Innate immunity

Question 1

What is innate immunity?

Answer 1

It is immunity present from birth- using strategy 1 (recognising molecular patterns).

Not enhanced by exposure- has no memory. Uses cellular and soluble components.

Question 2

Is innate immunity fast?

Answer 2

Yes! Can respond within minutes to hours. Very effective and directs adaptive immunity

Question 3

What are the pattern recognition strategies?

Answer 3

• PAMP (pathogen associated molecular patterns)
• DAMP (damage associated molecular patterns)

Both above are not antigen specific and they use pattern recognition receptors (PRR)

• They also detect ‘self’. Natural killer cells

Question 4

Innate immunity physical barriers

Answer 4

Skin- mechanical barrier, acidic environment

Mucous membranes- mucus secretions trap microorganisms, cilia (respiratory) expel microorganisms

Question 5

Physiological barriers innate immunity

Answer 5

• Body Temp
• low pH
• Chemical mediators (lysozymes, interferons, complement)

Phagocytic:cells ingest material (neutrophils)

Inflammatory:local vascular permeability increases

Question 6

Which cells are involved in innate immunity?

Answer 6

Neutrophil- phagocytosis of microbe

Eosinophil- phagocytosis, granule release, defence against parasitic infection, help B cell response in GALT

Basophil- may act as APC

Monocyte/macrophage- phagocytosis, cytokine release act as APC

mast cell- granule release histamine

Nk cells- lysis of infected cell (cytotoxic t cells)

Dendritic cells- antigen capture and presentation

Question 7

What is the function of a neutrophil

Answer 7

40-75% of leukocytes

Short lived

Migrate to tissues- first cells to be recruited to a site of tissue damage/ infection

Question 8

What is the function of a macrophage?

Answer 8

Dispersed throughout tissues.

Signal infection by releasing soluble mediators (cytokines)

Question 9

Characteristics of neutrophils?

Answer 9

• Multilobed nucleus
• Primary granules- site of the enzymes that are going to kill the phagocytosed pathogen
• Secondary granule- replenish teh primary granules and regulate toxins that are produced in the lysis
• Primary granules stain darker than secondary granules
• The granules fuse with the vacuole to form a phagolysosome

Question 10

What do neutrophils need to do?

Answer 10

• Move from the cirulation into tissues where the infection is
• Bind to the pathogen
• Phagocytose the pathogen
• Kill the pathogen

Move towards–> bind —> phagocytose —> kill

Question 11

How do neutrophils move into tissue?

Answer 11

Rolling –> activation—> adhesion

• Near the site of infection there will be some damage or activated macrophages. Initially, will have low affinity for selective binding.
• When it gets to endothelium, chemokines are released which bind to the local endothelium layer ( from macrophage)
• Chemokines are only present on the endothelium if there is an infection
• Neutrophils roll along the surface with low affinity interactions (binding to selectin)- integrin in a low affinity state
• Integrin activation when chemokine receptor on neutrophil binds to chemokine on endothelium surface- it is activated ta high energy state
• Integrin binds strongly to integrin ligand, immobilising the neutrophil.
• Cells migrate into the tissue and the cells follow a chemokine gradient to figure out where to go (chemotaxis)

Question 12

What is diapedesis?

Answer 12

Movement across the endothelial layer

Question 13

How does migration of neutrophils to tissues start?

Answer 13

Macrophage with microbes release signals of infection - CHEMOKINES

They are released to local endothelium to activate it so cells know where to leave the circulation and enter the tissue

Question 14

What is opsonisation?

Answer 14

Coating of microorganisms with proteins to facilitate phagocytosis.

They bind to antigens AND phagocytes.

It makes it easier for neutrophils to recognise the pathogen

Question 15

Give 2 examples of opsonins

Answer 15

Antibodies

Complement

(humoral immunity)- the soluble component

Question 16

Describe how neutrophils bind to opsonins

Answer 16

• Antibody binds to receptor on the pathogen (the antigen)
• Complement binds to the cell SURFACE of the pathogen
• The bound antibody and complement can then bind to the neutrophil and activate it.
• The neutrophil will engulf the bacteria and lyse it.

Question 17

How do neutrophils kill pathogens?

Answer 17

1. OXYGEN INDEPENDENT- enzymes, lysozymes, hydrolytic enzymes, antimicrobial peptides
2. OXYGEN DEPENDENT- respiratory bursts, superoxide anion, hydrogen peroxide, NO and reactive nitrogen intermediates

Question 18

What are neutrophil extracellular traps? (NETs)

Answer 18

Activated neutrophils release granule proteins and chromatin to form extracellular fibres. It stops microorganisms from spreading everywhere and contains the site of infection.

Question 19

What is the difference between a monocyte and macrophage?

Answer 19

Monocytes leave circulation to mature into macrophages

Macrophages are bigger than monocytes

When in the blood, they are called monocytes. When in tissues, they are called macrophages.

They have lysosomes and are phagocytic- they have pattern recognition receptors.

Question 20

Describe macrophage function

Answer 20

Signal infection by releasing soluble mediators (alarm cytokines)

This helps to recruit other cells (like neutrophils) and activate subsequent adaptive immune responses.

Question 21

What do mast cells do?

Answer 21

They secrete histamine and other inflammatory mediators, including cytokines. There are different types:

• mucosal mast cells (lung)
• connective tissue mast cells (skin and peritoneal cavity, near blood vessels)

The recognise, phagocytose and kill bacteria. They can be activated by complement products (anaphylatoxins).

