is chemical barriers such as enzymes, pH, salt, interferons and complement, natural killer cells, inflammation, phagocytosis, and fever
• Third line of defense includes cellular and humoral immune response.

Overview of the Immune System

• The innate immune system provides innate immunity through multiple components that protect against a wide array of substances, including skin and mucosal membranes (preventing entry) and nonspecific internal defenses
• Internal defenses involve cells (macrophages, NK cells), chemicals (interferon, complement), and physiologic responses (inflammation, fever).
• The adaptive immune system provides adaptive immunity through lymphocytes activated to replicate and respond when stimulated by a specific antigen
• Lymphocytes involve T-lymphocytes (cell-mediated immunity) and B-lymphocytes (humoral immunity)
• Plasma cells synthesize and release antibodies.

Effects of Interferon

• Infected cells release Interferon which acts on normal cells and NK cells to causes NK cells to attack
• Infected cells are phagocytized by a Macrophage

Complement System

• Is a group of over 30 plasma proteins, works along with ("complement") antibodies, is identified with letter “C” and number (e.g., C2), is synthesized by the liver, and continuously released in inactive form
• Activation occurs via enzyme cascade and is especially potent against bacterial infections.

Complement System Actions

• Opsonization: Complement (C) binds to pathogen and acts as opsonin
• Increased Inflammation: Complement activates and attracts various innate immune cells
• Cytolysis: Complement proteins create MAC to lyse cell
• Elimination of Immune Complexes: Complement (C) cross-links immune (antigen-antibody) complexes to erythrocyte, which transports to liver and spleen

Inflammation Events

• Injured tissue, basophils, mast cells, and infectious organisms release chemicals that initiate response
• Chemicals include histamine, leukotrienes, prostaglandins, and chemotactic factors cause vascular changes
• Released chemicals cause vasodilation, increased capillary permeability, and increased endothelial expression of molecules for leukocyte adhesion
• Recruitment of leukocytes; leukocytes release cytokines stimulating leukopoiesis in marrow
• Macrophages may release pyrogens
• Delivery of plasma proteins to site: Immunoglobulins, complement, clotting proteins, and kinins
• Clotting proteins form clots that wall off microbes and kinins stimulate pain receptors, and increase capillary permeability

Inflammation Effects

• Fluid (exudate) moves from blood to injured or infected area and fluids eliminate pathogens, promote healing
• Vasodilation brings more blood to the area and increases capillary permeability
• Loss of plasma proteins: Extra fluid is taken up by lymphatic capillaries in the area (“washing") that carry away debris and allow lymph node monitoring of its contents. Additionally, some fluid remains in interstitial space (swelling)
• Within 72 hours, the inflammatory response slows
• Macrophages eat bacteria, damaged host cells, and dying neutrophils
• Tissue repair begins as fibroblasts form new connective tissue.

Key Steps of Inflammation

• Release of inflammatory and chemotactic factors, vascular changes, recruitment of immune cells, and delivery of plasma proteins.

Cardinal Signs of Inflammation

• Redness is from increased blood flow
• Heat is from increased blood flow and increased metabolic activity within the area
• Swelling is from increase in fluid loss from capillaries
• Pain is from the stimulation of pain receptors due to compression (extra fluid) and chemical irritants (kinins, prostaglandins, microbial secretions)
• Loss of function results from pain and swelling in severe cases
• Duration of acute inflammation averages 8 to 10 days.

Fever

• (pyrexia): abnormal body temperature elevation of 1°C or more from normal (37°C). Also results from the release of pyrogens from immune cells or infectious agents
• Pyrogens circulate through blood and target the hypothalamus
• In response, the hypothalamus releases prostaglandin E2 then raises temperature set point leading to fever

Benefits of Fever

• Inhibits reproduction of bacteria and viruses
• Promotes interferon activity and increases activity of adaptive immunity
• Accelerates tissue repair and increases immune cells migrating out of blood
• It is recommended to leave a low fever untreated.

Risks of a High Fever

• High fevers are potentially dangerous, may cause changes in metabolic pathways and denaturation of proteins.
• Also possible seizures, irreversible brain damage greater than 106 F (41.1°C) are possible
• Death is likely if temperature is greater than 109 F (42.8°C).

