Immunology 3- Innate Immunity

Question 1

What is the innate immunity

Answer 1

“inbuilt”, present from birth
not enhanced by second exposure (has no memory)
uses cellular and soluble components
rapid response, minutes to hours, cooperates
with and directs adaptive immunity
A series of non-specific defences that are in constant readiness to fight infection.

Question 2

What ‘patterns’ does the innate immune system recognise

Answer 2

Detect conserved microbial structures (PAMP)

Detect consequences of cell infection or injury (DAMP)

Detect ‘missing self’ - viruses can down regulate cell surface receptors
(Natural Killer cells)

Question 3

How does the innate system discriminate between self and non self

Answer 3

Using pattern recognition receptors.

Question 4

List some examples of PAMP

Answer 4

Flagellin, LPS

Question 5

List some examples of DAMP

Answer 5

Fragments of the ECM

Question 6

What are the roles of the innate immune system

Answer 6

Use pattern recognition receptors to recognise PAMPs, respond to invading pathogens, activate other parts of the immune system through the secretion of cytokines and other inflammatory mediators (danger signals), recognise and respond to damage to self.

Question 7

What are the anatomical barriers of the innate immune system

Answer 7

Skin - mechanical barrier, acidic environment

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

Question 8

Describe how the skin has evolved as a barrier to infection, describe the role of the keratinocytes and the Langerhans cells in the immune response.

Answer 8

The dense outer layer of keratinocytes prevents penetration of organisms in deeper tissues. The keratinocytes are active components of the innate immune system, secreting cytokines such as IL-8 and tumour necrosis factor if they are damaged- e.g inflammation that occurs after exposure to UV light. Langerhans cells are sentinel cells of the dendritic cell lineage, after exposure to microorganisms, these cells migrate to the lymph node to present antigens to T cells (Adaptive immunity).

Question 9

How is the skin typical of the innate immune system

Answer 9

It responds rapidly to infection to stimulate and activate the adaptive immune system,

Question 10

Describe the role of the respiratory tract as a barrier to infection (upper segment)

Answer 10

The respiratory tract is divisible into upper and lower segments. The upper airway begins at the nose and ends in the bronchioles and is protected by a mucocililary escalator. Mucus secreted by goblet cells forms a fine layer that lines the airway and traps microorganisms. Cilia waft mucus towards the mouth and nose, where trapped microorganism are cleared by sneezing or coughing

Question 11

Describe the role of the respiratory tract as a barrier to infection (lower segment)

Answer 11

In the lower respiratory tract, in terminal bronchioles and alveoli, layers of cilia and mucus can obstruct oxygen diffusion. The main defences here are surfactants secreted by specialised cells that line the alveoli, type 2 pneumocytes. Surfactants are a mixture of protein and phospholipids that prevent alveoli from collapsing during expiration. Surfactant also contains pathogen-binding proteins, which are members of the collectin family. The collectins have globular lectin-like heads that bind to sugars on microorganisms and long collagen-like tails that bind to phagocytes (stimulating phagocytosis) or complement. These molecules have a pattern recognition role.

Question 12

What is the problem in patients with cystic fibrosis and ciliary dyskinesia

Answer 12

Mucus secretion is abnormal in patients with cystic fibrosis (due to imbalance of Fe) and cilia are defective in patients with ciliary dyskinesia. Patients with these conditions have recurrent respiratory tract infections.

Question 13

How does the GI tract act as a barrier to infection

Answer 13

It has a low pH.

Question 14

Describe the physiological barriers to infection

Answer 14

Body temperature / fever
Low pH - acidic pH of stomach kills many ingested microorganisms
Chemical mediators - lysozyme, interferons, complement

Question 15

What is the role of phagocytes

Answer 15

To engulf invading microorganisms to kill them, release signals to alert other immune cells to the infection.

Question 16

Where are phagocytes produced

Answer 16

Bon-marrow (myeloid cells).

Question 17

List the different types of phagocytes, explaining briefly their function.

