Bio2305 Immune System Body Defenses

Reconnaissance, Recognition, and Response

Must defend from the many dangerous pathogens it may encounter in the environment

• 
  Detect invader/foreign cells
  
• 
  Communicate alarm & recruit immune cells
  
• 
  Suppress or destroy invader
  

• 
  Innate immunity and acquired immunity
  

• 
  Innate immunity provides broad defenses against infection
  
• 
  Present before any exposure to pathogens and is effective from the time of birth
  
• 
  Involves nonspecific responses to pathogens
  
• 
  A pathogen that successfully breaks through an animal’s external defenses encounters several innate cellular and chemical mechanisms that impede its attack on the body
  
• 
  Non-selective and no lag time – immediate response, no previous exposure required
  
• 
  Protects against infections, toxins
  
• 
  Works with specific (acquired) immune response
  

- Depends on B and T lymphocytes

- Specific immune response directed attack against pathogens (antigen)

- Lag time

- Previous Antigen exposure required

- Protects against pathogens and cancer cells

- Types

- Antibody-mediated: B cells

• 
  Physical barriers, secretion, chemical toxins
  
• 
  Phagocytosis - macrophages neutrophils engulf and digest recognized "foreign" cells – molecules
  
• 
  Inflammatory response - localized tissue response to injury producing swelling, redness, heat, pain
  
• 
  Natural Killer cells – special class of lymphocyte-like cells that destroy virus infected cells and cancer cells
  
• 
  Complements system activated proteins that destroy pathogen plasma membranes and enhance phagocytosis, inflamation
  
• 
  Interferon - proteins that non-specifically defend against viral infection
  

• 
  Physical barriers prevent entry of microorganisms & viruses
  

1. 
   Epidermis - provides a physical barrier, periodic shedding removes microbes
   
2. 
   Mucous membranes and mucus - traps microbes and foreign particles
   
3. 
   Hair - within the nose filters air containing microbes, dust, pollutants
   
4. 
   Cilia - lines the upper respiratory tract traps and propels inhaled debris to throat
   
5. 
   Lacrimal apparatus - produces tears that cleanse the eye
   
6. 
   Saliva - dilutes the number of microorganisms and washes the teeth and mouth
   
7. 
   Urine - flush microbes out of the urethra
   
8. 
   Defecation and vomiting - expel microorganisms.
   

• 
  Chemical factors
  

1. 
   Skin acidity - inhibit bacterial growth b/w 3 & 5
   
2. 
   Sebum -unsaturated fatty acids provide a protective film and inhibit growth, toxic to microbes
   
3. 
   Lysozyme- found in perspiration, tears, saliva can breakdown the cell wall of certain bacterial
   
4. 
   Hyaluronic acid - gelatinous substance that slows the spread of noxious agents
   
5. 
   Gastric Juice - strong acid that destroys ingested microbes and most toxins
   

1. Scavenge dead, dying body cells

2. Destroy abnormal (cancerous)

3. Protect from pathogens & foreign molecules: parasites, bacteria, viruses

• 
  Detect invader/foreign cells, communicate alarm & recruit immune cells, suppress or destroy invader
  

• 
  Scavenge dead, dying body cells, remove cellular debris
  
• 
  Engulf and digest recognized "foreign" cells
  
• 
  Destroy abnormal (cancerous)
  
• 
  Protect from pathogens & foreign molecules: parasites, bacteria, viruses
  

• 
  Monocyte - macrophage system – free and fixed
  
• 
  Margination – stick to the inner endothelial lining of capillaries of affected tissue
  
• 
  Move by diapedesis – move thru capillary walls
  
• 
  Microphages – Neutrophils and eosinophils
  
• 
  Exhibit chemotaxis
  

• 
  Kinins - stimulate complement system (plasma proteins), chemotaxins, pain
  
• 
  Clotting factors – walling off invasion
  
• 
  Lysosomal enzymes – destroy invaders
  

Fastest response of all WBC to bacteria and parasites

Direct actions against bacteria

- Release lysozymes which destroy/digest bacteria

- Release defensive proteins that act like antibiotics

- Release strong oxidants (bleach-like, strong chemicals) that destroy bacteria

- Leave capillaries to enter tissue fluid

- Attack parasitic worms

- Phagocytize antibody-antigen complexes

- Take longer to get to site of infection, but arrive in larger numbers

- Become free (roaming) macrophages, once they leave the capillaries

- Destroy microbes and clean up dead tissue following an infection

• 
  Phagocytes attach to their prey via surface receptors and engulf them, forming a vacuole that fuses with a lysosome
  

