Prof. Mohamed Osman Gad El RabProf. Mohamed Osman Gad El Rab..

College of Medicine & KKUHCollege of Medicine & KKUH..

Human defense mechanisms.

Natural immunity.

What mechanisms prevent infections?

We live in a very hostile environment! The atmosphere is full of microbes ,(bacteria

Viruses ,molds , parasites ( .

Important for survival .,infections can be devastating.

The first attempts to induce immunity were performed by The first attempts to induce immunity were performed by Chinese & Chinese & Turks in the fifteenth century. Turks in the fifteenth century.

Lady Mary Montagu observed the positive effects of variolation (crusts from mall pox pustules inhaled or

inserted into small cuts in the skin ) .

Edward Jenner , in 1798 observed that milkmaids who contract mild cowpox become immune to smallpox.

He inoculated an 8-year old boy with fluid from cowpox and later infected the child with smallpox. The child did

not develop the disease. .

The induction of immunity to cholera by the experiments of Louis Pasteur led to the next major advance in immunology.

He induced immunity by using attenuated bacterial cultures.He called this attenuated bacterial strain a vaccine.

Latin (vacca , meaning cow ) in honor of Jenners work with cowpox inoculation.

He also vaccinated a group of sheep with an attenuated culture of anthrax bacillus.

These experiments marked the beginnings of the disciplineof immunology.

In 1885 , Pasteur administered his first vaccine to a human,,.

A boy called Joseph Meister , bitten by a rabid dog was Inoculated with a series of attenuated rabies virus preparations.

Historical observations.

1798 : Edward Jenner - vaccination (small pox ) .

L. Pasteur - cholera & rabies vaccine.1901 : von Behring - serum antitoxin.

) won the Noble prize in medicine(

1905 : Koch - cellular immunity to T.B.

1908: Metchinkoff - phagocytosis .

Protective mechanisms : immunity.

The discipline : Immunology .

Various stimuli cause cell injury & induce a complex vascular & cellular response called :

Inflammation.

Mechanisms of protection?.

Inflammation ,a complex vascular & cellular responseInflammation ,a complex vascular & cellular response..

Hypoxia.Hypoxia.

Physical & chemical agents .Physical & chemical agents .

Microbial agents. (defective immunity).Microbial agents. (defective immunity).

Immune reactions. (abnormal responses)Immune reactions. (abnormal responses)

Genetic factors .Genetic factors .

Nutritional imbalances.Nutritional imbalances.

Cell injury can result from:

Protective immune response.

Sub-clinical infections are common. ) no symptoms or signs.(

* important for maintenance of immunity

Clinical infections are quite rare . ) indicate failure to control infections .(

Effectiveness of defense mechanisms determine pattern of infections.

All defense mechanisms are collectively called

immunity .

Natural ( innate ) non-specific.

Adaptive ( acquired ) Specific.

1 .well-integrated.2 .Connected by

inflammatory pathways.

11. . Recognition Recognition of microbes. of microbes. cell receptors on phagocyte : limitedcell receptors on phagocyte : limited.(fewer .(fewer

than 100 )than 100 )

cell receptors on lymphocytes : diversecell receptors on lymphocytes : diverse..( possibly up ( possibly up

to 10 / 18 different receptors )to 10 / 18 different receptors )

22. Effector . Effector protective mechanisms .protective mechanisms . natural immunity: non-specific .natural immunity: non-specific . adaptive immunity : specific .adaptive immunity : specific .

33. Immunologic . Immunologic memory.memory. (no retention of memory with(no retention of memory with natural immunity ) natural immunity )

Natural & Adaptive immunity differ in 3 main features:

A critical early defense , ( mobilizedA critical early defense , ( mobilized within minutes after invasion by microbes)within minutes after invasion by microbes)

A warning signal that a microbe is invading the A warning signal that a microbe is invading the . tissues (phagocyte receptors) . tissues (phagocyte receptors)

Stimulate & influence adaptive immunity.Stimulate & influence adaptive immunity. ( secrete cytokines & activate cells).( secrete cytokines & activate cells).

Natural immunity serve as:

Antibody-mediated .) humoral ( -

Cell-mediated) cellular.(

Extracellular microbe. Intracellular microbe.

Mechanical barrier retards entry of microbes. acidic environment (pH 3–5) retards growth microbes .

Normal flora compete with microbes for attachment sites and nutrients

*Mucus secreted by goblet cells entraps foreign bodies & microbes .

• Cilia propel microorganisms out of the body by sneezing or coughing.

• )mucocilliary - escalator system (

Effector mechanisms of natural immunity.

