Human Anatomy and Physiology II The Immune System Chapter 21 BSC 2086

Immune System Ch21 Outline Describe immunity and know how it is regulated by innate and adaptive defenses Know the cells involved in each and the functions they have Understand the difference between humoral and cellular immunity

Overview Immunity Resistance to disease Immune system has two intrinsic systems 1. Innate (nonspecific) defense system 2. Adaptive (specific) defense system

Surface barriers • Skin • Mucous membranes Innate defenses Internal defenses • Phagocytes • NK cells • Inflammation • Antimicrobial proteins • Fever Humoral immunity • B cells Adaptive defenses Cellular immunity • T cells

Innate Defense System Two lines of defense 1. Surface Barriers Skin and mucosa first line of defense Functions Mechanical barrier Inhibit entrance of pathogens Mucus, acidity, lysozyme

Innate Defense System Internal Defenses Cellular and chemical defenses are second line of defense Protection if microorganisms invade deeper in tissues Cells Phagocytes, Natural Killer (NK) cells, Mast cells, WBCs Chemicals interferons, complement Inflammation Fever

Immune Cells Phagocytes -engulf and destroy pathogens that breach epithelial barriers Macrophages Develop from monocytes and become the chief phagocytic cells Neutrophils Become phagocytic on encountering infectious material in tissues

An example of the body’s first line of defense is ____________. Macrophages Fever Inflammation Mucus

Immune Cells Natural Killer (NK) Cells Large granular lymphocytes Functions Attack cells that lack “self” cell-surface receptors Induce apoptosis in cancer cells and virus-infected cells Secrete potent chemicals that enhance the inflammatory response www.healingcancernaturally.com

Chemicals Antimicrobial Proteins Attack microbes or hinder their ability to reproduce Interferons Complement proteins

Interferons Viral infected cells secrete interferons Functions An SOS to neighboring cells Functions Induce other cells to secrete Anti-viral proteins Activate macrophages and mobilize NK cells

Antiviral proteins block viral reproduction. Innate defenses Internal defenses Virus 1 Virus enters cell. New viruses Viral nucleic acid Antiviral proteins block viral reproduction. 5 2 Interferon genes switch on. DNA Nucleus mRNA 4 Interferon binding stimulates cell to turn on genes for antiviral proteins. Cell produces interferon molecules. 3 Interferon Host cell 2 Binds interferon from cell 1; interferon induces synthesis of protective proteins Host cell 1 Infected by virus; makes interferon; is killed by virus

Complement ~20 plasma proteins that circulate in an inactive form Major mechanism for destroying foreign substances Functions of Activated Complement Enhances inflammation Promotes phagocytosis Causes cell lysis

Inflammation Cardinal signs of acute inflammation Redness Heat Swelling Pain

Inflammation Triggered whenever body tissues are injured or infected Prevents the spread of damaging agents Disposes of cell debris and pathogens Sets the stage for repair and healing Release of inflammatory mediators by injured tissue, phagocytes, lymphocytes, basophils, and mast cells Histamine, cytokines, kinins, prostaglandins (PGs), leukotrienes, and complement

Inflammatory Response Results Vasodilation and increased vascular permeability Inflammatory chemicals cause Dilation of arterioles Increased permeability of local capillaries and edema

Fever Systemic response to invading microorganisms Leukocytes and macrophages exposed to foreign substances secrete pyrogens Pyrogens reset the body’s thermostat upward

Fever Benefits of moderate fever Causes the liver and spleen to sequester iron and zinc (needed by microorganisms) Increases metabolic rate, which speeds up repair High fevers are dangerous because heat denatures enzymes (proteins)

Why is a moderate fever helpful in the immune response? Speeds up metabolism Causes liver and spleen to sequester iron and zinc Slows metabolism Both A and B Both B and C

Surface barriers • Skin • Mucous membranes Innate defenses Internal defenses • Phagocytes • NK cells • Inflammation • Antimicrobial proteins • Fever Humoral immunity • B cells Adaptive defenses Cellular immunity • T cells

Adaptive Defenses Adaptive immune response Is specific Is systemic Has memory Two separate overlapping arms of defense Humoral (antibody-mediated) immunity Cellular (cell-mediated) immunity

Cells of the Adaptive Immune System Lymphocytes Originate in red bone marrow B cells mature in the red bone marrow T cells mature in the thymus Become immunocompetent when mature Two requirements of immunocompetence They are able to recognize and bind to a specific antigen Self-tolerance – unresponsive to self antigens

Development of Self Tolerance Positive selection: T cells must recognize self major histocompatibility proteins (self-MHC). Antigen- presenting thymic cell Developing T cell Failure to recognize self-MHC results in apoptosis (death by cell suicide). MHC T cell receptor Self-antigen Recognizing self-MHC results in MHC restriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceed to negative selection.

