The Immune System.

The Immune System

Immune System functional system rather than organ system Hematopoetic
Vasculature Lymphatic Fig 21.1

Innate vs. Adaptive Immune System – Introduction
Innate: structural defenses; responds to nonspecific foreign substances First line: external surface epithelium & membranes Second line: inflammatory processes – antimicrobial proteins, phagocytes, etc. Fig 21.1

Innate vs. Adaptive Immune System – Introduction
Adaptive: responds to specific foreign substances Innate & adaptive mechanisms work together Fig 21.1

Innate, Surface Defenses
Skin physical barrier to microbes Keratin resistant to most bacterial enzymes & toxins secretions are acidic pH 3-5 Mucosa physical barrier & produces a variety of protective chemicals Gastric mucosa very acidic & produces proteolytic enzymes Saliva & lacrimal fluid contain lysozyme Mucous traps bacteria & moves them away from epithelial surface

Innate, Internal Defenses
Based on recognition of surface carbohydrates (glycocalyx) Glycocalyx is recognized as “self” or “non-self” Figure 3.3

Phagocytes Macrophages: derived from monocytes Free Macrophages: roam through tissues Fixed Macrophages: Kupffer cells (liver) & microglia (brain) Ingest cellular debris, foreign material, bacteria, fungi Neutrophils: ingest pathogens Eosinophils: weakly phagocytic of pathogens. Attack parasites (degranulation) Mast Cells: phagocytic of various bacteria

Phagocytic mechanisms: Adherence: cell binds to invader Aided by opsonization (a chemical process that enhances binding via complement & antibodies) Ingestion: formation of phagolysosomes Respiratory Bursts: merge phagosome with lysosome & flood phagolysosome with free radicals (macrophage) Defensins: proteins that crystallize out of solution & pierce pathogen membranes (neutrophils)

Mechanism of Phagocytosis
Figure 21.2

Natural Killer Cells: Small population of large granular lymphocytes Non specific for “non-self” Not phagocytic: attack is by release of perforins that perforate the target cell plasma membrane. Shortly after perforation the target nucleus disintegrates. Release chemicals that enhance the inflammatory response

Innate, Internal Defenses: Inflammation
tissue response to injury Triggered by injury – trauma, heat, chemical irritation, infection, etc. Beneficial effects Prevents spread of injury Disposes of cellular debris & pathogens Promotes repair

cardinal signs of inflammation Redness Heat Swelling Pain (functional impairment Rigor)

Inflammatory response: signs are associated with vasodilation & increased vascular permeability Dilation: redness, heat Permeability: edema, (increased pressure) pain Pain also associated with bacterial toxins & some mediators (kinins, PGs)

Innate, Internal Defenses: Inflammatory Response
Mechanisms causing vasodilation & vascular permeability Injured cells release inflammatory mediators Histamines Kinins Prostaglandins Complement Cytokines (also activated by receptors on macrophages in response to microbial glycocalyx)

Edema Dilutes harmful substances Provides nutrients (& O2) for repair Enhances entry of clotting protein Epithelial breaches also stimulate b-defensin release from epithelial cells

Events in Inflammation
Figure 21.3

Phagocyte mobilization: infiltration of damaged area by neutrophils & macrophages

Leukocytosis: leukocytosis inducing factors released by injured cells promote rapid release of WBCs from marrow Margination: increased vascular permeability causes decreased fluid in vessels; blood flow slows & neutrophils are able to move to vessel margins. Here endothelial markers (CAMs) allow neutrophils to cling to vessel walls (pavementing).