1 .Anatomic barriers:

The skin

The mucus membranes

* * Burns , cut wounds , skin diseases (eczema)Burns , cut wounds , skin diseases (eczema)

) ) predispose to infectionspredispose to infections(.(.

* *Aseptic techniques. ( taking a blood sampleAseptic techniques. ( taking a blood sample,,

I / V catheters etcI / V catheters etc( .( .

* *Disruption of the mucus membraneDisruption of the mucus membrane..

) ) dental proceduresdental procedures( (

Effects of barrier disruptions:

Temperature: Normal body temperature inhibits growth of some pathogens .

) fever inhibits growth of pathogens (.

Low pH Acidity: of stomach contents kills most ingested microbes .

Chemical mediators: Lysozyme cleaves bacterial cell wall.

Collectins : disrupt cell wall of pathogens.

Natural antibiotics : defensins , cryptidins.

2 .Physiologic barriers:

* * Coughing , sneezing , voiding urineCoughing , sneezing , voiding urine,,

tears , saliva in oral cavity etctears , saliva in oral cavity etc..

* * Inability to cough ( chest trauma, muscleInability to cough ( chest trauma, muscle

diseasedisease( (

* * Urine retentionUrine retention. .

) )when absent predispose to infectionswhen absent predispose to infections .( .(

Physiologic functions:

1. Neutrophils.1. Neutrophils.

2. Macrophages.2. Macrophages.

3. Natural killer (NK) cells. (viral immunity).3. Natural killer (NK) cells. (viral immunity).

4. Eosinophils, (parasitic immunity).4. Eosinophils, (parasitic immunity).

5. Mast cells , (mediators of inflammation ).5. Mast cells , (mediators of inflammation ).

6. Platelets (coagulation). 6. Platelets (coagulation).

7. B-1 cells ( distinct from B-2 cells ) found in fetus 7. B-1 cells ( distinct from B-2 cells ) found in fetus & neonates . Carry mainly IgM & CD5 . Found& neonates . Carry mainly IgM & CD5 . Found

mainly in peritoneum & respond to bacterial mainly in peritoneum & respond to bacterial antigens,( polyssacharides ) antigens,( polyssacharides )

Circulating effector cells

Phagocytic cells recognize pathogens by surface receptors

Toll - like receptors (TLRs) ,recognize lipopolysaccaride) LPS(

on gram negative bacteria.

Pattern-recognition receptors on phagocytic cells recognize) PAMPs(

Pathogen - associated molecular patterns on microbes .

Mediate the early phase ofMediate the early phase of

inflammation. inflammation.

* They are recruited to the site of infections * They are recruited to the site of infections

by a process called chemotaxis.by a process called chemotaxis.

* Chemotactic agents , cytokines & adhesion* Chemotactic agents , cytokines & adhesion

molecules are important factors in themolecules are important factors in the

process of chemotaxis .process of chemotaxis .

Neutrophils:

* comprise ( 60 -70 percent. O f the WBC.)* comprise ( 60 -70 percent. O f the WBC.)

* Short - lived cells.* Short - lived cells.

* phagocytose extra - cellular microbes .* phagocytose extra - cellular microbes .

* Contain enzymes.* Contain enzymes.

* Perform killing by:* Perform killing by:

- Oxygen - dependent mechanisms.- Oxygen - dependent mechanisms. - Oxygen - independent mechanisms.- Oxygen - independent mechanisms.

Neutrophils:

1. Rolling ( loose adherence ) to 1. Rolling ( loose adherence ) to endothelium.endothelium.

2. Activation of cells.2. Activation of cells.

3. Stable adherence to endothelium.3. Stable adherence to endothelium.

4. Transmigration into tissue spaces.4. Transmigration into tissue spaces.

Chemotaxis of phagocytic cells involve the following steps:

* Monocytes & Macrophages .* Monocytes & Macrophages . - Long - lived cells.- Long - lived cells. - Contain enzymes & secrete- Contain enzymes & secrete many cytokines .many cytokines . - phagocytose intra-cellular microbes.- phagocytose intra-cellular microbes.

* Professional phagocytic cells.* Professional phagocytic cells. * Antigen – presenting cells * Antigen – presenting cells

*important in both natural & adaptive immunity.*important in both natural & adaptive immunity.

Mononuclear cells.

1. Sub- epithelial connective tissue.1. Sub- epithelial connective tissue.

2. Interstitia of organs . 2. Interstitia of organs .

3. Vascular sinusoids of the liver & spleen.3. Vascular sinusoids of the liver & spleen.

4. Lymph nodes .4. Lymph nodes .

(They constitute the mononuclear (They constitute the mononuclear phagocyte system )phagocyte system )

Circulating monocytes enter tissues & become resident macrophages .