Overview of Adaptive Immunity

• Adaptive immunity involves specific lymphocyte responses to an antigen; contact with an antigen causes lymphocyte proliferation
• The immune response consists of lymphocytes and their products
• Has a longer response time than innate immunity
• Takes days to develop and is considered the third line of body's defense.
• Two branches of adaptive immunity: cell-mediated immunity involving T-lymphocytes, and humoral immunity involving B-lymphocytes.

Adaptive Immunity - Cell-Mediated vs Humoral

• In cell-mediated immunity, T-lymphocytes are effective against antigens within cells and requires an antigen-presenting cell
• In Humoral immunity, B-lymphocytes are effective against antigens outside cells and do not require an antigen-presenting cell.
• T-lymphocytes form cytotoxic T-lymphocytes that destroys cells through apoptosis and Helper T-lymphocytes which releases molecules that regulate the immune system
• B-lymphocytes form plasma cells that produce antibodies.

Formation of Lymphocytes

• Naive immunocompetent B-lymphocytes originates and developed in the red bone marrow
• Pre-T-lymphocytes migrate from the red bone marrow to the Thymus where they develop to becomes naive immunocompetent T-lymphocytes.

T-Cell development in the Thymus

• Includes 3 steps
• Positive selection: survival dependent upon ability to bind to MHC molecule
• Negative selection: survival dependent upon not recognizing self-antigen
• Selective loss of either CD4 or CD8 proteins
• Only 2% of cells survive the selection process in the thymus.
• Regulatory T-lymphocytes (T-Regs) are a subtype of helper T-Cells, where CD4+ cells that are formed from T-cells that mildly bind self-antigens
• Help to in inhibiting immune response.

T-Lymphocytes and B-Lymphocytes

• Helper T-Lymphocytes (Helper T Cells/CD4+) stimulate Cytotoxic T cells, macrophages, and B cells to make immune responses.
• Cytotoxic T-Lymphocytes (Cytotoxic T-Cells/CD8+ Cells) can kill foreign cells, cancer cells, and cells infected with a virus.

Activation of T-Lymphocytes & Antigen Presenting Cells

• T-lymphocytes require that another cell display the foreign antigen on their plasma membrane; the T-Cell can then bind with the antigen and activate its immune response. These are known as Antigen Presenting Cells (APCs).
• Two types of cells can present Antigens
• Our own bodies cells (they present self antigens, which our T-Cells recognize and don't attack) have self antigens that are attached to MHC Class 1 molecules on the cell surface.
• Damaged or infected cells will change the self antigen on the MHC 1 molecule for a foreign antigen, which will be recognized by the T-Cells - the T-cells will mount an immune response to destroy it
• Immune Antigen Presenting Cells (APCS)
• Dendrites and macrophages are professional APCs which come in contact with a foreign cell and engulf the cell (phagocytosis)
• APC's present foreign cell's antigens on specialized MHC II (MHC class 2) receptors on their cell surface; the T-Cells recognize this and activate an immune response.

Antigen and Formation of MHC class I Molecules

• MHC class I molecules are continuously synthesized by the Rough endoplasmic reticulum (RER)
• During production, peptide fragments of the cell (self-antigens) bind with the MHC class I molecules
• Transport vesicles that contain MHC class I molecules with bound self-antigen are produced from the RER and shipped by the endomembrane system through the Golgi apparatus to the plasma membrane, where they are displayed.

Unhealthy Cell - Antigen and Formation of MHC class I Molecules

• Proteins of viral particles (or other microbes) are digested by proteasomes into peptide fragments and taken up into the RER
• MHC class I molecules are synthesized by the RER, and peptide fragments of the viral particle (foreign antigen) become attached to MHC class I molecules
• Transport vesicles are produced from the RER that contain MHC class I molecules with viral peptide fragments; they are shipped by the endomembrane system through the Golgi apparatus to the plasma membrane
• MHC class I molecules with bound foreign antigen are displayed within the plasma membrane.

