The Immune System: Innate and Adaptive Body Defenses: Part A

10/9/2014

PowerPoint® Lecture Slides Immunity prepared by Barbara Heard, Atlantic Cape Community • Resistance to disease College • Immune system – Two intrinsic systems C H A P T E R 21 • Innate (nonspecific) defense system • Adaptive (specific) defense system The Immune System: Innate and Adaptive Body © Annie Leibovitz/Contact Press Images © 2013 Pearson Education, Inc. Defenses: © 2013 Pearson Education, Inc. Part A

Immune System Immunity

• Functional system rather than organ • Innate defense system has two lines of system defense • Innate and adaptive defenses intertwined – First - external body membranes (skin and • Release and recognize many of same mucosae) defensive molecules – Second - antimicrobial proteins, phagocytes, • Innate defenses do have specific and other cells pathways for certain substances • Inhibit spread of invaders • Innate responses release proteins that • Inflammation most important mechanism alert cells of adaptive system to foreign molecules

Immunity Figure 21.1 Overview of innate and adaptive defenses. Surface barriers • Skin • Mucous membranes • Adaptive defense system Innate – Third line of defense attacks particular foreign defenses Internal defenses • Phagocytes substances • Natural killer cells • Inflammation • Takes longer to react than innate system • Antimicrobial proteins • Fever

Humoral immunity • B cells Adaptive defenses

Cellular immunity • T cells

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Innate Defenses Surface Barriers

• Surface barriers ward off invading • Protective chemicals inhibit or destroy pathogens microorganisms – Acidity of skin and secretions – acid mantle – – Skin, mucous membranes, and their inhibits growth secretions – Enzymes - lysozyme of saliva, respiratory • Physical barrier to most microorganisms mucus, and lacrimal fluid – kill many • Keratin resistant to weak acids and bases, microorganisms bacterial enzymes, and toxins – Defensins – antimicrobial peptides – inhibit • Mucosae provide similar mechanical barriers growth – Other chemicals - lipids in sebum, dermcidin in sweat – toxic

Surface Barriers Internal Defenses: Cells and Chemicals

• Respiratory system modifications • Necessary if microorganisms invade – Mucus-coated hairs in nose deeper tissues – Cilia of upper respiratory tract sweep dust- – Phagocytes and bacteria-laden mucus toward mouth – Natural killer (NK) cells • Surface barriers breached by nicks or cuts – Antimicrobial proteins (interferons and - second line of defense must protect complement proteins) deeper tissues – Fever – Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)

Phagocytes Mechanism of Phagocytosis

• Neutrophils most abundant but die fighting • Phagocyte must adhere to particle – Become phagocytic on exposure to infectious – Some microorganisms evade adherence with material capsule • Macrophages develop from monocytes – chief • Opsonization marks pathogens—coating by phagocytic cells – robust cells complement proteins or antibodies • Free macrophages wander through tissue spaces, • Cytoplasmic extensions bind to and engulf e.g., alveolar macrophages • Fixed macrophages permanent residents of some particle in vesicle called phagosome organs; e.g., stellate macrophages (liver) and • Phagosome fuses with lysosome  microglia (brain) phagolysosome

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Figure 21.2a Phagocytosis. Figure 21.2b Phagocytosis. Slide 1 1 Phagocyte Innate defenses Internal defenses adheres to pathogens or debris.

2 Phagocyte forms pseudopods that Phagosome eventually engulf the (phagocytic particles, forming a vesicle) phagosome. Lysosome 3 Lysosome fuses with the phagocytic vesicle, forming a phagolysosome. Acid hydrolase enzymes 4 Lysosomal enzymes digest the particles, leaving a residual body.

5 Exocytosis of the A macrophage (purple) uses its cytoplasmic vesicle removes extensions to pull rod-shaped bacteria indigestible and (green) toward it. Scanning electron residual material. micrograph (4800x). Events of phagocytosis. © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc.

Mechanism of Phagocytosis Natural Killer (NK) Cells

• Pathogens killed by acidifying and digesting with • Nonphagocytic large granular lymphocytes lysosomal enzymes • Attack cells that lack "self" cell-surface • Helper T cells cause release of enzymes of receptors respiratory burst, which kill pathogens resistant to lysosomal enzymes by – Induce apoptosis in cancer cells and virus- infected cells – Releasing cell-killing free radicals

– Producing oxidizing chemicals (e.g., H2O2) • Secrete potent chemicals that enhance – Increasing pH and osmolarity of phagolysosome inflammatory response • Defensins (in neutrophils) pierce membrane

Inflammatory Response Inflammatory Response

• Triggered whenever body tissues injured • Cardinal signs of acute inflammation: • Prevents spread of damaging agents 1. Redness • Disposes of cell debris and pathogens 2. Heat • Alerts adaptive immune system 3. Swelling 4. Pain • Sets the stage for repair (Sometimes 5. Impairment of function)

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Inflammatory Response Inflammatory Response