Macrophages are strategically located at sites where Microbes enter the tissues .

They recognize microbes first by their receptors (PRR ) Become activated ,secrete cytokines and attract

Neutrophils .

Macrophages are activated by Bacterial products .

LPS .)gram neg. bacteria( Bacterial DNA

Secrete cytokines, attract neutrophils

Induce local inflammation .

1. IL-1. 1. IL-1. 2. TNF.2. TNF.

3. IL-6. 3. IL-6. 4. IL-8. 4. IL-8. 5. IL-12.5. IL-12.

Macrophages produce many cytokines:

Act on various tissues & cells.

1. Induce local inflammation.1. Induce local inflammation.

2. Perform phagocytosis.2. Perform phagocytosis. 3. Activate coagulation .3. Activate coagulation .

4. Enhance antigen presentation.4. Enhance antigen presentation.

5. Initiate tissue repair .5. Initiate tissue repair .

And perform multiple functions:

MacrophageMacrophage MacrophageMacrophage

Thcell

MacrophageMacrophage

Cytokines Lymphokines

Cytokines

Anti-microbial functions

Anti-tumor function

Activa

te

Invading agent Antigen presentation Activated macrophage

Functions of macrophagesFunctions of macrophages: :

1. Lysosomal enzymes .1. Lysosomal enzymes .

2. Production of reactive oxygen2. Production of reactive oxygen

intermediates .intermediates .

3. Production of nitric oxide . 3. Production of nitric oxide .

Mechanism of intracellular killing by phagocytic cells

1. IL-12.1. IL-12.

2. IL-15.2. IL-15.

Produced by macrophages.Produced by macrophages.

Functions:Functions:

1. anti - viral activity.1. anti - viral activity.

2. anti – tumor activity.2. anti – tumor activity.

NK-cells are activated by:

A. The complement proteins .A. The complement proteins . Activation of the complement system lead to Activation of the complement system lead to

initiation of important effects which include :initiation of important effects which include : 1. Release of chemotactic factors .(C3a,1. Release of chemotactic factors .(C3a, C5a )C5a ) 2. Opsonisation of microbes .(C3b ).2. Opsonisation of microbes .(C3b ).

3. Lysis of target cells . (C8 & C9 ).3. Lysis of target cells . (C8 & C9 ).

4 .Circulating effector proteins:

**on activation acquire enzymatic activityon activation acquire enzymatic activity . . Become activated by 3 pathwaysBecome activated by 3 pathways: :

11 . .classical pathwayclassical pathway, require antigen antibody, require antigen antibody

22 . .alternative pathway alternative pathway , activated by bacterial, activated by bacterial

products (LPS ,DNA )products (LPS ,DNA )

33 . .lectin pathway lectin pathway , activated by mannan-binding , activated by mannan-binding lectinlectin . .

The complement system.

MEMBRANE ATTACK COMPLEXMEMBRANE ATTACK COMPLEX. .

C5 b

C6

C7

C9

C8

C9 C

9

CC

C9

C9

1. Mannose- binding lectin .1. Mannose- binding lectin .

2. C – reactive protein2. C – reactive protein

..

3. Coagulation factors.3. Coagulation factors.

4. Cytokines .4. Cytokines .

Other circulating effecter proteins:

The cytokines IL-1 , IL-6 & TNF-alphaThe cytokines IL-1 , IL-6 & TNF-alpha

act on various organs : act on various organs :

1. Liver1. Liver to induce the synthesis of acute phase to induce the synthesis of acute phase proteins. proteins.

2. Bone marrow2. Bone marrow to stimulate mobilization of to stimulate mobilization of neutrophils .neutrophils .

Cytokines of natural immunity coordinate body responses to infection:

3.Hypothalamus3.Hypothalamus to increase body temperature. to increase body temperature.

( induce fever ) ( induce fever )

4.Fat & muscle 4.Fat & muscle to supply proteins & energy. to supply proteins & energy.

5.T- & B- Lymphocytes5.T- & B- Lymphocytes to become activated & to become activated & produce adaptive immune responses. produce adaptive immune responses.

1. Natural Immunity is the first line1. Natural Immunity is the first line of defense.of defense.

2. It influence & stimulate subsequent2. It influence & stimulate subsequent adaptive immune responses .adaptive immune responses .

3. The immune response is a :3. The immune response is a : * Protective. * Protective. * Sub clinical .* Sub clinical . * Localized reaction.* Localized reaction.

Summary.