Diapedesis: neutrophils migrate through capillary walls Chemotaxis – inflammatory chemicals attract neutrophils to move up the chemical concentration gradient (neutrophils respond first) As the process continues, monocytes diapedes into the area & become macrophages. With chronic inflammation, macrophages predominate

Inflammatory Response: Phagocytic Mobilization
Figure 21.4

Macrophages clean up cellular debris & pathogens If pathogens were associated with the injury, activation of the complement cascade occurs & elements of adaptive immunity join the process

Viral replication – (viruses lack metabolic processes) Viruses release nucleic acid (RNA or DNA) into cytoplasm. The information on the nucleic acid is incorporated into the cell’s DNA. Normal cellular mechanisms then produce viral structural components. Multiple new viral particles are produced & released from the cell (sometimes killing the cell)

Antiviral proteins: interferon & complement Interferon: some cells produce & release interferons (IFNs) when invaded by virus Released interferons stimulate nearby cells to produce proteins (PKR) that interfere with viral replication by disrupting protein synthesis & the ribosome Not virus specific.

Interferon (IFN) Figure 21.5

Complement – a group of plasma proteins (20) that are activated in the presence of foreign substances Complement activation enhances & amplifies inflammation Bacteria & some other cell types are lysed by complement activation Complement activation enhances both innate & adaptive defenses

Complement activation pathways Classical pathway: requires antibodies Antibodies bind to target (antigen) Complement protein C1 binds to the antibody-antigen complex (complement fixation) Alternative pathway: complement factors interact with microorganism glycocalyx Both pathways lead to a cascade of protein activation, leading to activation of C3

C3 is the start of the; Final Common Pathway C3 cleaves to form C3a & C3b C3a (& C5a) enhance inflammation by increasing histamine release, increasing vascular permeability & stimulating chemotaxis C3b coats bacterial membrane supplying adhesion points (opsonization) C3b initiates the cascade forming the membrane attack complex (MAC) The MAC forms a hole in the cell membrane & enhances Ca2+ influx  cell lysis

Innate, Internal Defenses; Complement
Figure 21.6

C-reactive proteins (CRP) produced by the liver in response to inflammatory molecules can activate the classical pathway by binding to membrane & activating C1. Also participates in opsonization. Fever – a systemic response to infection. Leukocytes & macrophages release pyrogens that raise the hypothalamic “set point” for temperature

ADAPTIVE DEFENSES ADAPTIVE DEFENSES
Innate & adaptive mechanisms work together in a cohesive fashion

Adaptive Defenses: Characteristics
Specificity: directed at specific targets Systemic: not restricted to initial site of infection / invasion Memory: after initial exposure & activation, a more rapid & more vigorous response is made to subsequent exposures to pathogens (secondary response)

Adaptive Defenses: Components
Humoral Immunity: (antibody mediated immunity) provided by antibodies floating free in body fluids Cell mediated immunity: lymphocytes directly attack specific invaders by lysis or indirect attack by initiating inflammation and/or activating other lymphocytes & macrophages

Adaptive, Humoral Immunity
Antigen = any substance that can mobilize the immune system & provoke an immune response* *Humoral and/or cell mediated

Complete antigens (proteins, nucleic acids, lipids, polysaccharides): Immunogenicity: the ability to stimulate specific lymphocytes & specific antibodies Reactivity: the ability to react with activated lymphocytes & antibodies Hapten (an incomplete antigen): a smaller molecule that is not immunogenic until attached to proteins

Antigenic determinants: sites on an antigenic molecule that are immunogenic Epitope Major Histocompatibility Complex (MHC): cell surface glycoproteins associated with self recognition Figure 21.7

Adaptive Immune System: Cells
Lymphocytes T-cells B-cells Antigen Presenting Cells (APCs)

Lymphocytes: initially uncommitted T-cells: are sorted in the Thymus Positive selection: recognize MHC survive Negative selection: react against to self-antigens on MHC killed 2% of initial T-cell precursors T-cells manage the immune response B-cells: are sorted in the marrow by an incompletely understood process Figure 21.9

Immunocompetence: as T- or B-cells mature they become immunocompetent, they display receptors on their cell membrane for a specific antigen. All of the receptors on one cell are identical; immunity depends upon genetic coding for appropriate receptors.