Exogenous Pathway - Antigen and Formation of MHC class II Molecules

• MHC class II molecules are synthesized by the Rough endoplasmic reticulum (RER) and shipped by the endomembrane system through the Golgi apparatus and form transport vesicles
• During the process of phagocytosis and destruction of an exogenous antigen, vesicles that contain digested peptide fragments (phagosomes) combine with a lysosome. This is a phagolysosome
• Secretory vesicles that contain MHC class II molecules merge with the phagolysosome containing the digested foreign antigen
• The antigen MHC class II molecules bind with foreign antigen and are displayed within the plasma membrane.

Helper vs Cytotoxic T-lymphocytes Effector Responses

• Helper T-lymphocytes effector response: releases cytokines (e.g., IL-2) that regulates the cells of the immune system (both adaptive and innate).
• Cytotoxic T-lymphocytes effector response: Releases cytotoxic chemicals which induces apoptosis of abnormal cells

B-Lymphocytes.

• B-cells are produced in the red bone marrow and migrate to secondary lymphoid structures where they await activation from foreign antigens
• Unlike T-cells, B-lymphocytes do not require antigen presentation from another cell in order to be activated.

Activation of B-Lymphocytes

• B-Cells reacts with a foreign cell, they will engulf that cell (phagocytosis)
• B-Cells then differentiate into Plasma Cells and Memory B-Cells
• Plasma cells produce antibodies; memory B-Cells responds to subsequent exposures of the same infectious/foreign cell

Antibodies (Immunoglobulins)

• Are immunoglobulin (Ig) proteins produced against a particular antigen
• Antibodies “tag” pathogens for destruction by immune cells
• Exhibit good defense against viruses, bacteria, toxins, and yeast spores

Antibody Functions

• Precipitation: Makes soluble antigens insoluble, aiding elimination.
• Agglutination: Links cell-bound antigens together, causing clumping.
• Neutralisation: Masks dangerous parts of pathogen (e.g. exotoxins, etc.)
• Inflammation: Triggers histamine release, increasing immune mobility
• Complement: Complement protein perforates the cell membrane (cell lysis)

Opsonization

• Is a process by which a pathogen is marked for phagocytosis by an antibody.

Types of Antibodies

• There are five major types of antibodies (immunoglobulins) that constitute the gamma globulin fraction of the plasma.
• IgG is in tissue fluid and plasma and defends against bacterial cells, viruses, and toxins; activates complement, and can cross the placenta
• IgA is in exocrine gland secretions (breast milk, saliva, tears, nasal fluid, gastric and intestinal juices, bile, urine). Prevents attachment of bacteria to mucous membranes
• IgM is found in plasma and activates complement and reacts with blood cells during transfusions.
• IgD is found on the surface of most B lymphocytes and functions in B cell activation.
• IgE is found in exocrine gland secretions and promotes allergic reactions; involved in the defense against worm infections

Primary and Secondary Response in Humoral Immunity

• Primary response takes longer and has a lower Serum antibody titer compared with the Secondary response

Practical Classification of Immunity

• Naturally acquired active immunity occurs after exposure to the antigen itself.
• Artificially acquired active immunity occurs through the use of vaccines, without the person becoming ill from the disease.
• Artificially acquired passive immunity involves the injection of gamma globulin (antiserum) and is short-lived.
• Naturally acquired passive immunity occurs as antibodies are passed from mother to fetus or baby.

Types of Immunity Summary

• Active Immunity: Production of memory cells due to contact with antigen
• Naturally acquired: Direct exposure to antigen following entry of the pathogen into the body naturally
• Artificially acquired: Antigen exposure from vaccine
• Passive Immunity: No production of memory cells; antibodies from another person or an animal
• Naturally acquired: Transfer is mother to child across the placenta or in breast milk
• Artificially acquired: Transfer of serum containing antibody from another person or an animal

Clinical View: Vaccinations

• Use a weakened or dead microorganism or component to stimulate the immune system to develop memory B-lymphocytes; provides a relatively safe means for initial exposure to microorganism
• if later exposed, secondary response triggered, and Immune system response predominantly from the humoral branch

Clinical View: Hypersensitivities

• Is an abnormal and exaggerated response of immune system to antigen
• Acute hypersensitivities occur within seconds (anaphylactic)
• Subacute hypersensitivities occur within 1 to 3 hours (or a bit longer) and involve humoral immunity
• Delayed hypersensitivities occur within 1 to 3 days and involves cell-mediated immunity