Development of Self Tolerance Positive selection: T cells must recognize self major histocompatibility proteins (self-MHC). Antigen- presenting thymic cell Developing T cell Failure to recognize self-MHC results in apoptosis (death by cell suicide). MHC T cell receptor Self-antigen Recognizing self-MHC results in MHC restriction—survivors are restricted to recognizing antigen on self-MHC. Survivors proceed to negative selection. Negative selection: T cells must not recognize self-antigens. Recognizing self-antigen results in apoptosis. This eliminates self-reactive T cells that could cause autoimmune diseases. Failure to recognize (bind tightly to) self-antigen results in survival and continued maturation.

Lymphocytes destined to become T cells Humoral immunity Red bone marrow: site of lymphocyte origin Adaptive defenses Cellular immunity Primary lymphoid organs: site of development of immunocompetence as B or T cells Immature lymphocytes Red bone marrow Secondary lymphoid organs: site of antigen encounter, and activation to become effector and memory B or T cells Lymphocytes destined to become T cells migrate (in blood) to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow. 1 Thymus Bone marrow Immunocompetent but still naive lymphocytes leave the thymus and bone marrow. They “seed” the lymph nodes, spleen, and other lymphoid tissues where they encounter their antigen. 2 Lymph nodes, spleen, and other lymphoid tissues Antigen-activated immunocompetent lymphocytes (effector cells and memory cells) circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body. 3

Humoral Immunity Cells and agents of Humoral Immunity B cells Plasma cells Memory B cells Antibodies Provide defenses against extracellular antigens

Review: Antigens Substances that can mobilize the adaptive defenses and provoke an immune response Most are large, complex molecules not normally found in the body (nonself)

Humoral Immunity Response Step 1: Antigen challenge First encounter between an antigen and a naive immunocompetent B lymphocyte Usually occurs in the spleen or a lymph node The antigen provokes a humoral immune response

Step 2: Clonal Selection B cell is activated when antigens bind to its surface receptors Stimulated B cell grows to form clones of identical cells bearing the same antigen-specific receptors

Fate of the Clones Most clone cells become plasma cells secrete specific antibodies at the rate of 2000 molecules per second for four to five days Secreted antibodies Circulate in blood or lymph Bind to free antigens Mark antigens for destruction

Fate of the Clones Clone cells that do not become plasma cells become memory cells Provide immunological memory Mount an immediate response to future exposures of the same antigen

Clonal Selection Primary response Antigen (initial encounter with antigen) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules

Immunological Memory Primary Immune Response Occurs on the first exposure to a specific antigen Lag period: three to six days Peak levels of plasma antibody are reached in 10 days Antibody levels then decline

Immunological Memory Secondary Immune Response Occurs on re-exposure to the same antigen Sensitized memory cells respond within hours Antibody levels peak in two to three days at much higher levels Antibodies bind with greater affinity Antibody levels can remain high for weeks to months

Primary response (initial encounter with antigen) Antigen Antigen binding to a receptor on a specific B lymphocyte (B lymphocytes with non-complementary receptors remain inactive) Proliferation to form a clone Activated B cells Plasma cells (effector B cells) Memory B cell— primed to respond to same antigen Secreted antibody molecules Subsequent challenge by same antigen results in more rapid response Secondary response (can be years later) Clone of cells identical to ancestral cells Plasma cells Secreted antibody molecules Memory B cells

Secondary immune response to antigen A is faster and larger; primary immune response to antigen B is similar to that for antigen A. Primary immune response to antigen A occurs after a delay. Anti- bodies to B Anti- bodies to A First exposure to antigen A Second exposure to antigen A; first exposure to antigen B Time (days)

When are memory cells first produced? Primary immune response Secondary immune response Neither A or B

Humoral immunity Active Passive Naturally acquired Artificially acquired Naturally acquired Artificially acquired Infection; contact with pathogen Vaccine; dead or attenuated pathogens Antibodies pass from mother to fetus via placenta; or to infant in her milk Injection of immune serum (gamma globulin)

Active Humoral Immunity Occurs when B cells encounter antigens and produce specific antibodies against them Two types Naturally acquired—response to a bacterial or viral infection Artificially acquired—response to a vaccine of dead or attenuated pathogens

Active Humoral Immunity Vaccines Spare us the symptoms of the primary response Provide antigenic determinants that are immunogenic and reactive Downside, target only one type of helper T cell, so fail to fully establish cellular immunological memory

Passive Humoral Immunity Two types Naturally acquired—antibodies delivered to a fetus via the placenta or to infant through milk Artificially acquired—injection of serum, such as gamma globulin Protection is immediate but ends when antibodies naturally degrade in the body B cells are not challenged by antigens Immunological memory does not occur

What part of the humoral immune defenses includes getting a flu vaccine? Naturally Acquired Passive Naturally Acquired Active Artificially Acquired Passive Artificially Acquired Active

Actions of Antibodies Antibodies inactivate and tag antigens Form antigen-antibody (immune) complexes Defensive mechanisms used by antibodies Neutralization and agglutination (the two most important) Precipitation and complement fixation