• Begins with chemicals released into ECF • Inflammatory mediators by injured tissues, immune cells, blood – Kinins, prostaglandins (PGs), and proteins complement • Macrophages and epithelial cells of • Dilate local arterioles (hyperemia) boundary tissues bear Toll-like receptors – Causes redness and heat of inflamed region (TLRs) • Make capillaries leaky • 11 types of TLRs recognize specific • Many attract leukocytes to area classes of infecting microbes • Some have inflammatory roles • Activated TLRs trigger release of cytokines that promote inflammation

Inflammatory Response: Edema Inflammatory Response

•  Capillary permeability  exudate to • Clotting factors form fibrin mesh tissues – Scaffold for repair – Fluid containing clotting factors and – Isolates injured area so invaders cannot antibodies spread – Causes local swelling (edema) – Swelling pushes on nerve endings  pain • Pain also from bacterial toxins, prostaglandins, and kinins – Moves foreign material into lymphatic vessels – Delivers clotting proteins and complement

Figure 21.3 Inflammation: flowchart of events. Innate defenses Internal defenses Phagocyte Mobilization

Initial stimulus Physiological response Signs of inflammation Tissue injury Result • Neutrophils lead; macrophages follow

Release of inflammatory chemicals Release of leukocytosis- (histamine, complement, inducing factor kinins, prostaglandins, etc.) – As attack continues, monocytes arrive

Leukocytosis (increased numbers of white • 12 hours after leaving bloodstream  blood cells in bloodstream)

Arterioles Increased capillary Attract neutrophils, macrophages dilate permeability monocytes, and lymphocytes to Leukocytes migrate to area (chemotaxis) injured area • These "late-arrivers" replace dying neutrophils and

Local hyperemia Capillaries (increased blood leak fluid Margination remain for clean up prior to repair flow to area) (exudate formation) (leukocytes cling to capillary walls)

Diapedesis • If inflammation due to pathogens, Leaked protein-rich Leaked clotting (leukocytes pass through fluid in tissue spaces proteins form interstitial capillary walls) clots that wall off area to prevent injury to complement activated; adaptive immunity surrounding tissue Phagocytosis of pathogens Heat Redness Pain Swelling and dead tissue cells (by neutrophils, short-term; by macrophages, long-term) elements arrive Locally increased Possible temporary Temporary fibrin Pus may form temperature increases impairment of patch forms metabolic rate of cells function scaffolding for repair Area cleared of debris

Healing

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Figure 21.4 Phagocyte mobilization. Slide 1 Phagocyte Mobilization Innate defenses Internal defenses

• Steps for phagocyte mobilization 1. Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis- Inflammatory inducing factors from injured cells chemicals diffusing 4 Chemotaxis. 2. Margination: neutrophils cling to walls of from the Neutrophils follow inflamed chemical trail. capillaries in inflamed area in response to site act as CAMs chemotactic Capillary wall agents. Basement 3. Diapedesis of neutrophils membrane Endothelium 4. Chemotaxis: inflammatory chemicals (chemotactic agent) promote positive

chemotaxis of neutrophils 1 Leukocytosis. 2 Margination. 3 Diapedesis. Neutrophils enter Neutrophils cling Neutrophils flatten blood from bone to capillary wall. and squeeze out of marrow. capillaries. © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc.

Antimicrobial Proteins Interferons

• Include interferons and complement • Family of immune modulating proteins proteins – Have slightly different physiological effects • Some attack microorganisms directly • Viral-infected cells secrete IFNs (e.g., IFN • Some hinder microorganisms' ability to alpha and beta) to "warn" neighboring reproduce cells – IFNs enter neighboring cells  produce proteins that block viral reproduction and degrade viral RNA – IFN alpha and beta also activate NK cells

Figure 21.5 The interferon mechanism against viruses. Slide 1 Interferons Innate defenses Internal defenses Virus Viral nucleic acid 1 Virus New viruses enters cell. • IFN gamma (immune interferon) 5 Antiviral proteins – Secreted by lymphocytes block viral reproduction. – Widespread immune mobilizing effects – Activates macrophages • Since IFNs activate NK cells and macrophages, Antiviral 2 Interferon mRNA indirectly & directly fight cancer. HOW- Neighboring cells genes switch DNA on. make anitiviral when IF stimulated ..after formed IF can Nucleus mRNA for activate NK cells to attack cancer cells . interferon

• Artificial IFNs used to treat hepatitis C, genital warts, 4 Interferon binding stimulates cell to multiple sclerosis, hairy cell leukemia 3 Cell turn on genes for produces Interferon antiviral proteins. interferon receptor molecules. Interferon Host cell 2 Host cell 1 Binds interferon Infected by virus; from cell 1; interferon makes interferon; induces synthesis of is killed by virus © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc. protective proteins

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Complement System (Complement) Complement

• ~20 blood proteins that circulate in inactive • Unleashes inflammatory chemicals that form amplify all aspects of inflammatory • Include C1–C9, factors B, D, and P, and response regulatory proteins • Kills bacteria and certain other cell types • Major mechanism for destroying foreign by cell lysis substances • Enhances both innate and adaptive • Our cells contain complement activation defenses inhibitors

Complement Activation Complement

• Three pathways to activation • Lectin pathway – Classical pathway – Lectins - produced by innate system to • Antibodies bind to invading organisms and to recognize foreign invaders complement components – When bound to foreign invaders can also bind • Called complement fixation and activate complement • First step in activation; more details later • Alternative pathway – Activated spontaneously, lack of inhibitors on microorganism's surface allows process to proceed

