Extracellular Innate Killing

Question 1

Eosinophils have

Answer 1

toxic granules

Question 2

Neutrophils have

Answer 2

toxic NETS

Question 3

Eosinophils create

Answer 3

extracellular traps

Question 4

Eosinophils extraceullar traps

Answer 4

• Eosinophils release mitochondrial DNA against bacteria
• When DNA is not properly folded it becomes very sticky so creates an environment which binds everything (trap for pathogens)

Question 5

Eosinophils granules are active against parasites:

Answer 5

• major basic protein (MBP)
• eosinophil cationic protein (ECP)
• eosinophil peroxidase (EPX)
• eosinophil-derived neurotoxin (EDN)

Question 6

When eosinophils release DNA they also release

Answer 6

lots of granules which are secreted into extracellular environment near pathogen, kills pathogen (creates toxic environment)

Question 7

Formation of Neutrophil Extracellular Traps (NETs)

Answer 7

• microbes recognised by neutrophil (receives input from cytokines and chemokines)
• neutrophil digests DNA and disintegrates nuclear envelope + DNA released
• when DNA is not folded properly = very sticky
• at the same time granules of neutrophil released into the sticky environment

Question 8

When killing is not possible, granuloma can

Answer 8

contain microbes
• When microbes cannot be killed by the immune system the infection is contained in a granuloma
- Coordinated response of Th1 T-cells and foamy macrophages which creates a layer of macrophages and outer layer of T cells which walls off the pathogen

Question 9

containing infection in the granuloma is important in

Answer 9

tuberculosis and in certain parasite infections

Question 10

Regulation simple

Answer 10

Communication between all cells of the immune system

Question 11

Regulation longer

Answer 11

• Phagocytosis occurs simultaneously with release of cytokines and chemokines (Every time there’s a phagocytosis, the receptors that trigger phagocytosis simultaneous signal to the innate immune mechanisms i.e. releasing cytokines and chemokines to recruit other cells i.e.
• Complement deposition triggers phagocytosis and recruitment of other immune cells
• Cytokines made by macrophages and dendritic cells trigger recruitment of neutrophils (most abundant cell in blood) and acute-phase response

Question 12

Regulation: Acute phase response

Answer 12

macrophages, dendritic cells and neutrophils detect invaders in tissue, macrophages produce inflammatory mediators i.e. IL-6, carried into blood stream causes local inflammation.
If levels high enough they will be carried into blood stream and will effect mechanism in the brain i.e. fever
IL1B, TNFA, IL-6. IL-6 acts directly on liver, hepatocytes on liver increase production of CRP, fibrinogen and mannose binding lectin (acute phase proteins)
All these proteins have effects that potentiate innate immune killing mechanism i.e. mannose-binding lectin binds carbohydrates on bacterial surfaces, acting as an opsonin and as a complement activator.
CRP binds phosphocholine on bacterial surfaces, acting as an opsonin and as a complement activator
So when there’s enough IL6 released into blood stream from site of infection, then the liver produces more innate immune mediators to kill and opsonin the bacteria.

Question 13

Many ways for regulation of the innate immune killing mechanisms

Answer 13

Different PRR and cytokines -> signal integration -> adaptation of responses to each pathogen

Question 14

Regulation each microbe

Answer 14

activates a set of PRRs as each PRR represents a specific structure different response based on ratio of signals allows a targeting of the response to pathogen and to tissue

Question 15

Regulation feedback mechanisms

Answer 15

Once other immune cells migrate into the tissue the cytokine and chemokine milieu modulates function of innate immune cells  differential activation of macrophages and monocytes ( and perhaps other cells)

Question 16

Regulation Preventing host damage

Answer 16

• Neutrophils produce NETs or perform phagocytosis:
• phagocytosis will release lots of inflammatory molecules and dangerous granules into a specialised contained compartment.
• The Net’s allow a containment of the cell and granules but when the neutrophils degranulate into the extracellular space the enzymes can diffuse and damage the host causing tissue damage.
• Once you have an infection you have to consider and modulate the amount of microbial killing you can do/tissue damage your host can tolerate.
• If too much tissue damage may be irreparable damage to tissue / or if it occurs in a chronic manner can cause degenerative or auto-immune disease

Question 17

Regulation: Preventing host damage 1

Answer 17

host cells have mechanisms to prevent activation of innate immune killing

Question 18

Regulation: Preventing host damage 2

Answer 18

2. intracellular signaling cascades triggered by PAMPS and DAMPS direct the magnitude and nature of the immune response, in a tissue-specific manner

Question 19

Danger Theory (DAMPS) by Polly Matzinger

Answer 19

• posited that the primary function of the immune system is to sense and respond to danger in the form of signals (ATP, adenosine) derived from damaged tissue, regardless of the source of damage. Danger-Associated Molecular Patterns (DAMPS)

Question 20

Pattern Recognition Theory by Charles Janeway Yale

Answer 20

• posited that lymphocyte activation is controlled by evolutionarily ancient system of germline-encoded pattern-recognition receptors (PRR) that detected conserved pathogen-associated molecular patterns (PAMPS) - predicted that PRR-PAMP interactions would induce costimulatory molecules on APCs.

Question 21

The DAMP and Pattern recognition theory frameworks

Answer 21

co-exist.

Question 22

Constant feedback mechanisms

Answer 22

• pathogen microbes PRR vs detection of host damage via DAMPS (Danger associated Molecular patterns)
• = constant feedback mechanisms
• When deregulated: CYTOKINE STORMS, IMMUNE-MEDIATED DAMAGE, ALLERGY, FIBROSIS
So need to regulate and control the innate immune system.

Question 23

Disorders of the immune system caused by

Answer 23

Deficiency in complement system

Question 24

what are the types of immune system deficiencies and what type of disease they will cause i.e.

Answer 24

Defect in complement – susceptible to disease by bacteria as it can’t be lysed and opsoninsed efficiently.