(cell-bound antigens) Antigen-antibody complex Antigen Antibody Inactivates by Fixes and activates Neutralization (masks dangerous parts of bacterial exotoxins; viruses) Agglutination (cell-bound antigens) Precipitation (soluble antigens) Complement Enhances Enhances Leads to Phagocytosis Inflammation Cell lysis Chemotaxis Histamine release

Cell-Mediated Immunity Antigen-Presenting Cells (APCs) Functions Engulf antigens Present fragments of antigens to be recognized by T cells Major types of APCs Dendritic cells in connective tissues and epidermis Macrophages in connective tissues and lymphoid organs B cells

Cell-Mediated Immunity T cells provide defense against intracellular antigens Four types of T cells helper T cells (TH) cytotoxic T cells (TC) destroy cells harboring foreign antigens Regulatory T cells (TREG) = Supressor T cells Memory T cells

(or regulatory T cells) Immature lymphocyte Red bone marrow T cell receptor T cell receptor Maturation Class II MHC protein Class I MHC protein CD4 cell CD8 cell Thymus Activation Activation APC (dendritic cell) Memory cells APC (dendritic cell) CD4 CD8 Lymphoid tissues and organs Effector cells Helper T cells (or regulatory T cells) Cytotoxic T cells Blood plasma

T Cell Activation APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells

Antigen Recognition Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) in a receptor on an APC T cells must simultaneously recognize Nonself (the antigen) Self (an MHC protein of a body cell)

T Cell Activation Step 2: T cells that are activated Enlarge, proliferate, and form clones Differentiate and perform functions according to their T cell class

Viral antigen Dendritic cell engulfs an exogenous antigen, processes it, and displays its fragments on class II MHC protein. 1 Class lI MHC protein displaying processed viral antigen Dendritic cell CD4 protein Immunocompetent CD4 cell recognizes antigen-MHC complex. Both TCR and CD4 protein bind to antigen-MHC complex. 2 T cell receptor (TCR) Immunocom- petent CD4 T cell Clone formation CD4 cells are activated, proliferate (clone), and become memory and effector cells. 3 Helper T memory cell Activated helper T cells

Actions of Helper T Cells Play a central role in the adaptive immune response Once primed by APC presentation of antigen Help activate T and B cells Induce T and B cell proliferation Activate macrophages and recruit other immune cells Without TH, there is no cellular immune response

TH cell help in cell-mediated immunity CD4 protein 1 Helper T cell Previously activated TH cell binds dendritic cell. Class II MHC protein APC (dendritic cell) TH cell stimulates dendritic cell to express co-stimulatory molecules (not shown) needed to activate CD8 cell. 2 IL-2 Dendritic cell can now activate CD8 cell with the help of interleukin 2 secreted by TH cell. 3 Class I MHC protein CD8 protein CD8 T cell

When do we produce memory T cells? Antigen challenge Primary immune response Secondary immune response Both B and C During a fever

Actions of Cytotoxic T Cells Directly attack and kill other cells Activated TC cells circulate in blood, lymph and lymphoid organs in search of body cells displaying antigen they recognize Targets Virus-infected cells Cells with intracellular bacteria or parasites Cancer cells Foreign cells (transfusions or transplants)

1 2 3 4 5 Adaptive defenses Cellular immunity Cytotoxic T cell (TC) TC binds tightly to the target cell when it identifies foreign antigen on MHC I proteins. 1 TC releases perforin and granzyme molecules from its granules by exocytosis. 2 Granule Perforin molecules insert into the target cell membrane, polymerize, and form transmembrane pores (cylindrical holes) similar to those produced by complement activation. 3 Perforin TC cell membrane Target cell membrane Granzymes enter the target cell via the pores. Once inside, these proteases degrade cellular contents, stimulating apoptosis. 4 Target cell Perforin pore Granzymes The TC detaches and searches for another prey. 5 A mechanism of target cell killing by TC cells.

Actions of Regulatory T Cells Dampen the immune response by direct contact or by inhibitory cytokines Important in preventing autoimmune reactions

physical attack on the Ag Cell-mediated immunity Humoral immunity Antigen (Ag) intruder Inhibits Inhibits Triggers Adaptive defenses Innate defenses Surface barriers Internal defenses Free Ags may directly activate B cell Ag-infected body cell engulfed by dendritic cell Antigen- activated B cells Becomes Clone and give rise to Ag-presenting cell (APC) presents self-Ag complex Activates Activates Memory B cells Naïve CD8 T cells Naïve CD4 T cells Activated to clone and give rise to Activated to clone and give rise to Induce co-stimulation Plasma cells (effector B cells) Memory cytotoxic T cells Memory helper T cells Secrete Activated cytotoxic T cells Activated helper T cells Cytokines stimulate Antibodies (Igs) Nonspecific killers (macrophages and NK cells of innate immunity) Circulating lgs along with complement mount a chemical attack on the Ag Together the nonspecific killers and cytotoxic T cells mount a physical attack on the Ag