Complement Activation Complement Activation

• Each pathway involves activation of • Cell lysis begins when – C3b binds to target cell  insertion of complement proteins in an orderly sequence proteins called membrane attack complex (MAC) • Each step catalyzes the next into cell's membrane – MAC forms and stabilizes hole in membrane  influx • Each pathway converges on C3, which of water  lysis of cell cleaves into C3a and C3b • C3b also causes opsonization • Common terminal pathway initiated that • C3a and other cleavage products amplify inflammation – Enhances inflammation, promotes – Stimulate mast cells and basophils to release phagocytosis, causes cell lysis histamine – Attract neutrophils and other inflammatory cells

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Figure 21.6 Complement activation.

Classical pathway Lectin pathway Alternative pathway Fever Activated by antibodies Activated by lectins Activated spontaneously. Lack of coating target cell binding to specific sugars inhibitors on microorganism’s on microorganism’s surface surface allows process to proceed • Abnormally high body temperature Together with other complement proteins and factors

C3 • Systemic response to invading

C3a C3b microorganisms C3b Opsonization: Enhances inflammation: C5b C5a Coats pathogen Stimulates histamine surfaces, which C6 release, increases blood • Leukocytes and macrophages exposed to enhances phagocytosis vessel permeability, MAC C7 attracts phagocytes by C8 chemotaxis, etc. foreign substances secrete pyrogens C9 MACs form from activated complement components (C5b and C6–C9) that insert into the target cell membrane, creating • Pyrogens act on body's thermostat in pores that can lyse the target cell. Pore hypothalamus, raising body temperature Complement proteins (C5b–C9)

Membrane of target cell

Fever Adaptive Defenses

• Benefits of moderate fever • Adaptive immune (specific defense) – Causes liver and spleen to sequester iron and system zinc (needed by microorganisms) – Protects against infectious agents and – Increases metabolic rate  faster repair abnormal body cells – Amplifies inflammatory response – Activates complement – Must be primed by initial exposure to specific foreign substance • Priming takes time

Adaptive Defenses Humoral Immunity

• Specific – recognizes and targets specific • Antibodies, produced by lymphocytes, antigens circulating freely in body fluids • Systemic – not restricted to initial site • Bind temporarily to target cell • Have memory – stronger attacks to – Temporarily inactivate "known" antigens – Mark for destruction by phagocytes or • Two separate, overlapping arms complement – Humoral (antibody-mediated) immunity • Humoral immunity has extracellular targets – Cellular (cell-mediated) immunity

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Cellular Immunity Antigens

• Lymphocytes act against target cell • Substances that can mobilize adaptive – Directly – by killing infected cells defenses and provoke an immune – Indirectly – by releasing chemicals that response enhance inflammatory response; or activating • Targets of all adaptive immune responses other lymphocytes or macrophages • Most are large, complex molecules not • Cellular immunity has cellular targets normally found in body (nonself)

Complete Antigens Haptens (Incomplete Antigens)

• Important functional properties • Small molecules (haptens) not – Immunogenicity: ability to stimulate immunogenic by themselves proliferation of specific lymphocytes – E.g., peptides, nucleotides, some hormones – Reactivity: ability to react with activated • May be immunogenic if attached to body lymphocytes and antibodies released by proteins and combination is marked immunogenic reactions foreign • Examples: foreign protein, • Cause immune system to mount harmful polysaccharides, lipids, and nucleic acids attack • Examples: poison ivy, animal dander, detergents, and cosmetics

Antigenic Determinants Antigenic Determinants

• Only certain parts (antigenic • Most naturally occurring antigens have determinants) of entire antigen are numerous antigenic determinants that immunogenic – Mobilize several different lymphocyte • Antibodies and lymphocyte receptors bind populations to them as enzyme binds substrate – Form different kinds of antibodies against them • Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

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Figure 21.7 Most antigens have several different antigenic determinants. Self-antigens: MHC Proteins

• Protein molecules (self-antigens) on Antigen- Antigenic determinants binding surface of cells not antigenic to self but sites Antibody A antigenic to others in transfusions or grafts • Example: MHC glycoproteins

Antigen – Coded by genes of major histocompatibility complex (MHC) and unique to individual – Have groove holding self- or foreign antigen Antibody B Antibody C • T lymphocytes can only recognize antigens that are presented on MHC proteins

Cells of the Adaptive Immune System Lymphocyte Development, Maturation, and Activation • Three types of cells • Five general steps – Two types of lymphocytes – Origin – all originate in red bone marrow • B lymphocytes (B cells)—humoral immunity – Maturation • T lymphocytes (T cells)—cellular immunity – Seeding secondary lymphoid organs and – Antigen-presenting cells (APCs) circulation • Do not respond to specific antigens – Antigen encounter and activation • Play essential auxiliary roles in immunity – Proliferation and differentiation

Figure 21.8 Lymphocyte development, maturation, and activation. Slide 1 Humoral immunity Primary lymphoid organs Maturation Adaptive defenses (red bone marrow and thymus) Cellular immunity Secondary lymphoid organs (lymph nodes, spleen, etc.)