Antigen Presenting Cells (APCs) APCs ingest foreign material, then present antigenic fragments on their cell surface where they are recognized by T-cells T-cells: respond to antigen only if it is displayed on plasma membrane. APCs: Macrophages & B lymphocytes Interactions between APCs & lymphocytes & lymphocyte-lymphocyte interactions are critical to immune response

Adaptive, Humoral response
Humoral response (clonal selection) B-cells: Antigen challenge to naïve immunocompetent B-cell Antigen binds to B-cell receptors & form cross-links between receptors Cross linked antigen-receptor complex undergoes endocytosis; B-cell presents to T-cell

Humoral Immunity Active humoral immunity: Passive humoral immunity:
B-cells encounter & respond to antigen to produce an antibody Passive humoral immunity: Introduced “non-native” antibody

Active Humoral Immunity
Naturally acquired: natural exposure to antigen (i.e. infection) Artificially acquired: vaccines; dead/attenuated or fragmented pathogen injected to elicit an immune response Bestow immunity without disease; primary response Booster shots (secondary response); intensify response Shortcomings – adverse reactions & the immunity is less durable (poor memory) & has less cell mediated component

Passive Humoral Immunity
Natural: maternal antibody crosses the placental barrier conferring temporary immunity to the baby (degrades after a few months) Artificial: antibodies harvested from an outside source given by injection protect from immediate threat but no memory is formed (antitoxins, antivenins , gamma globulin, etc.)

Antibodies A.K.A Immunoglobulins & gamma globulins Structure variable
hypervariable constant Figure 21.13a

Antibodies Constant (C) region defines antibody class
determines chemical & cellular interactions determines how class functions to eliminate antigens

Antibody Classes Antibody Classes: IgM, IgG, IgA, IgD, IgE (Ig = immunoglobulin)

Antibody Classes IgG: the most abundant circulating Ig. The dominant circulating Ig of the primary & the secondary response. Crosses the placenta. Complement binding (Monomer). IgA: the Ig of secretions. Helps prevent antigen penetration of membranes (Dimer). IgD: the Ig of B-cell activation. Found on B-cell surface (Monomer).

Antibody Classes IgM: occurs as a monomer & a pentamer
Occurs on the B-cell surface (Monomer). The Ig of early primary plasma cell response, circulating antibody; a potent agglutinator. Complement binding (Pentamer).

Antibody Classes IgE: the Ig associated with allergies.
Stem binds to mast cells & basophils. Receptor binding results in histamine release & inflammation. Found mostly in mucosa of respiratory & GI tract (Monomer).

Antibody Targets & Functions
Immune complex formation = antigen-antibody binding. All the following events are initiated by antigen-antibody binding. Complement fixation: Neutralization: Agglutination: Precipitation: Inflammation & phagocytosis prompted by debris

Complement fixation: cells & bacteria. Immune complex formation exposes a complement binding site on the C region of the Ig. Complement fixation results in cell lysis. Neutralization: immune complex formation blocks specific sites on virus or toxin & prohibit binding to tissues Agglutination: cells are crosslinked by immune complexes & clump together Precipitation: soluble molecules (such as toxins) are crosslinked, become insoluble, & precipitate out of the solution Inflammation & phagocytosis prompted by debris Figure 21.14

Monoclonal antibodies: antibodies produced by descendants of a single cell Pure antibody preparations that are specific for a single antigenic determinant Research / diagnostic / therapeutic use

Cell Mediated Immune Response
T-cell activation: involves recognition of PM surface antigens only Antigen is combined with MHC & displayed on PM T-cell receptors: bind to the MHC & are stimulated by the associated antigen The addition of a co-stimulator (cytokines, interleukins, etc) prompts the T-cell to form a clone In the absence of a co-stimulator the T-cell becomes tolerant to antigen (anergy)

Cell Mediated: MHC MHC occurs as two classes
MHC I on virtually all tissue cells MHC II only on PM some immune system cells

Cell Mediated: MHC display properties
Figure 21.16a MHC I on virtually all tissue cells Display only proteins produced inside the cell Endogenous antigens = foreign proteins produced by the cell (viral / cancer) Stimulate the CD8* cell population form cytotoxic T-cells (Killer T, TC) *formerly T8 cells

