Download ppt - The Immune System Chapter 21. Immune System functional system rather than organ system Hematopoetic Vasculature Lymphatic Fig 21.1

The Immune System

Chapter 21

Immune System

functional system rather than organ systemHematopoetic VasculatureLymphatic

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

Innate, Internal Defenses

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

Innate, Internal Defenses: Inflammation cardinal signs of inflammation

Redness Heat Swelling Pain (functional impairment Rigor)

Weapons of the Spanish Inquisition

http://www.youtube.com/watch?v=uprjmoSMJ-o

Innate, Internal Defenses: Inflammation Inflammatory response: signs are

associated with vasodilation & increased vascular permeabilityDilation: redness, heatPermeability: edema, (increased pressure)

painPain 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)

Innate, Internal Defenses: Inflammatory Response Edema

Dilutes harmful substancesProvides nutrients (& O2) for repairEnhances entry of clotting protein

Epithelial breaches also stimulate -defensin release from epithelial cells

Events in Inflammation

Figure 21.3

Innate, Internal Defenses: Inflammatory Response Phagocyte mobilization: infiltration of damaged

area by neutrophils & macrophages

Innate, Internal Defenses: Inflammatory Response 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).

Innate, Internal Defenses: Inflammatory Response 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

Innate, Internal Defenses: Inflammatory Response 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

Adaptive, Humoral Immunity

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

Adaptive, Humoral Immunity 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

LymphocytesT-cellsB-cells

Antigen Presenting Cells (APCs)

Adaptive Immune System: Cells 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: 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

Antibody Targets & Functions 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

Antibody Targets & Functions

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

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

Figure 21.16a

Cell Mediated: MHC display properties

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

Figure 21.16b

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


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

Figure 21.19a


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 drugsRadiation 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

Red bone marrow

1

2

3

Immunocompetent, but still naive, lymphocyte migrates via blood

Mature (antigen-activated) immunocompetent lymphocytes circulate continuously in the bloodstream & lymph & throughout the lymphoid organs of the body.

Key: = Site of lymphocyte origin

= 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

lymphocytesCirculation in blood

1

1 Lymphocytes destined to become T cells migrate to the thymus & develop immunocompetence there. B cells develop immunocompetence in red bone marrow.

Thymus

Bonemarrow

Lymph nodes, spleen, & other lymphoid tissues

2 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.

3 3

Activated immunocompetent B & T cells recirculate in blood & lymph

Immunocompetent B or T cells

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