Red bone marrow 1 Origin • "Educated" to become mature; B cells in • Both B and T lymphocyte precursors originate in red bone marrow. Lymphocyte bone marrow, T cells in thymus precursors

2 Maturation • Lymphocyte precursors destined to become T cells migrate (in blood) to the thymus and mature there. – Immunocompetence – lymphocyte can • B cells mature in the bone marrow. • During maturation lymphocytes develop immunocompetence Thymus and self-tolerance. recognize one specific antigen by binding to it Red bone marrow • B or T cells display only one unique type of antigen 3 Seeding secondary lymphoid organs and circulation • Immunocompetent but still naive lymphocytes leave the receptor on surface when achieve maturity – bind thymus and bone marrow. • They “seed” the secondary lymphoid organs and circulate through blood and lymph. only one antigen Antigen

4 Antigen encounter and activation – Self-tolerance Lymph node • When a lymphocyte’s antigen receptors bind its antigen, that lymphocyte can be activated. • Lymphocytes unresponsive to own antigens

5 Proliferation and differentiation • Activated lymphocytes proliferate (multiply) and then differentiate into effector cells and memory cells. • Memory cells and effector T cells circulate continuously in the blood and lymph and throughout the secondary lymphoid organs. © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc.

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T cells

• START THURSDAY • T cells mature in thymus under negative and positive selection pressures ("tests") – Positive selection • Selects T cells capable of recognizing self-MHC proteins (MHC restriction); failures destroyed by apoptosis – Negative selection • Prompts apoptosis of T cells that bind to self- antigens displayed by self-MHC • Ensures self-tolerance

Figure 21.9 T cell education in the thymus. Adaptive defenses Cellular immunity B cells 1. Positive Selection T cells must recognize self major histocompatibility proteins (self-MHC) Antigen- presenting Developing thymic cell T cell • B cells mature in red bone marrow

Failure to recognize self- MHC results in apoptosis • Positively selected if successfully make (death by cell suicide).

Self-MHC T cell receptor antigen receptors Self-antigen

Recognizing self-MHC results in survival. • Those that are self-reactive Survivors proceed to negative selection. – Eliminated by apoptosis (clonal deletion)

2. 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.

Antigen Encounter and Activation Table 21.3 Overview of B and T Lymphocytes

• Clonal selection – Naive lymphocyte's first encounter with antigen  selected for further development – If correct signals present, lymphocyte will complete its differentiation

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Figure 21.11a Clonal selection of a B cell. Immunological Memory

Adaptive defenses Humoral immunity • Primary immune response Primary response Antigen (initial encounter Antigen binding with antigen) to a receptor on a – Cell proliferation and differentiation upon first specific B lymphocyte (B lymphocytes with antigen exposure Proliferation to noncomplementary form a clone receptors remain – Lag period: three to six days Activated B cells inactive) – Peak levels of plasma antibody are reached in 10 days – Antibody levels then decline Plasma cells Memory B cell— (effector B cells) primed to respond to same antigen Secreted antibody molecules

Figure 21.12 Primary and secondary humoral responses. Immunological Memory Secondary immune response to Primary immune antigen A is faster and larger; primary response to antigen immune response to antigen B is A occurs after a delay. similar to that for antigen A. • Secondary immune response – Re-exposure to same antigen gives faster, 104 more prolonged, more effective response

• Sensitized memory cells respond within hours 103 • Antibody levels peak in two to three days at much higher levels 102 • Antibodies bind with greater affinity 101 • Antibody level can remain high for weeks to Anti- Anti- Bodies Bodies

months (arbitraryunits) plasma in to A to B 100

0 7 14 21 28 35 42 49 56 Antibody titer (antibody concentration) concentration) (antibody titer Antibody First exposure Second exposure to antigen A; to antigen A first exposure to antigen B Time (days) © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc.

Active Humoral Immunity Active Humoral Immunity

• When B cells encounter antigens and • Vaccines produce specific antibodies against them – Most of dead or attenuated pathogens • Two types of active humoral immunity: – Spare us symptoms of primary response – Naturally acquired—response to bacterial or – Provide antigenic determinants that are viral infection immunogenic and reactive – Artificially acquired—response to vaccine of dead or attenuated pathogens

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Passive Humoral Immunity Passive Humoral Immunity

• Readymade antibodies introduced into • Two types body 1. Naturally acquired—antibodies delivered to • B cells are not challenged by antigens fetus via placenta or to infant through milk • Immunological memory does not occur 2. Artificially acquired—injection of serum, such as gamma globulin • Protection ends when antibodies degrade • Protection immediate but ends when antibodies naturally degrade in body

Figure 21.13 Active and passive humoral immunity. Antibodies Humoral immunity • Immunoglobulins—gamma globulin portion of blood Active Passive • Proteins secreted by plasma cells • Capable of binding specifically with antigen detected by B cells Naturally Artificially Naturally Artificially acquired acquired acquired acquired • Grouped into one of five Ig classes Infection; Vaccine; Antibodies Injection of contact dead or passed from exogenous with attenuated mother to antibodies pathogen pathogens fetus via (gamma placenta; or globulin) to infant in her milk