• 
  Chemotaxis
  
  • 
    Attraction to certain chemical mediators
    
  • 
    Released at the site of damage
    
  • 
    Chemotaxins induce phagocytes to injury
    
• 
  Opsonization
  
  • 
    Identify (mark) pathogen
    
  • 
    Coated with chemical mediators
    
  • 
    Most important opsonins
    
• 
  Toll-like receptors (TLR’s)
  
  • 
    Phagocytic cells studded with plasma membrane receptor proteins
    
  • 
    Bind with pathogen markers
    
  • 
    Recognition - Allow phagocytes to “see” and distinguish from self-cells
    

• 
  Inflammation – histamine release from mast cells and other chemicals released from injured cells promote changes in blood vessels
  
• 
  Changes allow more fluid, phagocytes, and antimicrobial proteins to enter tissues
  
• 
  Effects of inflammation include
  
  • 
    Mobilization of local, regional, and systemic defenses
    
  • 
    Slow the spread of pathogens
    
  • 
    Temporary repair of injury
    

• 
  Macrophages, mast cells release histamine
  
  • 
    Localized vasodilation
    
  • 
    Capillary permeability - increased gaps in capillaries bring more WBC's & plasma proteins
    
  • 
    Swelling, redness, heat and pain are incidental
    
• 
  Injured cells and phagocytes release cytokines (chemical signals)
  
  • 
    Kinins - stimulate complement system (plasma proteins)
    
  • 
    Chemotaxins – attract more phagocytes
    
  • 
    Clotting factors – walling off invasion
    

- Patrol the body and attack virus-infected body cells and cancer cells

- Recognize cell surface markers on foreign cells

- Destroy cells with foreign antigens

- Rotation of the Golgi toward the target cell and production of perforins

- Release of perforins by exocytosis

• 
  Proteins function in innate defense by attacking microbes directly or impeding their reproduction
  
  • 
    Complement System - About 30 proteins involved in the lysis of invading cells and helps trigger inflammation
    
  • 
    Interferons – small proteins provide innate defense against viruses and help activate macrophages
    

• 
  System of inactive proteins produced by liver circulating in blood and on cell membranes
  
• 
  Cascade of plasma complement proteins (C) activated by antibodies or antigens causing cascade of chemical reactions
  
• 
  Direct effect is lysis of microorganisms by destroying target cell membranes
  
• 
  Indirect effects include:
  
  • 
    Chemotaxis
    
  • 
    Opsonization
    
  • 
    Inflammation: recruit phagocytes, B & T lymphocytes
    

• 
  Small antiviral proteins released by lymphocytes, macrophages, virally infected cells
  
• 
  3 Major types of interferons are:
  
  • 
    Alpha– produced by leukocytes and attract/stimulate NK cells
    
  • 
    Beta– secreted by fibroblasts causing slow inflammation
    
  • 
    Gamma – secreted by T cells and NK cells stimulate macrophage activity
    
• 
  Type I interferons – Alpha and Beta
  
  • 
    Induced during many virus infections
    
    • 
      IFN- a: Mainly by leukocytes
      
    • 
      IFN- b: Mainly by fibroblast cells
      
  • 
    Binds to membranes of adjacent, uninfected cells
    
  • 
    Triggers production of proteins that interfere with viral replication
    
  • 
    Enhances macrophage, natural killer, and cytotoxic T cell & B cell activity
    
  • 
    Slows cell division and suppresses tumor growth
    
• 
  Type II Interferon - gamma
  
  • 
    Activates macrophages and other immune cells
    

• 
  In acquired immunity, lymphocytes provide specific defenses against infection
  
• 
  Involves
  
  • 
    Cell mediated immunity: T cells
    
  • 
    Antibody mediated immunity: B cells
    
• 
  Depends on B and T lymphocytes - specific immune response directed attack against pathogens (antigen)
  