Cell Mediated: MHC display properties
Figure 21.16b MHC II found only on PM of B-cells, some T-cells & APCs Display proteins derived from a phagocytized target Exogenous antigen: foreign protein from outside the cell – presented to PM surface Stimulates the CD4* cell population form Helper T-cells (TH) *formerly T4 cells

Cell Mediated: T-cell roles
Helper T-cells (TH) stimulate B-cells & other T-cells to proliferate Figure 21.18

Activated TH cells interact with B-cells displaying antigen & produce cytokines that prompt the B-cell to mature & form antibody Figure 21.18

TH cells also produce cytokines that promote TC cells TH cells recruit other WBCs & amplify innate defenses (inflammatory) Subpopulations of TH cells specialize in specific sets of activations Figure 21.18

Cytotoxic T-cells (TC, Killer T): directly attack & kill cells with specific antigen Activated TC cells are co-stimulated by TH cells

Figure 21.19a TC mechanism (Cytotoxic T-cells, Killer T) TC binds to cell & releases perforin & granzymes In the presence of Ca2+ perforin forms pores in target cell PM Granzymes enter through pores & degrade cellular contents TC then detaches & moves on Macrophages clean up

Other T-cells *Regulatory T-cells (TReg): release inhibitory cytokines that suppress B-cell & T-cell activity Help to prevent autoimmune events *formerly Suppressor T (TS) Gamma Delta T-cells (Tgd): live in the intestine. Function in surveillance & are triggered much like NK cells

Organ Transplants/Rejections
Types of Organ Transplants Autograft: tissue graft from one body site to another (same person) Isograft: graft received from a genetically identical donor (identical twin) Allograft: graft received from genetically non-identical donor (same species) Xenograft: graft received from another species of animal

Transplant rejection: mediated by the immune system (especially TC, NK, antibodies) Auto/Isograft: MHC compatible Xenograft: most MHC incompatible Allograft: attempt to obtain the best MHC match

Immunosuppressive therapy: used to delay/prevent rejection Corticosteroids: suppress inflammation Antiproliferative: prevent/kill rapidly dividing cells Immunosuppressant: prevent/kill rapidly dividing cells Side effects tend to be harsh Increased risk of infection

Immunologic Dysfunction
Immunodeficiency Congenital/Genetic: varied inborn errors Acquired: Drugs: immunosuppressive / cancer drugs Radiation therapy – marrow Cancer: can be viewed as a failure of immune surveillance Hodgkin’s disease: lymph node cancer AIDS/HIV: kills TH cells

Autoimmune disease: production of antibody & TH against self tissues Examples & tissue effected Multiple sclerosis: white matter of nervous system Graves disease: thyroid Type I diabetes mellitus: beta cells of pancreas Systemic Lupus Erythrematosis: (anti DNA) kidneys, heart, lungs & skin Rheumatoid Arthritis: destroys joints (cartilage) Glomerulonephritis: impaired renal function (may be secondary to other autoimmune disease)

Mechanisms of immunologic dysfunction Failure of lymphocyte programming New self antigens Gene mutation Structural change – haptens, infection Foreign antigens that closely resemble self antigen resulting in cross reactivity.

Hypersensitivities (Allergies): the immune system responds to a harmless substance as if it were a threat. Allergen = antigens of an allergic response Figure 21.21

Hypersensitivities: Types
Immediate hypersensitivity (Type I): symptoms within seconds of exposure to an allergen (requires sensitization = previous exposure) Figure 21.21

Hypersensitivities: Type I
Anaphylaxis (IgE mediated; mast / basophils) Local: histamine induced vasodilation & increased permeability. Watery eyes, runny nose, itching & redness. Respiratory  allergy induced asthma Systemic: anaphylactic shock: associated with allergens that have systemic distribution. Widespread vasodilation, airway swelling Atopy: the tendency to display Type I symptoms to certain environmental antigens without prior sensitization

Hypersensitivities: Types II & III
Subacute hypersensitivity (IgG & IgM mediated) Cytotoxic reactions (Type II): antibodies bind to cellular antigens promoting complement fixation / inflammation / phagocytosis (transfusion reaction) Immune complex h. (Type III): widely distributed antigen reacts with antibody. Antigen-antibody complexes cannot be cleared; persistent inflammation / tissue damage (farmer’s lung; associated with autoimmune disorders)