Basic Antibody Structure Figure 21.14a Antibody structure. Adaptive defenses Humoral immunity

• Constant (C) regions of stem Antigen-binding – Determine antibody class (IgM, IgA, IgD, IgG, site or IgE) – Serve common functions in all antibodies by Heavy chain dictating variable region Heavy chain • Cells and chemicals that antibody can bind constant region Hinge region • How antibody class functions to eliminate Light chain Stem region antigens variable region Light chain constant region Disulfide bond

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Classes of Antibodies Table 21.4 Immunoglobulin Classes (1 of 2)

• IgM – Pentamer (larger than others); first antibody released – Potent agglutinating agent – Readily fixes and activates complement • IgA (secretory IgA) – Monomer or dimer; in mucus and other secretions – Helps prevent entry of pathogens

Classes of Antibodies Classes of Antibodies

• IgD • IgE – Monomer attached to surface of B cells – Monomer active in some allergies and – Functions as B cell receptor parasitic infections (EEEK !) • IgG – Causes mast cells and basophils to release histamine – Monomer; 75–85% of antibodies in plasma – From secondary and late primary responses • B cells can switch antibody classes but retain antigen specificity – Crosses placental barrier – IgM at first; then IgG – Almost all secondary responses are IgG

Table 21.4 Immunoglobulin Classes (2 of 2) Antibody Targets and Functions

• Antibodies inactivate and tag antigens; do not destroy them – Form antigen-antibody (immune) complexes • Defensive mechanisms used by antibodies – Neutralization and agglutination (the two most important) – Precipitation and complement fixation

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Figure 21.15 Mechanisms of antibody action.

Adaptive defenses Humoral immunity T cell Activation: Proliferation and

Antigen Antigen-antibody Antibody complex Differentiation

Inactivates by Fixes and activates • Primary T cell response peaks within a week

Neutralization Agglutination Precipitation Complement • T cell apoptosis occurs between days 7 and 30 (masks dangerous (cell-bound antigens) (soluble antigens) parts of bacterial exotoxins; viruses) – Benefit of apoptosis: activated T cells are a hazard – produce large amount inflammatory cytokines  hyperplasia, cancer • Effector activity wanes as amount of antigen

Enhances Enhances Leads to declines

Phagocytosis Inflammation Cell lysis • Memory T cells remain and mediate secondary responses

Chemotaxis

Histamine release

Cytokines Cytokines

• Chemical messengers of immune system • IL-2 key growth factor, acting on cells that • Mediate cell development, differentiation, release it and other T cells and responses in immune system – Encourages activated T cells to divide rapidly • Include interferons and interleukins • Other cytokines amplify and regulate • Interleukin 1 (IL-1) released by innate and adaptive responses macrophages co-stimulates bound T cells – E.g., tumor necrosis factor – cell toxin to – E.g., gamma interferon – enhances killing power of macrophages – Release interleukin 2 (IL-2) – Synthesize more IL-2 receptors

Roles of Helper T (TH) cells Helper T cells: Activation of B cells

• Play central role in adaptive immune • Interact directly with B cells displaying antigen response fragments bound to MHC II receptors – Activate both humoral and cellular arms • Stimulate B cells to divide more rapidly and begin antibody formation – Once primed by APC presentation of antigen, they • B cells may be activated without TH cells by • Help activate T and B cells binding to T cell–independent antigens • Induce T and B cell proliferation – Response weak and short-lived • Their cytokines recruit other immune cells • Most antigens require TH co-stimulation to activate B cells: T cell–dependent antigens • Without TH, there is no immune response

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Figure 21.18a The central role of helper T cells in mobilizing both humoral and cellular immunity. Slide 1 Helper T cells: Activation of CD8 cells Helper T cells help in humoral immunity

Helper T cell • CD8 cells require TH cell activation into 1 TH cell binds T cell receptor (TCR) with the self-nonself destructive cytotoxic T cells complexes of a B cell that has encountered • Cause dendritic cells to express co- Helper T cell its antigen and is CD4 protein displaying it on stimulatory molecules required for CD8 MHC II on its surface. MHC II protein cell activation of B cell displaying processed antigen 2 TH cell releases interleukins as co- IL-4 and other stimulatory signals to cytokines complete B cell activation.

B cell (being activated)

Figure 21.18b The central role of helper T cells in mobilizing both humoral and cellular immunity. Slide 1 Helper T cells: Amplification of Innate Helper T cells help in cellular immunity Defenses CD4 protein Helper T cell • Amplify responses of innate immune Class II MHC 1 TH cell binds dendritic cell. protein system APC (dendritic cell) • Activate macrophages  more potent 2 TH cell stimulates dendritic IL-2 killers cell to express co-stimulatory • Mobilize lymphocytes and macrophages molecules. and attract other types of WBCs 3 Dendritic cell can now activate Class I CD8 CD8 cell with the MHC protein protein help of interleukin 2 CD8 T cell secreted by TH cell. (becomes TC cell after activation)