This leads to vasodilation and increased vascular permeability.

Question 22

What do natural killer cells do?

Answer 22

They are large granulated lymphocytes: cytotoxic, lyse target cells and secrete the cytokine interferon-gamma. They kill self

•5-10% peripheral blood lymphocytes

•no antigen-specific receptor, but express both activating and inhibitory receptors. 50/50 - this is why there are two mechanisms for cell recognition

• have receptors which bind to antibody-coated cells (Antibody DependentCell-mediatedCytotoxicity)
• important in defence against tumour cells and viral infections (esp. herpes)

Question 23

How do NK cells recognise target cells?

Answer 23

There are 2 types of target cell recognition:

1. Missing self recognition
2. Induced self recognition

Question 24

What is missing self recognition?

Answer 24

Healthy cells present MHC Class I. Receptors on NK cells can bind to this and they send inhibitory signals to stop lysis of the cell. When the cell is infected MHC class I expression is downregulated- they go ‘missing’. Inhibitory signal does not exist

Question 25

What is induced self recognition?

Answer 25

when we are stressed, cells start expressing new molecules- an abnormal pattern of self proteins. NK cells have activating receptors, which recognise stress patterns. once activated, the NK cells will try to kill the target cell

Question 26

What are cytokines?

Answer 26

* Small secreted proteins * cell-to-cell communication * messengers of the immune system * act locally * low biological effects at low concentration * short lived to control powerful effects

Question 27

What are the different types of cytokines?

Answer 27

* Interleukines: between leukocytes * interferons- antiviral effects * chemokines- chemotaxis * growth factors- proliferation and differentiation of cells * cytotoxic- tumour necrosis factor (TNF)

Question 28

How many types of interferons are there?

Answer 28

2 Type 2 is expressed and used by immune cells. Lots of other cells use type 1

Question 29

How are cytokines produced?

Answer 29

Inducing stimulus in cytokine producing cell (e.g. macrophage). Signal is delivered to transcribing gene. Once the cytokine is produced, released and reaches the receptor of target cell, it will have many different biological effects on over 100 genes.

Question 30

What are the three ways in which cytokines act?

Answer 30

1. Autocrine- the cytokines act on the same cells they were produced and secreted by. 2. Paracine- the cytokines act on a cell that is nearby the cell that produced it. 3. Endocrine- the cytokines travel a long distance through circulation to get to the target cell. In general, however, cytokines act over a short distance

Question 31

Examples of some cytokines that are secreted by macrophages

Answer 31

IL-1: alarm cytokine, fever TNF-alpha: alarm cytokine IL-6 acute phase proteins (liver) IL-8 chemotactic for neutrophils

Question 32

What do dendritic cells do?

Answer 32

Network of cells located at likely sites of infection. The recognise microbial patterns and secrete cytokines. They capture pathogens and migrates to local lymph node to present antigens to adaptive immune system (important APC)

Question 33

What is the complement system?

Answer 33

It is a system of functionally linked proteins that interact with one another, complementing the activity of specific antibody in lysing bacteria. It is a triggered enzyme cascade system and is rapid. The components are produced in the liver.

Question 34

The complement system's triggered enzyme cascade- describe it?

Answer 34

Components are synthesised as inactive precursors. Part of the protein has to be cleaved off before it becomes active. After activation, they become active enzymes the proteins can then catalyse the cleavage of lots of molecules. It is like a chain reaction- the substrate of the next enzyme was the product of the last one. This is why there is a huge amplification.

Question 35

What are the complement activation pathways?

Answer 35

1. Classical- antigen + antibody. A conformational change in the antibody leads to complement activation 2. Alternative- direct activation from bacterial surfaces contact 3. Lectin pathway- pattern recognition receptor. Binds to carbohydrates that are only present on pathogens.

Question 36

What is the Y of complement?

Answer 36

All the pathways converge at C3. C3 (complement component 3)- activation of C3 is common final pathway which leads to formation of MAC- membrane attack complex This is what lyses infected cells. The cleavage products are not waste- they have pro-inflammatory properties.

Question 37

Control mechanisms of complement

Answer 37

* Lability of components * Dilution of components in biological fluids * Specific regulatory proteins –circulating –membrane bound

Question 38

What are the functions of complement?

Answer 38

Activation of inflammatory response. Can cause mast cell degranulation- proinflammatory Lysis and osponisation

Question 39

Describe a local acute inflammatory response

Answer 39

* Macrophages in the tissue with PRR bind to PAMPs * Macrophages are activated and release cytokines and chemokines * Local vascualr permeability changes because of this and the lymphoctyes and neutrophils will migrate into the tissue to site of infection. * Complement will be activated by classic or alternative pathway. Classic if you have seen the bacteria before. * Complement activation will lead to proinflammatory fragments (anaphylatoxins) * Anaphylatoxins will bind to mast cells and permeability and dilation of vessels happens * Some of the products of degranulation are directly chemotactic for neutrophils

Question 40

What is the acute phase response

Answer 40

Happens after local inflammatory response. Fever, increased production of WBC and production of acute phase proteins in the liver- induced by cytokines.

Question 41

What are acute-phase proteins?

Answer 41

CRP- c reactive protein- activates complement Mannan binding lectin (MBL)- same complement fibrinogen (clotting)