• 
  Lag time ~ two weeks, previous Antigen exposure required
  
• 
  Protects against pathogens and cancer cells
  

• 
  Antigen triggers an immune response
  
• 
  Activates T cells and B cells
  
  • 
    T cells are activated after phagocytes exposed to antigen
    
• 
  T cells attack the antigen and stimulate B cells
  
• 
  Activated B cells mature and produce antibody
  
• 
  Antibody attacks antigen
  

• 
  Specificity – activated by and responds to a specific antigen
  
• 
  Versatility – is ready to confront any antigen at any time
  
• 
  Memory – “remembers” any antigen it has encountered
  
• 
  Tolerance – responds to foreign substances but ignores normal tissues
  

• 
  Primary lymphatic organs – Bone marrow and Thymus
  
  • 
    Lymphocytes mature into functional cells (red bone marrow B cells and thymus T cells)
    
  • 
    Bone marrow – origin of blood cells
    
  • 
    Thymus – site of maturing T Lymphocytes
    
• 
  Secondary lymphatic organs - lymph nodes, spleen
  
  • 
    Site of immune response – lymph nodes
    
  • 
    Lymph nodes – Exchange Lymphocyte w/ lymph (remove, store, produce, add)
    
    • 
      Resident macrophages remove microbes and debris from lymph
      
    • 
      Lymphocytes produce antibodies and sensitized T cells released in lymph
      
  • 
    Spleen – Exchange Lymphocytes with blood, residents produce antibodies and sensitized T cells released in blood
    

• 
  B cells originate and mature in bone marrow
  
• 
  T cells originate in bone marrow, migrate then mature in thymus
  

• 
  An antigen is any foreign molecule that is specifically recognized by lymphocytes and elicits a response from them
  
• 
  A lymphocyte actually recognizes and binds to just a small, accessible portion of the antigen called an epitope or antigenic determinant
  
  • 
    Antigenic determinants - Specific regions of a given antigen recognized by a lymphocyte
    
  • 
    Antigenic receptors -Surface of lymphocyte that combines with antigenic determinant
    

• 
  A single B cell or T cell has about 100,000 identical antigen receptors
  
• 
  All antigen receptors on a single cell recognize the same epitope
  

• 
  Antigens that stimulate this response are mainly intracellular (cell to cell).
  
• 
  Requires constant presence of antigen to remain effective
  
• 
  Involves numerous cytokines, over 100 have been identified
  
• 
  Stimulate and/or regulate immune responses
  
  • 
    Interleukins: Communication between WBCs
    
  • 
    Interferons: Protect against viral infections
    
  • 
    Chemotaxins: Attract WBCs to infected areas
    

• 
  Over 18 different types of interleukins are known; designated IL-1, IL-2…IL-18, etc.
  
• 
  IL-1 and IL-2 are primarily responsible for activating T and B lymphocytes, with IL-2 being a stimulant of T- and B-cell growth and maturation
  
• 
  IL-1, along with IL-6, is also a mediator of inflammation.
  
• 
  IL-4 often leads to an increase in antibody secretion by B lymphocytes
  
• 
  IL-12 causes a greater number of the leukocytes cytotoxic T cells and natural killer cells to be made
  
• 
  The set of interleukins produced by the presence of a specific infectious agent determines which cells will respond to the infection
  

• 
  Cytotoxic T cells – attack foreign cells
  
• 
  Helper T cells - activate other T cells and B cells
  
• 
  Suppressor T cells– inhibit the activation of T and B cells
  
• 
  Memory T cells – function during a second exposure to antigen
  
• 
  T cell membranes contain CD markers
  
  • 
    CD3 markers present on all T cells
    
  • 
    CD8 markers on cytotoxic and suppressor T cells
    
  • 
    CD4 markers on helper T cells
    

• 
  T cells are activated when they detect and bind to small fragments of antigens that are combined with to cell-surface glycoproteins called major histocompatability complex (MHC) molecules
  
• 
  Lymphocytes respond to antigens bound to either class I or class II MHC proteins depending on the source of the MHC molecule and antigen presenting cell
  
• 
  Class I MHC molecules are displayed on the surface of infected nucleated cells, resulting in destruction of cells
  
• 
  Class II MHC molecules are displayed on the surface of phagocytes (antigen-presenting cells), resulting in activation of immune cells
  

• 
  Macrophages & Dendritic Cells engulf foreign antigens by phagocytosis, proteins broken down into peptides
  
• 
  Peptides go to ER and Golgi where they are attached to new MHC self antigen molecules
  
• 
  New self antigen and its antigen fragment are added to the cell membrane and presented to lymphocytes
  