Helper T cells: Subsets of TH cells Cytotoxic T (TC) cells

• TH1 – mediate most aspects of cellular • Directly attack and kill other cells immunity • Activated TC cells circulate in blood and • TH2 – defend against parasitic worms; lymph and lymphoid organs in search of mobilize eosinophils; promote allergies body cells displaying antigen they recognize • TH17 – link adaptive and innate immunity by releasing IL-17; may play role in autoimmune disease

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Roles of Cytotoxic T (TC) cells Cytotoxic T cells

• Targets • Lethal hit – two methods:

– Virus-infected cells – TC cell releases perforins and granzymes by – Cells with intracellular bacteria or parasites exocytosis – Cancer cells • Perforins create pores through which granzymes enter target cell – Foreign cells (transfusions or transplants) • Granzymes stimulate apoptosis

– TC cell binds specific membrane receptor on target cell, and stimulates apoptosis

Figure 21.19 Cytotoxic T cells attack infected and cancerous cells. Natural Killer cells

Adaptive defenses Cellular immunity

Cytotoxic 1 2 T releases 3 Perforin molecules insert into T identifies C T cell (TC) C perforin and the target cell membrane, foreign antigens granzyme polymerize, and form transmembrane on MHC I proteins molecules from its pores (cylindrical holes) similar to and binds tightly • Recognize other signs of abnormality granules by those produced by complement to target cell. exocytosis. activation. – Lack of class I MHC Granule Perforin – Antibody coating target cell

TC cell membrane Cytotoxic T cell – Different surface markers of stressed cells

Target • Use same key mechanisms as T cells for cell C membrane

Target Cancer cell killing their target cells cell Perforin pore Granzymes • Immune surveillance—NK and TC cells 4 Granzymes enter the 5 The TC detaches target cell via the pores. prowl for markers they recognize and searches for Once inside, granzymes another prey. activate enzymes that trigger apoptosis.

A mechanism of target cell killing by TC cells. Scanning electron micrograph of a TC cell killing a cancer cell (2100x).

Figure 21.20 Simplified summary of the primary immune response.

Cellular Humoral Antigen (Ag) intruder Organ Transplants immunity immunity

Inhibits Inhibits Triggers

Adaptive defenses Innate defenses

Surface Internal • Four varieties barriers defenses – Autografts: from one body site to another in Free Ags may directly activate B cell Ag-infected body cell engulfed same person by dendritic cell Antigen- activated Becomes B cells – Isografts: between identical twins Clone and give rise to Ag-presenting cell (APC) presents self-Ag complex – Allografts: between individuals who are not

Activates Activates Memory B cells identical twins Naive Naive CD8 CD4

T cells stimulate release and cytokines

T cells - Co Present Ag Present Ag to activated T helper cells – Xenografts: from another animal species Activated to clone Activated to clone and give rise to Induce and give rise to Memory Plasma cells Memory co-stimulation (effector B cells) CD8 CD4 T cells T cells

Secrete Cytotoxic Helper T cells T cells

Cytokines stimulate

Nonspecific killers Antibodies (Igs) Together the nonspecific killers (macrophages and and cytotoxic T cells mount a NK cells of innate Circulating lgs along with complement physical attack on the Ag immunity) mount a chemical attack on the Ag © 2013 Pearson Education, Inc. © 2013 Pearson Education, Inc.

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Organ Transplants Prevention of Rejection

• Success depends on similarity of tissues • After surgery – Autografts and isografts ideal donor tissues – Patient treated with immunosuppressive • Almost always successful if good blood supply and therapy no infection • Corticosteroid drugs to suppress inflammation – Research into successful xenografts from • Antiproliferative drugs genetically engineered animals • Immunosuppressant drugs – Most common is allograft • Many of these have severe side effects • ABO, other blood antigens, MHC antigens matched as closely as possible

Immunosuppressive Therapy Problems Immunosuppressive Therapy Problems

• Patient's immune system suppressed • Research to induce tolerance – Cannot protect from foreign agents – Chimeric immune system – Bacterial and viral infections  death • Suppress recipient's bone marrow – Must balance drugs for graft survival but no • Douse recipient's bone marrow with bone marrow from donor of new organ toxicity • "Combined" immune system may treat – Use antibiotics to control infections transplanted organ as self – Best circumstances – rejection after 10 years – Harness regulatory T cell to suppress immune in 50% of patients reactions

Immunodeficiencies Congenital Immunodeficiencies

• Congenital or acquired conditions that • Severe Combined Immunodeficiency impair function or production of immune (SCID) Syndrome - genetic defect cells or molecules such as complement or – Marked deficit in B and T cells antibodies – Defective adenosine deaminase (ADA) enzyme • Metabolites lethal to T cells accumulate – Fatal if untreated; treated with bone marrow transplants

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Hodgkin's Disease Acquired Immune Deficiency Syndrome (AIDS) • Acquired immunodeficiency • Cripples immune system by interfering • Cancer of B cells with activity of helper T cells • Leads to immunodeficiency by depressing • Characterized by severe weight loss, night lymph node cells sweats, and swollen lymph nodes • Opportunistic infections occur, including pneumocystis pneumonia and Kaposi's sarcoma

