Lec 10 (Ch14, 15): Nonspecific Immunity – Host Defenses

Topics - Defense Mechanisms (innate, acquired) - Systems (anatomic, immunological) - Non-specific immunity (general response)

1

Kinds of Resistance • 2 Major divisions: – Nonspecific – Specific

• 3 Lines of Defense – Exterior – General response – Specialized response 2

Defense Mechanisms • Inate and nonspecific – First line of defense (barriers) – Second line of defense (phagocyres, inflammation, fever, antimicrobials)

• Acquired and specific – Third line of defense (specific resistance, B&T lymphocytes, Abs 3

1

Major Components of Host Defenses

4

First line of defense

(mechanical, chemical, normal flora)

• Barriers – – – –

Anatomical Chemical Normal Flora Genetic

5

Anatomical barriers • Skin – Outermost layer – Hair follicles – Skin glands

• Mucous membrane – – – –

Digestive Urinary Respiratory Eye 6

2

The trachea contain cilia that entrap and propel particles out of the respiratory tract.

F

7

Chemical barriers • Antimicrobial peptides: – Sebaceous secretions – Eyelid glands – meibomian gland – Tears and saliva – lysozyme

• Acidic pH – – – – –

Sweat Stomach Skin Semen Vagina 8

1st Line Nonspecific Chemical Defenses

• Toll-like receptors (TLRs) – Integral membrane proteins produced by phagocytic cells – Bind pathogen-associated molecular patterns (PAMPs) – Initiate defensive responses • Apoptosis • Secretion of inflammatory mediators • Production of stimulants of adaptive immune response • NOD proteins – Cytosolic proteins that bind PAMPs

9

3

Primary anatomical and chemical defense barriers

10

Normal Flora as 1st Line Microbial antagonism Normal flora compete against potential pathogens: •Nutrients •Environment •Stimulate second line of defense •Promote health (provide vitamins)

11

Genetic barriers • Different level of sensitivity and resistance to infectious agents – Malaria – Tuberculosis – Leprosy – Fungal infections

12

4

2nd Line of Defense

13

2nd line of Defense – What is it? • Response to pathogen penetration (skin or mucous membranes) • Cells, antimicrobial chemicals • Blood Chemistry: – Plasma – Serum – Erythrocytes (O2) – Leucocytes (white cells) (5 kinds) – Platelets (blood clotting) • Immunology • Protective cells 14

What is Immunology? • Study of the development of resistance to infectious agents by the body – Surveillance of the body – Recognition of foreign material – Destruction of foreign material or agent

• Involve nonspecific and specific immune defense systems • White blood cells (wbc) or leukocytes are involved 15

5

Non-specific Phagocytosis • Phagocytes (white cells) • Migration of roaming cells • also histiocytes Kupffer’s cells, alveolar, microglial etc. 16

WBC • WBC recognize self markers on the host cell – Do not attack or do not respond to host cell

• WBC recognize nonself markers on the invading microbe – Attack or respond to microbe

17

WBC must recognize and destroy non-self cells

18

6

Systems - connections • All systems are integrated – – – –

Recticuloendothelial system (RES) Extracellular fluids system (ECF) Blood or circulatory Lymphatic

19

Reticuloendothelial (RES) • Network of connective tissue fibers (Reticulum) • Interconnects cells • Allows immune cells to bind and move outside the blood and lymphatic system

20

Extracellular fluid (ECF) • The spaces surrounding tissue cells and RES • Enable immune cells to move

21

7

Blood • Stem cells precursors • Hemopoiesis • Components : (Blood Chemistry) – – – –

Plasma Serum Erythrocytes (O2) Leucocytes (white cells) (5 kinds) – Platelets (blood clotting) 22

Stem cells • From blood cells – RBC – platelets

• Hematopoietic stem cells (yolk sack and liver, then bone marrow) – Neutraphils, basophils, eosinophils, monocytes

• Lymphoid stem cells – T cells – B cells 23

Hematopoiesis

24

8

The three types of stem cells -

differentiate into: •Blood •platelets •Granulocytes •agranulocytes

25

Leucocytes (white blood cells) • Leukocytes – Granulocytes (large cytoplasmic granules) • Neutrophils  phagocytes, digestive enzyme, 1st to arrive • Basophils  histamine, like eosinophiles, localized ones called mast cells • Eosinophils phagocytosis, eukaryotic pathogens, inflammation & allergy

– Agranulocytes (very small granules) • T cells  cell-mediated • B cells  Ab production • Monocytes  mature into macrophage 26

Leukocytes (Blood Smear)

27

9

Lymphocytes • Specific immunity – T cells (cell-mediated) – B cells (Ab-mediated)

• Present throughout the body: – Phagocytes (white cells) – Migration of roaming cells – also histiocytes Kupffer’s cells, alveolar, microglial etc. 28

Phagocytosis • Chemotaxis • Adherence (opsins can increase this)… • Ingestion via phagocytic vessicle phagosome – pH to 4.0, enzymes kick in

• Lysosomes fuse w/ phagosome phagolysosome • 30 minutes bacteria dead 29

Phagocytosis

– the artist’s rendition

30

10

How to evade phagocytosis! (run away run away!)