• 
  T Cells Only Recognize Antigen Associated with MHC Molecules on Cell Surfaces
  

• 
  Infected cells produce class I MHC molecules which bind to antigen fragments and then are transported to the cell surface in a process called antigen presentation
  
• 
  Binds and activates with cytotoxic T cell receptor
  
• 
  Cytotoxic T cell response
  
  • 
    Clonal production of cytotoxic T cells and memory cells
    
  • 
    Destruction of virus-infected cells, tumor cells, and tissue transplants
    

• 
  Killer Ts or CD8
  
• 
  Recognize and destroy host cells that are infected with viruses or bacteria, cancer cells, transplanted tissue
  
• 
  Release protein called perforin which forms a pore in target cell, causing lysis of infected cells.
  
• 
  Produce cytokines, which promote phagocytosis and inflammation
  
• 
  Undergo apoptosis when stimulating antigen is gone.
  

• 
  Produced by dendritic cells, macrophages, and B cells
  
• 
  Macrophages & dendritic cells phagocytize antigens, proteins broken down into antigen fragments (peptides) and combined with Class II MHC molecules
  
• 
  Binds and activates Helper T cells
  
  • 
    Clonal production of Helper T cells
    
  • 
    Activation of Cytotoxic T cells
    
  • 
    Activation of B cells
    

• 
  T Helper (TH) Cells: main role in immune response
  
• 
  Recognize antigen on the surface of antigen presenting cells
  
• 
  Secrete Interleukin II (T-cell growth factor), interferon and cytokines which stimulate lymphocyte activity
  
  • 
    Production and activation of Cytotoxic T cells and more Helper T cells
    
  • 
    Stimulate B cells to produce antibodies
    

• 
  Can survive a long time and give lifelong immunity from infection
  
• 
  Can stimulate memory B-cells to produce antibodies
  
• 
  Can trigger production of killer T cells
  
• 
  Thymosin - hormone important in T cell lineage, enhances capabilities of existing T cells and the proliferation of new T cells in lymphoid tissues - decreases after age 30-40
  

• 
  Involves production of antibodies against foreign antigens
  
• 
  Antibodies are produced B cells
  
• 
  B cells that are stimulated will actively secrete antibodies and are called plasma cells
  
• 
  Antibodies (immunoglobulins, Ig) are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells.
  
• 
  Defend against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells
  
• 
  Also cause certain reactions against transplanted tissue
  
• 
  1000s of different B cells, each recognizes a different antigen on the surface of a macrophage.
  
• 
  Each antigen stimulates production of a single specific antibody that the B cells (along with T cells) come in contact with
  
• 
  They are stimulated (by TH cells) to produce many clones, plasma cells, which make antibodies.
  
• 
  Memory B cells – secondary response = faster, more sensitive
  

• 
  Antibodies or Immunoglobulins (Ig)
  
  • 
    Classes: IgG, IgM, IgA, IgE, IgD
    
  • 
    Structure
    
    • 
      Variable region - combines with anitgenic determinant of antigen
      
    • 
      Constant region - responsible for other binding activities
      

• 
  (Immunoglobulins, Ig) are proteins that recognize specific antigens and bind to them.
  
• 
  They are found in extracellular fluids (blood plasma, lymph, mucus, etc.) and the surface of B cells
  
• 
  Defense against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they enter cells.
  
• 
  Also cause certain reactions against transplanted tissue.
  
• 
  Antigenic determinants - specific regions of a given antigen recognized by a lymphocyte
  
• 
  Antigenic receptors are found on surface of lymphocyte that combines with antigenic determinant to form Antigen-Antibody Complex
  
• 
  Antibodies affinity: A measure of binding strength.
  

• 
  Agglutination - antibodies cause antigens (microbes) to clump together
  
• 
  Opsonization and Phagocytosis
  
• 
  Activates Complement System / Inflammatory Response
  
• 
  Neutralization
  
• 
  Antibody dependent NK / eosinophil cell response
  

• 
  Activate B lymphocyte production of:
  
  • 
    Memory cells for secondary immune response to that antigen
    
  • 
    Plasma cells that secrete antibodies
    

• 
  Percentage serum antibodies: 80%,
  

• 
  location: Blood, lymph, intestine Only lg that crosses placenta, thus conferring passive immunity on fetus
  

• 
  Promotes opsonization, neutralization, and agglutination of antigens, protects fetus and newborn
  

• 
  Enhances phagocytosis, neutralizes toxins and viruses, protects fetus and newborn.
  

