Bio2305 Immune System Body Defenses



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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

  • Two major kinds of defense have evolved that counter these threats

    • Innate immunity and acquired immunity


Innate 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


Innate Immunity

  • Non-selective

  • No lag time – immediate response

    • No previous exposure required

  • Protects against infections, toxins

  • Works with specific (acquired) immune response


Acquired (Adaptive) 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 Immunity (aka Humoral Immunity)

      • B Lymphocytes (B cells)

    • Cell-mediated immunity

      • T Lymphocytes (T cells)


Types of Immunity


Types of Immune Cells



Body Defenses



Innate Immunity

  • Physical barriers, secretions, 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, inflammation

  • Interferon – proteins that non-specifically defend against viral infection


Innate Immunity/External Defenses

  • Barriers - prevent entry of microorganisms and viruses

    • Physical barriers

      • Epidermis

      • Mucous Membranes

      • Hair, Cilia

      • Excretions - lacrimal, saliva

    • Chemical barriers

      • Skin acidity between 3 and 5, which is acidic enough to prevent colonization

      • Sebum toxic to microbes

      • Lysozymes digests the cell walls of many bacteria


Innate Immunity – Phagocytosis

  • Functions:

    • Scavenge dead and dying body cells, remove cellular debris

    • Destroy abnormal cells (cancerous and virus-infected cells)

    • Protect from pathogens & foreign molecules: parasites, bacteria, viruses

  • Exhibit Margination – leukocyte adhesion to the inner endothelial lining of capillaries of affected tissue

  • Move via Diapedesis – movement across capillary walls

  • Exhibit Chemotaxis – concentration-dependent movement of a cell in response to the detection of chemokines


Innate Immunity – Phagocytosis

  • Monocyte - Macrophage System:

    • vessel-bound, free, and fixed

    • monocytes and macrophage that accumulate in lymph nodes, spleen, and lungs

  • Monocytes:

    • Macrophage-precursors that remain within vessels

  • Macrophages:

    • Monocytes that have left the body’s vessels

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

  • Monocytes become free (roaming) macrophages, once they leave the capillaries

  • Destroy microbes and clean up dead tissue following an infection

Innate Immunity – Phagocytosis

  • Neutrophils

    • 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

  • Eosinophils

    • Leave capillaries to enter tissue fluid

    • Attack parasitic worms

    • Phagocytize antibody-antigen complexes

  • Dendritic Cells

    • a type of antigen presenting cells (with the broadest range)

    • present in tissues in contact with the external environment

    • Examples: Langerhans cells of the skin and follicular dendritic cells in the lymph nodes


Phagocytic Cells

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


Phagocytosis Mechanisms

  • 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 (antibodies, compliment proteins)

    • Marked for death, and phagocytized by phagocyte

  • 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



Inflammatory Response

  • 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


Inflammatory Response

  • Macrophages and 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


Natural Killer Cells

  • 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

  • Interaction of perforins causing cell lysis



Natural Killer Cells Kill Cellular Targets



Antimicrobial Proteins

  • 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



Complement System

  • System of inactive proteins produced by liver circulating in blood and on cell membranes

  • Cascade of plasma complement proteins 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

Complement Activation





Innate Cytokines – Interferons

  • Small antiviral proteins released by lymphocytes, macrophages, virally infected cells

  • 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

Integrated Defense

Acquired Immunity

  • In acquired immunity, lymphocytes provide specific defenses against infection

  • Involves

    • Cell mediated immunity

    • Antibody mediated immunity


Acquired Immunity

  • 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


Properties of Acquired Immunity

  • 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


Lymphatic System

  • Primary lymphatic organs – Bone marrow and Thymus

  • Secondary lymphatic organs - Lymph nodes, Spleen

    • 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



Lymphocytes

  • B and T cells originate in bone marrow

  • B cells remain in bone marrow for maturation

  • T cells leave bone marrow, and migrate to thymus gland for maturation

Lymphocytes – B and T cells


  • B cells – Antibody-mediated immunity (grenade launchers)




  • T cells – Cell-mediated immunity (hand-to-hand combat)


Antigens

  • 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


Antigen Recognition by Lymphocytes

  • 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



Cell-Mediated Immunity – T Cells

  • 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


Lymphocyte Communication

  • 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


Types of T cells

  • 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 Cell Activation

  • T cells are activated when they detect and bind to small fragments of antigens that are combined with to cell-surface glycoproteins called major histocompatibility 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 the antigen presenting cell

  • Class I MHC molecules are displayed on the surface of infected nucleated cells

  • Class II MHC molecules are displayed on the surface of phagocytes


Class I MHC molecules

  • 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



Cytotoxic T (TC) Cells – 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.


Class II MHC molecules

  • 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 – CD4

  • 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



T Cell Overview


Memory T-Cells

  • Can survive a long time and give lifelong immunity from infection

  • Can stimulate memory B-cells to produce antibodies

  • 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


Proliferation of Lymphocytes


Antibody-Mediated (Humoral) Immunity

  • Involves production of antibodies against foreign antigens

  • Plasma cells - B cells that are stimulated and begin actively secrete antibodies

  • Antibodies (immunoglobulins, Ig) are Y-shaped proteins 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


Antibody-Mediated (Humoral) Immunity

  • 1000s of different B cells, each recognizes a different antigen on the surface of a macrophage (specificity)

  • 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 provide secondary response (faster, more sensitive)


Antibody Structure

  • 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


Consequences of Antigen-Antibody Binding

  • Agglutination - antibodies cause antigens (microbes) to clump together

  • Opsonization and Phagocytosis – coating foreign substance with antibodies, allowing Phagocytes to grip and engulf the invader

  • Complement System / Inflammatory Response – lyse the invader and attract other immune cells (chemotaxis)

  • Neutralization – coat foreign substance, rendering it harmless

  • Antibody dependent NK/eosinophil cell response – Directly attack and lyse the cell using perforins



Consequences of Antigen-Antibody Binding


Antigen-Antibody Complex On B Cell

  • Activate B lymphocyte production of:

    • Memory B cells for secondary immune response to that antigen

    • Active Plasma Cells that secrete antibodiess


Immunoglobulin Classes

  • IgG

    • 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.

  • IgA

    • 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

  • IgM

    • 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



  • IgD

    • 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)

  • IgE

    • 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 Cell Sensitization And Activation

  • Sensitization – the binding of antigens to the B cell membrane antibodies

  • Activation - Helper T cells present same antigen to stimulate B cell

  • Division - Stimulated B cells divide into many clones called plasma cells, which actively secrete antibodies

  • Secretion - Each B cell secrete antibodies that will recognize only one antigenic determinant

  • Differentiation - Active B cells also differentiate into Memory B Cells


Immunological Memory

  • 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

  • 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


Apoptosis

  • Apoptosis - 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


Autoimmune Diseases: Failure of “Self-Tolerance”

  • Some diabetes mellitus – attack - cells

  • Multiple sclerosis – attack on myelin nerve sheath

  • Rheumatoid arthritis – attack joint cartilage

  • Myasthenia gravis – ACh-receptors at endplate attacked


Allergic Response: Inflammation Reaction to Non-pathogen

  • First exposure: sensitization

    • Activation

    • Clone B cells

    • Form antibodies

    • Memory cells

  • Re-exposure

    • Many antibodies

    • Activated T cells

    • Intensified

    • Inflammation



Hemagglutination

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



Summary

  • 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




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