Acquired Immune Deficiency Syndrome Treatment of Autoimmune Diseases (AIDS) • Caused by human immunodeficiency virus • Suppress entire immune system (HIV) transmitted via body fluids—blood, – Anti-inflammatory drugs, e.g., corticosteroids semen, and vaginal secretions – Blocking cytokine action • HIV enters the body via – Blocking co-stimulatory molecules – Blood transfusions; blood-contaminated • Research needles; sexual intercourse and oral sex; – Activating regulatory T cells; inducing self- mother to fetus tolerance using vaccines; directing antibodies • HIV against self-reactive immune cells

– Destroys TH cells  depresses cellular immunity

Immediate Hypersensitivity Anaphylactic Shock

• Acute (type I) hypersensitivities (allergies) • Systemic response to allergen that directly begin in seconds after contact with enters blood and circulates rapidly allergen • Basophils and mast cells enlisted throughout body • Initial contact is asymptomatic but • Systemic histamine release may cause sensitizes person – Constriction of bronchioles; tongue may swell • Reaction may be local or systemic – Sudden vasodilation and fluid loss from bloodstream may  – Circulatory collapse (hypotensive shock) and death • Treatment: epinephrine

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Class I MHC Proteins

• Just extra outline from TEXT not covered • Bind with fragment of protein synthesized in the in class cell (endogenous antigen) • Endogenous antigen is self-antigen in normal cell; a nonself antigen in infected or abnormal cell • Crucial for CD8 cell activation • Inform cytotoxic T cells of microorganisms hiding in cells (cytotoxic T cells ignore displayed self- antigens) • Act as antigen holders; form "self" part that T cells recognize

Class II MHC Proteins MHC Restriction

• Bind with fragments of exogenous • CD4 and CD8 cells have different antigens that have been engulfed and requirements for MHC protein that broken down in a phagolysosome presents antigens to them

• Recognized by helper T cells – CD4 cells that become TH – bind only class II MHC proteins typically on APC surfaces • Signal CD4 cells that help is required – CD8 cells that become cytotoxic T cells – bind only class I MHC proteins on APC surfaces • Once activated, cytotoxic T cells seek same antigen on class I MHC proteins on any cell

MHC Restriction Antigen-presenting Cells (APCs)

• CD8 cells activated by class I MHC • Engulf antigens proteins • Present fragments of antigens to T cells • How do APCs get endogenous antigens for recognition from another cell and display them on • Major types class I MHCs? – Dendritic cells in connective tissues and – Dendritic cells engulf dying virus-infected or epidermis tumor cells, or import antigens via temporary – Macrophages in connective tissues and gap junctions with infected cells—then display lymphoid organs both class I and class II MHCs – B cells

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Dendritic Cells and Macrophages Figure 21.10 Dendritic cell. Scanning electron micrograph (1050x).

• Dendritic cells phagocytize pathogens, enter lymphatics to present antigens to T cells in lymph node – Most effective antigen presenter known – Key link between innate and adaptive immunity • Macrophages widespread in lymphoid organs and connective tissues – Present antigens to T cells to activate themselves into voracious phagocytes that secrete bactericidal chemicals

B lymphocytes Adaptive Immunity: Summary

• Do not activate naive T cells • Uses lymphocytes, APCs, and specific • Present antigens to helper T cell to assist molecules to identify and destroy nonself own activation substances • Depends upon ability of its cells to – Recognize antigens by binding to them – Communicate with one another so that whole system mounts specific response

Activation and Differentiation of B Cells Fate of the Clones

• B cell activated when antigens bind to its • Most clone cells become plasma cells surface receptors and cross-link them  – Secrete specific antibodies at rate of 2000 • Receptor-mediated endocytosis of cross- molecules per second for four to five days, linked antigen-receptor complexes (clonal then die selection)  – Antibodies circulate in blood or lymph • Bind to free antigens and mark for destruction by • Proliferation and differentiation into innate or adaptive mechanisms effector cells

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Fate of the Clones Neutralization

• Clone cells that do not become plasma • Simplest defensive mechanism cells become memory cells • Antibodies block specific sites on viruses – Provide immunological memory or bacterial exotoxins – Mount an immediate response to future • Prevent these antigens from binding to exposures to same antigen receptors on tissue cells • Antigen-antibody complexes undergo phagocytosis

Agglutination Precipitation

• Antibodies bind same determinant on • Soluble molecules are cross-linked more than one cell-bound antigen • Complexes precipitate and are subject to • Cross-linked antigen-antibody complexes phagocytosis agglutinate – Example: clumping of mismatched blood cells

Complement Fixation and Activation Complement Fixation and Activation

• Main antibody defense against cellular • Activated complement functions antigens (bacteria, mismatched RBCs) – Amplifies inflammatory response • Several antibodies bind close together on – Promotes phagocytosis via opsonization a cellular antigen  complement-binding –  Positive feedback cycle that enlists more sites on stem regions align and more defensive elements – Triggers complement fixation into cell's surface –  Cell lysis

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Basic Antibody Structure Cytotoxic T cells

• T- or Y-shaped antibody monomer of four • Bind to a self-nonself complex looping polypeptide chains linked by • Can destroy all infected or abnormal cells disulfide bonds • Two identical heavy (H) chains with hinge region at "middles" • Two identical light (L) chains • Variable (V) regions at one end of each arm combine to form two identical antigen-binding sites