• 
  Percentage serum antibodies: 5-10%
  
• 
  Location: Blood, lymph, B cell surface (monomer)
  
• 
  First antibodies produced during an infection. Effective against microbes, complement activation and agglutinating antigens
  

• 
  Percentage serum antibodies: 10-15%
  
• 
  Location: Secretions (tears, saliva, intestine, breast milk), blood and lymph
  
• 
  Provides localized defense of mucous membranes by agglutination and neutralization of antigens
  
• 
  Localized protection of mucosal surfaces. Presence in breast milk confers passive immunity on nursing infant
  

• 
  Percentage serum antibodies: 0.2%
  
• 
  Location: Found primarily on surface of naive B cells that have not been exposed to antigens
  
• 
  Acts as antigen receptor in antigen-stimulated proliferation and differentiation of B cells (clonal selection)
  

• 
  Percentage serum antibodies: 0.002%
  
• 
  Location: Bound to mast cells and basophils throughout body
  
• 
  Triggers release of histamine and other chemicals that cause allergic reactions
  

• 
  B cells develop from stem cells in the bone marrow of adults (liver of fetuses).
  
• 
  After maturation B cells migrate to lymphoid organs (lymph node or spleen).
  
• 
  Clonal Selection: When a B cell encounters an antigen it recognizes, it is stimulated and divides into many clones called plasma cells, which actively secrete antibodies.
  
• 
  Each B cell produces antibodies that will recognize only one antigenic determinant.
  

• 
  Sensitization – the binding of antigens to the B cell membrane antibodies
  
• 
  Helper T cells present the same antigen to stimulate B cell
  
• 
  Stimulated B cells divide into many clones called plasma cells, which actively secrete antibodies
  
• 
  Each B cell produces antibodies that will recognize only one antigenic determinant
  
• 
  Active B cells also differentiate into Memory B Cells
  

• 
  Primary Response:
  
  • 
    After initial exposure to antigen, no antibodies are found in serum for several days. A gradual increase number of Abs, first of IgM and then of IgG is observed.
    
  • 
    Most B cells become plasma cells, but some B cells become long living memory cells. Gradual decline of antibodies follows.
    
• 
  Secondary Response - Subsequent exposure to the same antigen displays a faster/more intense response due to the existence of memory cells, which rapidly produce plasma cells upon antigen stimulation
  

• 
  Clonal Selection: B cells (and T cells) that encounter stimulating antigen will proliferate into a large group of cells.
  
• 
  Why don’t we produce antibodies against our own antigens? We have developed tolerance to them.
  
• 
  Tolerance: To prevent the immune system from responding to self-antigens
  
  • 
    Clonal Deletion: B and T cells that react against self antigens are normally destroyed during fetal development
    
  • 
    Preventing activation of lymphocytes – activate suppressor T cells, control the immune system when the antigen / pathogen has been destroyed
    

• 
  Programmed cell death (“Falling away”).
  
• 
  Human body makes 100 million lymphocytes every day. If an equivalent number doesn’t die, will develop leukemia.
  
• 
  B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to dispose of their remains.
  
• 
  Many virus infected cells will undergo apoptosis, to help prevent spread of the infection.
  

• 
  Some diabetes mellitus – attack b- cells
  
• 
  Multiple sclerosis – attack on myelin nerve sheath
  
• 
  Rheumatoid arthritis – attack joint cartilage
  
• 
  Myasthenia gravis – ACh-receptors at endplate attacked
  

- First exposure: sensitization and activation clone B cells that form antibodies and memory cells

• 
  Body defends itself with barriers, chemicals & immune responses
  
• 
  WBCs and relatives conduct direct cellular attack: phagocytosis, activated NK & cytotoxic T cells and produce attack proteins (i.e. antibodies, complement, & membrane attack complex)
  
• 
  Cytokines, communicate cell activation, recruitment, swelling, pain, & fever in the inflammation response
  
• 
  Defense against bacteria is mostly innate while viral defense relies more on acquired immune responses
  
• 
  Autoimmune diseases are a failure of self-tolerance
  

• 
  Agglutination of red blood cells used to determine ABO blood types and to detect influenza and measles viruses