Lecture 22: Infection and innate immunity

Question 1

Internal innate immunity can be divided into cellular and humoral components, list examples of each:

Answer 1

Cellular:

• Natural Killer Cells
• Natural killer T cells
• Eosinophils, Neutrophils, Basophils
• Macrophages
• Mast cells
• Dendritic cells

Humoral factors:

• Complements i.e C3
• Mannose binding lectin
• Antimicrobial peptides
• C-reactive protein
• LPS binding protein

Question 2

What does innate immunity provide?

Answer 2

The first line of defence or immediate response to pathogen invasion

Question 3

Does the body have the same defence strategy against all pathogens?

Answer 3

No, each has a different defence strategy

Question 4

What does defence against viruses rely on and why?

Answer 4

Defence relies on antibodies and cellular immunity - Need to be able to distinguish infected from normal cells.

Because: Viruses are intracellular pathogens, they require cells to replicate.

Question 5

What does defence against bacteria rely on and why?

Answer 5

Defence is primarily mediated by innate mechanisms and phagocytosis

Because bacteria are MOSTLY extracellular pathogens

Question 6

How does the body deal with protozoa and parasites? Whats a specific mechanism?

Answer 6

Protozoa and parasites are complex multicellular organisms requiring direct killing by chemical mediators released by specialist myeloid cells (WBC)

Specifically:
- Granules filled with cytotoxic chemicals. Degranulation releases these toxic inflammatory chemicals such as histamine i.e mast cells.

Basophils and eosinophils important here too

Question 7

What two main bacteria are distinguished by gram staining?

Answer 7

Gram positive

Gram negative

Question 8

Write some notes on gram positive:

Answer 8

Gram positive bacteria have a thick peptidoglycan cell wall as defence. Requires phagocytosis and are not killed directly by compliment.

i.e

S. Aureus and S. Pyogenes

Question 9

Write some notes on gram negative:

Answer 9

Gram negative bacteria have a thin peptidoglycan layer surrounded by an outer membrane. These bacteria can often be lysed directly by complement membrane attack complex

i.e E. Coli and H. Influenza

Question 10

What sort of antibiotics block peptidoglycan synthese?

Answer 10

B-lactam antibiotics such as penicillin block peptidoglycan synthase.

Question 11

How do neutrophils find infections from the confines of blood vessels?

Answer 11

Chemotaxis and activation of the endothelial cells.

Question 12

There are five steps in neutrophil extravasation, describe steps 1 and 2:

Answer 12

1) ACTIVATION. CHEMOKINES from tissue injury or inflammation activate the local endothelial cells lining an adjacent capillary wall.
2) TETHERING - Neutrophil tethers to the inside capillary wall. Mediated by SELECTINS unregulated on endothelial cells and SIALYL LEWIS X (SLex), a carbohydrate antigen on neutrophils.

Question 13

There are five steps in neutrophil extravasation, describe steps 3,4,5:

Answer 13

3) ADHESION - Strong binding between neutrophil INTEGRINS and ICAM-1 on the endothelium. Neutrophil immobilises and flattens.
4) DIAPEDESIS - Neutrophil squeezes between endothelial cells into the interstitial space.
5) CHEMOTAXIS. Neutrophil migrates along a chemical gradient to the site of infection.

(Whole process only takes minutes from the first point of tissue injury)

Question 14

Describe what are some chemotaxic factors for neutrophils and what enhances phagocytosis:

Answer 14

Chemoattracts i.e C5a are sensed by the leading edge of Neutrophils.

Neutrophils migrate up the chemoattractant gradient. - Polymerizing actin filaments at their leading edge and de-polymerizing those filaments at their trailing edge.

Neutrophils have receptors that bind deposited complement proteins, mainly C3b on the surface (Opsonised bacteria)

Question 15

Write some notes on complement receptors:

Answer 15

Myeloid cell receptors that bind activated compliment components deposited on bacteria.

CR1 is the main neutrophil receptor receptor and binds C3b.

Cross linking on the surface CRs initiates phagocytosis.

Question 16

What is the Fc region of an antibody?

Answer 16

Antibodies are Y shaped and the Fc region is at the bottom of the Y. It is bound the the FcR (Fc Receptor) on neutrophils.

Question 17

Describe the 7 steps of FcR (Antibody) mediated phagocytosis:

Answer 17

1. Antibody (IgM and IgG) bind to bacterial antigens
2. Exposes the antibody Fc region
3. Neutrophil FcR binds multivalent Fc
4. Activates phagocytosis
5. Membrane invaginates forming a phagosome
6. Fuses with lysosome to form phagolysosome
7. Phagolysosome acidifies and superoxides kill bacteria

Question 18

Molecular pattern recognition is an important feature of the innate immune mechanism, describe an example of innate molecular pattern recognition and what happens:

Answer 18

• Pattern recognition receptors (PRR) bind complesx molecules that are unique to microbes. i.e Toll Like Receptors (TLR) (THERE ARE OTHERS)
• Activation through TLR stimulates a strong innate response through an important inflam pathway

Question 19

What are PAMPS?

Answer 19

Pattern Associated Molecular Patterns

Question 20

Writes some notes on PAMPS:

Answer 20

• Molecules unique to microbes, that are recognised by PRRs
• Structurally very complex i.e lipopolysaccharides.
• Evolutionary stable i.e dont change much
• They stimulate the ‘power’ switch for the adpative response.

Question 21

Whats a specific TLR and what PAMP does it recognise? describe the response:

Answer 21

TLR4 recognises lipopolysaccharide (LPS)[PAMP]

• LPS is membrane component of all gram -ve bacteria
• Tiny amount induce powerful innate response.

Question 22

Why is LPS {PAMP} so bad that it requires a powerful immune response?

Answer 22

• LPS is a pryogen
• When injected into bloodstream, causes fever, thus in pharma industry must be removed from any injections.
• RELEASE OF LPS BY GRAM -VE BACTERIAL INFECTIONS LEADS TO LIFE THREATENING SEPTIC SHOCK