• Adherence inhibition via M protein or capsule • Toxins (Staph produces leukocydins, Streps produce streptolysin) • Membrane attack proteins • Special adaptive factors and tolerances

31

Non-phagocytic Killing • Eosinophils: – Attack parasitic helminths (surface attachment) – Secrete toxins (weaken or kill helminth) – Eosinophilia (elevated) often = helminth infestation – Eosinophil mitochondrial DNA and proteins form structure that kills some bacteria • Natural Killer Cells (lymphocytes): – Secrete toxins onto surface of virally infected cells and tumors – Differentiate normal body cells because they have membrane proteins similar to the NK cells 32

Non-phagocytic Killing (cont.) • Neutraphils: – Produce chemicals that kill nearby invaders – Generate extracellular fibers [neutrophil extracellular traps (NETs)] that bind to and kill bacteria

33

11

Lymphatic system • Network of vessels that extend to most body areas • Includes nodes, spleen, thymus… • Connected to the blood system • Provides an auxiliary route for the return of extracellular fluid to the circulatory system • “Drain off” system for inflammatory response • Contains lymphocytes, phagocytes and antibodies 34

Artist’s rendition- Lymphatic System

35

Lymphatic Fluids • Plasma-like fluid (lymph) – Water – Dissolved salts – Proteins (antibodies, albumin) – White blood cells – No red blood cells

• Formed from blood components – Diffuse into the lymphatic capillaries 36

12

Lymphatic Vessels

(carry lymphatic fluid…) • Parallels the blood system • Returns lymph to the blood system • Movement of lymph depends on muscle contractions • Permeates the body except the cns, bone, placenta, and thymus.

37

Lymph nodes • Exist in clusters • Located – along the lymphatic channels and blood vessels – in the thoracic and abdominal cavity regions, armpit, groin and neck

• Filter for the lymph • Provide environment for immune reactions

38

Spleen • Located in the upper left portion of the abdominal cavity • Filter for blood – traps pathogens and phagocytizes pathogens

• Adults can survive without spleen • Asplenic children are severely immunocompromised 39

13

Thymus • Embryo – two lobes in the pharyngeal region – Differentiate immature T-cells into mature t-cells – High activity (releases mature T cells) until puberty

• Adult – Gradually shrinks – Lymph node and spleen supply mature T cells 40

Gut-Associated Lymphoid Tissue (GALT) • Recognized incoming microbes from food • Supply lymphocytes for antibody response • Ex. Appendix, lacteals, Peyer’s patches, isolated lymphoid follicles (ILF)

41

Non-specific Immunity • • • •

Inflammation Phagocytosis Interferon Complement

42

14

Inflammation • •

Triggered by damage Five (4 major) symptoms  1. 2. 3. 4. 5.

•

Redness Warmth Swelling Pain *Loss of function

Acute vs. Chronic 43

Typical symptoms that occur after injury.

44

Inflammation •

Causes:

•

3 Functions:

•

Stages:

– Trauma – Tissue injury due to physical or chemical agents – Specific immune reactions – Destroy agent (and remove or destroy) – Limit wall or confine – Repair or replace

Results in: • Mobilization and attraction of immune components to the site of injury • Aid in repair of tissue damage • Localized, remove of harmful substances • Destroy microbes and block their invasion

– vascular – edema – fever 45

15

The major events in inflammation: injury, vascular reactions, edema, resolution

46

3 Stages of Inflammation 1. Vascular changes

(vasodilation = increased permeability)

2. Edema

(phagocytic migration and phagocytosis)

3. Fever

(followed by tissue repair)

47

1-Vascular changes • Blood cells, tissue cells, and platelets release chemical mediators and cytokines • Chemical mediators (Cause fever, stimulate lymphocytes, prevent virus spread, cause allergic reactions)

– Vasoactive • Affect endothelial cells, smooth muscles of blood vessels • histamines • permeability rise = edema  nerve damage, toxin irritation, pressure etc.)

– Chemotactic (chemokines) • Affect WBC 48

16

Effects of chemical mediators during inflammation

49

2 - Edema • Leakage of vascular fluid (exudate) into tissue • Exudate - plasma proteins, blood cells (wbc), debris, and pus • Migration of wbc is called diapedesis or transmigration – Chemotaxis 50

Transmigration (diapedesis) of WBCs is followed by chemotaxis

51

17

3 - Fever • Caused by pyrogens – reset the hypothalamic thermostat (increase temperature) – Vasoconstriction

• • • •

Phagocytes release IL-1 increase t-cells Increases interferon effect (Fe++) Speeds up metabolism Inhibits microbe and viral multiplication ( reduces nutrient availability, increases immune reactions )

52

Fever (pyrexia) •

• •

elevation in the thermoregulatory set-point: release of prostaglandin E2  hypothalamus Caused by pyrogens Endogenous – (cytokines, IL-6, tumornecrosis factor)

OR • Exogenous – Microbes and their products (ex. Endotoxins, LPS, superantigens) 53

Neutrophils and eosinophils • Early responders to inflammation • Neutrophils are primary components of pus • Eosinophils are primary responders to parasitic infections

54

18

Macrophages • Monocytes transform into macrophages • Scavengers – Histiocytes – reside in one location (ex. Alveolar, Kupffer, Langerhans) – Drift throughout the RES

• Undergo phagocytosis, • Interact with B and T cells 55

Histiocytes Macrophages can become histiocytes by taking up permanent residence in the lung (alveolar), liver (Kupffer) and skin (Langerhans).

56

Macrophage mechanism • • • •

Chemotaxis Ingestion Phagolysosome Destruction

57

19

Chemotaxis • Directed by – Pathogen-associated molecular patterns (PAMPs) • Peptidoglycan • LPS

– Foreign debris

58

Ingestion • Pseudopods enclose the pathogen or foreign material • Form a phagosome

59

Phagolysosome • Lysosomes fuse with the phagosome • Other antimicrobials chemicals are released into the phagolysosome

60

20

Destruction • Within the phagolysosome – Oxygen-dependent system • Oxidative burst (oxidizing agents)

– Enzymes – Nitric oxide

• Undigestible debris are released

61

Phagocytosis mechanism

62

2nd Line includes: Nonspecific Chemical Defenses – Interferons Interferons – Protein molecules released by host cells to nonspecifically inhibit the spread of viral infections – Cause many symptoms associated with viral infections – Two types • Types I (alpha and beta) • Type II (gamma) 63

21

Interferon •Produced in response to: •viral infections •microbe infections •RNA •immune products •antigens

• •

Synthesis: WBCs,Tissue cells Classes:

1. Alpha = prod of lymphoctes and macrophages 2. Beta = prod of fibroblasts and epithelial cells 3. Gamma = prod of T-cells

64

Interferon activity • Ex. Virus - binds to host cell • A signal is sent to the nucleus to synthesized (transcription and translation) interferon • Interferon is secreted • Binds to other host cells • Host cells produce antiviral proteins – inhibit viral multiplication or translation • Not virus-specific 65

Interferon mechanism: produced, released, and taken-up by a near-by cell, original cell is not protected but recipient cell is protected

66

22

Alpha & Beta Interferons

67

Other Interferon roles • Activates and instructs T and B cell development • Inhibits cancer cells • Activates macrophages

68

Complement – What is it? • Causes cell lysis • Consist of 26 blood proteins • Produced by liver hepatocytes, lymphocytes, and monocytes • 3 major Pathways • Cascade reaction • What are the stages? 69

23

Complement pathways • Classical – activated by the presence of antibody bound to microbes

• Lectin – activated when a host serum protein binds a sugar (mannan) in the wall of fungi and other microbes

• Alternative – activated when complement proteins bind to cell wall or surface components of microbes 70

The complement pathways, activators, and involved proteins

71

Complement Pathwaysanother view

72

24

Complement Stages 1. 2. 3. 4.

Initiation Amplification and cascade Polymerization Membrane attack !!

73

The Cascade

74

Classical pathway

Begins when C1 components bind to antibodies. It completes by puncturing small pores through the membrane. This results in lysis.

75

25

Membrane Attack Complex= Lysis!

76

Onward!

…to Specific Immunity – The 3rd Line of Defense

Graphic from: Oat Willie’s Logo, Austin Texas

77

Some additional Info

78

26