Hypersensitivities: Type IV
Delayed hypersensitivity (cell mediated) takes one to three days to react. Involves TC, TH1 & macrophages. Allergic contact dermatitis (poison ivy, heavy metals, TB tine tests). Agents act as haptens & elicit response after binding to tissue

Developmental Aspects of the Immune System
Stem cells arise from embryologic liver & spleen Self tolerance develops in Thymus (T-cells) & bone marrow (B-cells) Immunocompetence: the “library” of receptors is genetically determined Immune system degrades with aging

Immunocompetent B or T cells
Key: = Site of lymphocyte origin Red bone marrow = Site of development of immunocompetence as B or T cells; primary lymphoid organs = Site of antigen challenge & final differentiation to activated B & T cells Immature lymphocytes Circulation in blood 1 1 1 Lymphocytes destined to become T cells migrate to the thymus & develop immunocompetence there. B cells develop immunocompetence in red bone marrow. Thymus Bone marrow 2 After leaving the thymus or bone marrow as naive immunocompetent cells, lymphocytes “seed” the lymph nodes, spleen, & other lymphoid tissues where the antigen challenge occurs. Immunocompetent, but still naive, lymphocyte migrates via blood 2 2 Lymph nodes, spleen, & other lymphoid tissues 3 Mature (antigen-activated) immunocompetent lymphocytes circulate continuously in the bloodstream & lymph & throughout the lymphoid organs of the body. 3 3 Activated immunocompetent B & T cells recirculate in blood & lymph Figure 21.8

Primary & Secondary Humoral Responses
Figure 21.10

Types of Acquired Immunity
Figure 21.11

Major Types of T Cells Figure 21.14

T Cell Activation: Step One – Antigen Binding
Figure 21.16

Helper T Cells (TH) Figure 21.17a

Helper T Cells Figure 21.17b

Summary of the Primary Immune Response
Figure 21.19

Innate immunity Properties of innate immunity
Components of innate immunity Epithelial barriers Cellular mechanisms Humoral mechanisms Role of innate immunity in stimulating adaptive immune response

Principle mechanisms of innate and adaptive immunity

Mechanisms of innate immunity
- phylogenetically older - exist before or react immediately after contact with pathogen - are not enhanced upon repetead contact with pathogen (no memory) - react predominantly to infectious agents - first line of defense - stimulate and shape adaptive imunity

Components of innate immunity
- epithelial barriers (skin and mucosal membranes) - cells (phagocytes, NK cells...) - humoral components (complement, cytokines etc.)

Functions of epithelia in innate immunty
physical barrier

physical barrier chemical barrier (production of antimicrobial peptides)

physical barrier chemical barrier (production of antimicrobial peptides) intraepithelial lymphocytes - normal bacterial flora

Cells of innate immunity
Cell type Pricipal function(s) Monocytes/Macrophages Phagocytosis, inflammation, T-cell activation, tissue repair Neutrophils Phagocytosis, inflammation NK cells Killing of infected or tumor cells Dendritic cells Phagocytosis, activation of naive T-cells Mast cells Inflammation Eosinophils Defense against parasites

Role of phagocytes in innate immunity
Order of events in infection 1. Entry of pathogen

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen (macrophages and dendritic cells) - molecular patterns and receptors

Molecular patterns Structures common for certain groups/classes of pathogens essential for their life, replication and/or infectivity not present on human cells Lipoproteins Flagellin Examples: structures of bacterial cell wall (LPS, peptidoglycan, flagellin...) nucleic acids of pathogens (dsRNA, unmethylated CpG dinucleotides...)

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen (macrophages) reactive oxygen species (ROS), nitric oxide (NO) and lysosomal enzymes

Phagocytosis and killing of microbes
Pathogen recognition

Zipping of membrane around microbe

Ingestion of microbe

Fusion of phagosome with lysosome

Phagocyte activation

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Induction of inflammation (macrophages) - production of pro-inflammatory cytokines (TNF, IL-1, chemokines...)