Figure 21.11 Clonal selection of a B cell. Seeding Secondary Lymphoid Organs and Adaptive defenses Humoral immunity

Circulation Primary response Antigen (initial encounter Antigen binding with antigen) to a receptor on a specific B lymphocyte • Immunocompetent B and T cells not yet (B lymphocytes with Proliferation to noncomplementary receptors remain form a clone exposed to antigen called naive Activated B cells inactive) • Exported from primary lymphoid organs

(bone marrow and thymus) to "seed" Plasma cells Memory B cell— (effector B cells) primed to respond to same antigen secondary lymphoid organs (lymph nodes, Secreted antibody spleen, etc.) molecules

Subsequent – Increases chance of encounter with antigen Secondary response Clone of cells challenge by same (can be years later) identical to antigen results in ancestral cells more rapid response

Plasma cells

Monoclonal Antibodies as Clinical and Summary of Antibody Actions Research Tools • Commercially prepared pure antibody • Antigen-antibody complexes do not – Specific for single antigenic determinant destroy antigens; prepare them for • Produced by hybridomas destruction by innate defenses – Cell hybrids: fusion of tumor cell and B cell • Antibodies do not invade solid tissue • Proliferate indefinitely and have ability to unless lesion present produce single type of antibody • Can act intracellularly if attached to virus • Used in research, clinical testing, and before it enters cell cancer treatment – Activate mechanisms that destroy virus

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Cellular Immune Response Cellular Immune Response

• T cells provide defense against • Two populations of T cells based on which intracellular antigens glycoprotein surface receptors displayed

• Some T cells directly kill cells; others – CD4 cells usually become helper T cells (TH); release chemicals that regulate immune activate B cells, other T cells, macrophages, response and direct adaptive immune response • Some become regulatory T cells – which moderate immune response – Can also become memory T cells

Figure 21.16 Major types of T cells. Cellular Immune Response Adaptive defenses Cellular immunity

Immature lymphocyte Red bone marrow – CD8 cells become cytotoxic T cells (TC)

• Destroy cells harboring foreign antigens T cell T cell receptor receptor Maturation

• Also become memory T cells Class II MHC Class I MHC CD4 CD8 protein displaying protein displaying cell cell – Helper, cytotoxic, and regulatory T cells are antigen Thymus antigen activated T cells Activation Activation

APC – Naive T cells simply termed CD4 or CD8 cells (dendritic cell) Memory APC cells (dendritic cell)

CD4 CD8

CD4 cells become Lymphoid CD8 cells become either helper T tissues and cytotoxic T cells or organs regulatory T cells cells

Effector cells

Blood plasma

MHC Proteins and Antigen Presentation MHC Proteins

• T cells respond only to processed • Two types of MHC proteins important to T fragments of antigens displayed on cell activation surfaces of cells – Class I MHC proteins – displayed by all cells • Antigen presentation vital for activation of except RBCs naive T cells and normal functioning of – Class II MHC proteins – displayed by APCs effector T cells (dendritic cells, macrophages, and B cells) • Both types are synthesized at ER and bind to peptide fragments

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Table 21.5 Role of MHC Proteins in Cellular Immunity Figure 21.17 Clonal selection of T cells involves simultaneous recognition of self and nonself. Slide 1 Adaptive defenses Cellular immunity

Bacterial antigen 1 Antigen presentation Class lI MHC Dendritic cell engulfs protein an exogenous displaying antigen, processes it, processed and displays its bacterial antigen fragments on class II Dendritic Co-stimulatory MHC protein. cell molecule

CD4 protein 2 Double recognition T cell 2a CD4 T cell receptor recognizes antigen- (TCR) MHC complex. Both TCR and CD4 proteins bind to antigen-MHC Co-stimulatory CD4 T cell complex. molecules 2b Co-stimulatory Clone molecules bind formation together.

3 Clone formation Activated CD4 T cells proliferate (clone), and become memory and effector cells. Memory CD4 T cell Helper T cells

Acquired Immune Deficiency Syndrome Acquired Immune Deficiency Syndrome (AIDS) (AIDS) • HIV multiplies in lymph nodes throughout • HIV reverse transcriptase  frequent asymptomatic period, ~10 years if untreated errors; high mutation rate and resistance • Symptoms when immune system collapses to drugs • Virus also invades brain  dementia • HIV-coated glycoprotein complex attaches to • Treatment with antiviral drugs CD4 receptor – Fusion inhibitors block HIV's entry into cell • HIV enters cell and uses reverse transcriptase to – Integrase inhibitors block viral RNA produce DNA from its viral RNA integration into host's DNA • The DNA copy (a provirus) directs host cell to – Reverse transcriptase and protease make viral RNA and proteins, enabling virus to inhibitors inhibit viral replication enzymes reproduce – Antiretroviral vaginal gel reduces risk by 50%

Autoimmune Diseases

• Immune system loses ability to distinguish self from foreign • Production of autoantibodies and sensitized TC cells that destroy body tissues • Examples include multiple sclerosis, myasthenia gravis, Graves' disease, type 1 diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis