Innate (Non-Specific) Immunity Divisions of the Immune System Mechanical, Chemical, and Physical...

Innate (Non-Specific) Immunity Divisions of the Immune System

Mechanical, Chemical, and Physical Barriers

Cells and Chemicals in Non-Specific Immunity

Inflammatory Response

• Release of Mobilizing Chemicals

• Attraction of Phagocytes

• Antimicrobial Chemicals

o Interferon as an Antiviral

o Complement Proteins as Lytic Agents and Opsonizers

• The role of fever

Body Defenses

Nonspecific (Innate) Body DefensesMechanical, Chemical, and Competitive Barriers

Saliva and tears destroy bacteria because they contain lysozyme.

Skin produces acidic sebum to limit bacterial growth.

Internal Defenses: Cells and Chemicals Necessary if microorganisms invade deeper tissues

• Phagocytes

• Natural killer (NK) cells

• Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals)

• Antimicrobial proteins (interferons and complement proteins)

• Fever

Defensive Cells in Non-Specific Defense Phagocytes

(neutrophils and macrophages)

• Engulf foreign material into a vacuole

• Enzymes from lysosomes digest the material

• Free macrophages wander through tissues; fixed macrophages are permanent (e.g liver Kupfer cells, brain microglia

Figure 21.2b

Lysosome

Phagosome(phagocyticvesicle)

Acidhydrolaseenzymes

(b) Events of phagocytosis.

1 Phagocyteadheres to pathogens or debris.

2 Phagocyte formspseudopods that eventually engulf the particles forming a phagosome.

3 Lysosome fuseswith the phagocytic vesicle, forming a phagolysosome.

4 Lysosomal enzymes digest the particles, leaving a residual body.

5 Exocytosis of thevesicle removes indigestible andresidual material.

Events of Phagocytosis

Mechanism of Phagocytosis Destruction of pathogens

• Acidification and digestion by lysosomal enzymes

• Respiratory burst

o Release of cell-killing free radicals

o Activation of additional enzymes

• Oxidizing chemicals (e.g. H2O2)

• Defensins (in neutrophils)

Natural Killer Cells Large granular

lymphocytes

Target cells that lack “self” cell-surface receptors

Induce apoptosis in cancer cells and virus-infected cells

Secrete potent chemicals that enhance the inflammatory response

Inflammatory Response 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

Inflammatory Response Cardinal signs of acute inflammation:

1. Redness

2. Heat

3. Swelling

4. Pain

(And sometimes 5. Impairment of function)


Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs)

TLRs recognize specific classes of infecting microbes

Activated TLRs trigger the release of cytokines that promote inflammation

Inflammatory Response Inflammatory mediators

• Histamine (from mast cells)

• Blood proteins

• Kinins, prostaglandins (PGs), leukotrienes, and complement

o Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells

Action of inflammatory chemicals

• Dilation of arterioles, resulting in hyperemia

• Increased permeability of local capillaries and edema (leakage of exudate)

Exudate moves foreign material into lymphatic vessels, delivers clotting proteins to form a scaffold for repair and to isolate the area

Inflammatory Response - Second Line of Defense

1. Release of histamines, complement, prostaglandins, and kinins from injured cells2. Vasodilation and increased permeability of local capillaries, increasing edema and swelling

3. Activation of pain receptors by swollen tissue pressure4. Attraction of phagocytes and other lymphocytes to the area through chemotaxis: leukocytosis, margination, diapedesis

Figure 21.4, step 1

Innatedefenses

Internaldefenses

Leukocytosis.Neutrophils enter bloodfrom bone marrow.

Capillary wallBasementmembraneEndothelium

Inflammatorychemicalsdiffusingfrom theinflamed siteact as chemotacticagents.

1

Steps of Attraction of Leukocytes

Figure 21.4, step 2

Innatedefenses

Internaldefenses


Margination.Neutrophils clingto capillary wall.



1 2


Figure 21.4, step 3

Innatedefenses

Internaldefenses



Diapedesis.Neutrophils flatten andsqueeze out of capillaries.



1 2 3


Figure 21.4

Innatedefenses

Internaldefenses



Diapedesis.Neutrophils flatten andsqueeze out of capillaries.

Chemotaxis.Neutrophilsfollow chemicaltrail.



1 2 3

4





5. Clotting proteins leaking into the area wall off damaged sections; interferon & complement may also be released

Antimicrobial Proteins: Inteferon

Produced by most leukocytes and lymphocytes

Function

• Reduce inflammation, active macrophages, activate macrophages and mobilize NK cells

• Hinder microorganisms’ ability to reproduce

1. Viral-infected cells secrete IFNs

2. IFNs enter neighboring cells

3. Neighboring cells produce antiviral proteins that block viral reproduction

Genetically engineered IFNs for hepatitis, herpes, MS

Figure 21.5, step 5

VirusNew viruses

Viral nucleic acid

DNA

mRNA

Nucleus

Interferon

Virusenters cell.

Interferongenes switch on.

Cell producesinterferonmolecules.

Interferonbindingstimulates cell toturn on genes forantiviral proteins.

Antiviralproteins blockviralreproduction.

Host cell 1Infected by virus;makes interferon;is killed by virus

Innate defenses Internal defenses

Host cell 2Binds interferon from cell 1; interferon induces synthesis ofprotective proteins

1

2

34

5

How Interferon Activates the Production of Antivirals

Antimicrobial Proteins: Complement What they are

• About 20 blood proteins that circulate in an inactive form

• Include C1–C9, factors B, D, and P, and regulatory proteins

Function

• Major mechanism for destroying foreign substances

• Amplifies all aspects of the inflammatory response

• Kills bacteria and certain other cell types by cell lysis

• Enhances both nonspecific and specific defenses

Complement Activation Two pathways

1. Classical pathway

o Antibodies bind to invading organisms

o C1 binds to the antigen-antibody complexes (complement fixation)

2. Alternative pathway

o Triggered when activated C3, B, D, and P interact on the surface of microorganisms

Complement Activation Each pathway involves activation of proteins

in an orderly sequence

Each step catalyzes the next

Both pathways converge on C3, which cleaves into C3a and C3b

Complement Activation Activated complement

• Enhances inflammation

• Promotes phagocytosis

• Causes cell lysis

o C3b initiates formation of a membrane attack complex (MAC)

o MAC causes cell lysis by inducing a massive influx of water

o C3b also causes opsonization, and C3a causes inflammation

Figure 21.6

Spontaneous activation

Stabilizing factors (B, D, and P)

No inhibitors on pathogensurface

Alternative pathway

Enhances inflammation:

Insertion of MAC and cell lysis(holes in target cell’s membrane)

Complementproteins(C5b–C9)

Pore

Membraneof target cell

+

+

stimulates histamine release,increases blood vessel permeability, attracts phagocytes by chemotaxis, etc.

complex

Opsonization:

+

coats pathogensurfaces, which enhances phagocytosis

Antigen-antibody complexClassical pathway

Transmembrane channel (membrane attack complex) causing lysis

Complement is Activated in Two Ways




5. Clotting proteins leaking into the area wall off damaged sections; interferon & complement may also be released

6. Increased local metabolic rate raises the local temperature to increase rate of repair processes7. Production of a fever (stimuated by pyogenic compounds)

. 8. Dead or dying neutrophils, dead cells, and pathogens

may form, walling off a sac of pus to form an abscess.

Figure 21.3

Tissue injury

Release of chemical mediators(histamine, complement,kinins, prostaglandins, etc.)

Vasodilationof arterioles

Increased capillarypermeability

Local hyperemia(increased blood

flow to area)

Locally increasedtemperature increasesmetabolic rate of cells

Leaked protein-richfluid in tissue spaces

Leaked clottingproteins form interstitialclots that wall off area

to prevent injury tosurrounding tissue

Temporary fibrinpatch forms

scaffolding for repair

Healing

Capillariesleak fluid

(exudate formation)

Attract neutrophils,monocytes, andlymphocytes to

area (chemotaxis)

Release of leukocytosis-inducing factor

Leukocytosis (increased numbers of whiteblood cells in bloodstream)

Leukocytes migrate toinjured area

Margination (leukocytes cling to

capillary walls)

Diapedesis (leukocytes pass through

capillary walls)

Phagocytosis of pathogensand dead tissue cells

(by neutrophils, short-term;by macrophages, long-term)

Area cleared of debris

Pus may form

Signs of inflammation

Initial stimulus

Physiological response

Result

Innate defenses Internal defenses

Possible temporarylimitation ofjoint movement

Heat Redness Pain Swelling

Fever Abnormally high body temperature

Hypothalmus heat regulation can be reset by pyrogens (secreted by white blood cells)

High temperatures inhibit the release of iron and zinc from liver and spleen needed by bacteria

Fever also increases the speed of tissue repair by increasing metabolic rate

Innate (Non-Specific) Immunity Divisions of the Immune System Mechanical, Chemical, and Physical...

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