Inflammation induction
Proinflammatory cytokines TNF ― Tumor Necrosis Factor IL-1 ― Interleukin-1 Chemokines ― Chemotactic cytokines

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site - adhesive molecules (selectins and integrins) and chemokines

Leukocytes arrive at the site of infection (extravasation)
Various adhesive molecules Selectins Integrins In some inflammatory diseases therapy is directed against proinflammatory cytokines or adhesive molecules (eg: TNF in rheumatoid arthritis or VLA-4 in multiple sclerosis) Weak binding and rolling Activation and firm binding Transmigration Endothelium TNF & IL-1 Arrival to the site of infection Macrophages Chemokines

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site 6. Pathogen elimination and/or adaptive immunity activation (dendritic cells) - cytokines, costimulatory molecules...

Order of events in infection 1. Entry of pathogen 2. Recognition of pathogen 3. Phagocytosis and killing of a pathogen 4. Inflammation induction 5. Attraction of cells to infection site 6. Pathogen elimination and/or adaptive immunity activation 7. Tissue repair and remodeling (macrophages) - enzymes and cytokines (growth factors, metaloproteinases...)

Role of NK cells in innate immunity
NK – Natural killer Killing of cells infected by intracellular pathogens (eg. viruses) and tumor cells

Role of NK cells in innate immunity
NK – Natural killer Killing of cells infected by intracellular pathogens (eg. viruses) and tumor cells Activation of macrophages (by IFN-γ)

NK cell killer function
Depends on balanse of signals by activating and inhibitory receptors Inhibitory Activating

Depends on balanse of signals by activating and inhibitory receptors Activating Inhibitory NK cell is inhibited NO KILLING

Depends on balanse of signals by activating and inhibitory receptors Inhibitory Activating NK cell is activated KILLING

Depends on balanse of signals by activating and inhibitory receptors Inhibitory Activating activating receptors recognize stress-derrived structures on cells (including infected and malignant cells) - inhibitory receptors recognize MHC class one molecule

Mechanism of NK cell recognition

Apoptosis induction in infected and tumor cells Killing mechanisms same as in cytotoxic T-cells - Perforin and granzymes - FasL and Fas granzymes Infected or tumor cell apoptosis NK cell perforin FasL Fas

Humoral mechanism of innate immunity
complement proteins (8th week seminar) - cytokines - other plasma proteins (CRP, MBL etc.)

Inflammation induction
Cytokines in innate immunity Inflammation induction (TNF, IL-1, chemokines...)

Cytokines in innate immunity
Macrophage and NK cell Activation (IL-12 and IFN-γ) Inflammation induction (TNF, IL-1, chemokines...) Antiviral effects (IFN type I, IFN-α and IFN-β) (eg. INF-α in HCV therapy) Differentiation of T-cell subpopulation (eg. IL-12)

Role of innate immunity in stimulation of adaptive immune response
T or B-cells need two signals for activation First signal antigen recognition Second signal derrived by innate immunity

Thanks for your attention!
Questions?

1. Receptors on innate immunity cells recognize a. Production of enzymes, ROS and NO 2. Epithelial cells provide chemical barrier for pathogens by b. Kill our own virus-infected cells 3. Macrophages stimmulate inflammation by production of c. Polysaccharide capsule production 4. Macrophages kill phagocytosed microbes by d. TNF, IL-1 and other mediators 5. NK cells e. molecules that provide “second signal” 6. NK cells are activated f. NK and T- cells 7. Chemokynes are important for g. Structures that a group of pathogens has in common 8. IL-12 produced by macrophages stimulates h. When a target cell does not express MHC class I 9. Bacteria can avoid phagocytosis by i. Leukocyte migration 10. Innate immunity cells stimulate adaptive immunity by j. Peptide antibiotics production 1.____ g 2.____ j 3.____ d 4.____ a 5.____ b 6.____ h 7.____ i 8.____ f 9.____ c 10.____ e

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