L11 - Effector responses against infection I

Question 1

Innate immune response: what lineage are the cells involved in this derived from and what do they recognise?

Answer 1

Myeloid lineage - derive from common myeloid progenitor cells in the bone marrow

Pathogen recognition receptors (PRRs)

Question 2

Myeloid cells: what are there?

Answer 2

Mast cells
Macrophages (P)
Dendritic cells (P)
Neutrophils (P) (G)
Basophils (G)
Eosinophils (G)

P - phagocytes
G - granulocytes

Question 3

Macrophages: what are they, where do they reside, where are they produced from, and what features do they have that allow them to do their function?

Answer 3

“Professional phagocytes”

Reside in tissues

• Monocytes (from bone marrow) that enter tissues from the circulation
• Embryonic cells during development

Special receptors on the surface to enable phagocytosis of pathogens

Question 4

Neutrophils: what are they, what do they do, how long do they live, how prevalent are they, and how do they sense pathogens?

Answer 4

Highly phagocytic granulocyte

Very readily activated granulocytes that move into sites of inflammation

Short life-span (dead neutrophils = pus)

90% of circulating granulocytes

Can sense and move via chemotaxis (like macrophages)

Question 5

Phagocytosis: what methods of pathogen killing are there

Answer 5

• Acidification of phagosome
• Contents of phagolysosome - e.g. enzymes, toxic oxygen species
• In neutrophils, fusion of cytoplasmic granules containing enzymes and anti-microbial peptides with the phagosome (watch lecture)

Question 6

Granulocytes: what examples are they and what are they most adept at?

Answer 6

Neutrophils:
* Good at phagocytosis
* Mediate effects by releasing toxic granules and chemical mediators

Eosinophils:
* Poor at phagocytosis
* Mediate effects by releasing toxic granules and chemical mediators

Basophils:
* Poor at phagocytosis
* Mediate effects by releasing toxic granules and chemical mediators

Question 7

Basophils: how frequent are they, what toxic granules do they use, and what do they do?

Answer 7

0.2% blood white blood cells

• Heparin
• Leukotrienes
• Prostaglandin
• Histamine

Activated to degranulate by the number of mechanisms - complement, antibody, cytokines, etc

Question 8

Eosinophils: how frequent are they, what toxic granules do they use, and what do they do?

Answer 8

2-5% blood white blood cells

• Eosinophil cationic protein
• Major Basic Protein

Activated to degranulate by the number of mechanisms - complement, antibody, cytokines, etc

Question 9

Mast cells: what are they, what do they do, and what are they activated by?

Answer 9

Basophil-like, but found in the tissue, not the blood

Bind IgE on the cell surface with high affinity at rest

Activated when IgE binds antigen (multivalent) and releases granules

Question 10

NK cells: what are they, what do they do, and what cells do they interact with?

Answer 10

Important innate Natural Killer cells

Produce cytotoxic molecules to kill ‘altered’ cells

Infected cells or tumour cells

Question 11

NK cells: how do they destroy target cells?

Answer 11

NK cells express inhibitory and activating receptors constitutively, these receptors bind to both activating ligands and inhibitory MHC class I ligands.

If the target cell is normal - the inhibitory MHC class I ligand is expressed and inhibits the killing of the target cell

If the target cell is abnormal, the abnormal cell downregulates ligands for NK cell inhibitory receptors and the killing of the cell is activated

Question 12

Do the innate immune response and adaptive immune response interact?

Answer 12

Cytokine production by the innate cells can help drive the more specific T and B-cell responses - adaptive immune responses

Cytokine and antibody production by the adaptive immune response can aid and regulate the more innate immune responses

Question 13

Complement system: what is it, what are they a component of, what do they do, how many collections are there, what activation pathways are there, and where are they made?

Answer 13

A system of plasma proteins that activate in response to pathogens and/or pathogen-associated cells which act to aid antibody-mediated killing of bacteria

Major component of the innate immune system

Provides important early antibody-independent killing of pathogens

Collection of over 30 different soluble proteins

• Classical pathway
• Alternative pathway
• Lectin pathway

Made in the liver as inactive precursors, present in the blood and other body fluids in an inactive form

Question 14

Complement proteins: what are they mostly, what is their inactive form, how do they become active, and what is significant about their activated form?

Answer 14

Enzymes

An inactive precursor that contains the full protein

Cleaving into two subunits

• One subunit - may be a mediator of inflammation
• Other subunit - two receptor sites, one binds an active enzymatic site and the other provides a binding site for the next protein in the cascade

Question 15

Central pathway of complement: what is it activated by?

Answer 15

All pathways generate a C3 convertase which cleaves C3, leaving C3b bound to the microbial surface and releasing C3a

Question 16

What are the classical, alternative, and lectin pathways of complement system activation?

Answer 16

Classical Pathway - complement binds to antibody bound to the pathogen surface

Alternative Pathway - Complement binds to pathogen surfaces

Lectin Pathway - Complement binds to Mannose-binding protein bound to the pathogen surface

Question 17

Classical pathway

Answer 17

Involves the first component of complement C1

Watch lecture (slide 28/29)

Question 18

Alternative pathway

Answer 18

Does NOT require antibody

Involves other complement factors B and D

Watch lecture (slide 32/33)

Question 19

Lectin Pathway: what does it get activated by, what is the key binding receptor protein, how does binding work, what does the binding complex do, and how does C4b activation work?

Answer 19

Mannose - often found on the surface of pathogens as glycoproteins/polysaccharides

Mannose-binding Lectin - present in serum

Once MBL has bound, MBL-associated proteases (MASPs) bind to MBL

MBL-MASP complex cleaves C4 and C2 in the same way as the classical pathway.

C4b → same sequence as classical pathway
↓
C3 activation (????? watch lecture)

Question 20

How does C3 cleavage lead to the removal of pathogens?

Answer 20

4 main ways pathogens get destroyed:

1. Induction of cell lysis
2. Opsonisation of pathogen (“prepare for table”)
3. Induction of chemotaxis and inflammation
4. Immune complex clearance (small antibody-soluble antigen complexes, not enough antibody to mediate phagocytosis)