Answer 17

Neutrophil: phagocytosis and killing of microbes
Eosinophil: phagocytosis, granule release, defence against parasitic infections, help B cell responses in GALT (IgA production)
Basophil: granule release, may act as APC for “type 2 immunity”
Monocyte / macrophage: phagocytosis, killing, cytokine release, act as APC
Mast cell: granule release (pro-inflammatory)
Dendritic cell: antigen capture and presentation
Natural killer cell: lysis of infected cells

Question 18

Describe the characteristics of neutrophils

Answer 18

Polymorphonuclear granulocytes, abundant (40-75%) of leukocytes,circulate in blood then migrate into tissues; first cells to be recruited to a site of tissue damage/infection. Highly variable production and blood levels- increase in infection
Neutrophil deficiency is associated with infections due to extracellular bacteria and fungi.

Question 19

How do neutrophils kill pathogens

Answer 19

Neutrophils are highly phagocytic cells, they bind to antigens and engulf the pathogens in a process known as phagocytosis. Neutrophils have multiple killing mechanism, the most important of which is oxygen dependent respiratory burst. Also produce NETs.

Question 20

How do neutrophils communicate with other cells of the immune system

Answer 20

Short lived chemokines recruits more neutrophils to the site of infection
Respond to IL-17 from the adaptive immune system
Do not provide many signals to the adaptive immune system.

Question 21

Ultimately, what does a neutrophil need to do to fight infection

Answer 21

1. move from circulation into tissues to site of infection
2. bind pathogen
3. phagocytose pathogen
4. kill pathogen

Question 22

What is the difference between monocytes and macrophages

Answer 22

Monocytes in the blood are immature cells migrating to their site of activity. When they migrate into tissues, they mature to form macrophages.

Question 23

Describe the characteristics of macrophages

Answer 23

less abundant, dispersed throughout the tissues; signal infection by release of soluble mediators.
Produced at a steady level
Blood levels steady
Migrate into tissue when no inflammation is present- may survive years

Question 24

Describe the different types of macrophages

Answer 24

Various mature forms depending on the tissue.
Bone marrow and lymph nodes- histiocytes
Gilal cells- nervous system- clear dead neuronal cells
Osteoclasts- most specialised- participate in regulating calcium metabolism by resorbing bone and releasing calcium into the blood.
Fixed macrophages- specialised phagocytes that line the spleen and liver (Kupffer cells). Their roleis to phagocytose circulating particulate matter and under certain circumstances, to phagocytose entire cells.
Alveolar- contribute to lung’s innate defences, involved in COPD.

Giant and epithelioid cells- sites of chronic inflammation, macrophages undergo further maturation and become multinucleated giant cells under the influence of T-cell cytokines.

Question 25

How do macrophages kill cells

Answer 25

Phagocytosis, release of toxic molecules and enzymes.

Question 26

Describe how macrophages communicate with other cells of the immune system

Answer 26

Recruit neutrophils to site of inflammation (IL-8,TNF and IL-1). Respond to IFN-gamma from adaptive immune system. Stimulate adaptive immune system by presenting processed antigen, providing, costimulation, and stimulating cytokines such as IL-2 and TNF.

Question 27

What is meant by phagocytosis.

Answer 27

The internalisation of particulate matter by cells into cytoplasmic vesicles and is triggered when phagocytes recognise pathogens. Phagocytes contain lysosomes, granules that contain enzymes that fuse with the vesicles and degrade the particulate matter. In addition, activation of a cascade of phagocyte enzymes which leads to the production of toxic molecules, the oxidative burst, necessary to kill phagocytosed organisms.

Question 28

What are the roles of phagocytes

Answer 28

Clearing small extracellular pathogens such as bacteria, protozoa, fungi and cellular debris. Also produce cytokines and cell-surface molecules, which alert the adaptive immune system to the presence of infection.

Question 29

Describe phagocyte production

Answer 29

Production is stimulated by colony stimulating factors, which are produced by tissue macrophages as part as an acute-phase response, ensure that neutrophils are produced in increasing numbers during infection. Recombinant granulocytes CSF, can be used to boost neutrophil numbers, for example, after a stem cell transplant.

Question 30

Describe the movement of neutrophils into tissues

Answer 30

IL-8 secreted by macrophages makes neutrophil integrins more adherent, which allows them to bind to the endothelium and undergo diapedesis ( passage through intact vessel walls into tissues). The final chemokine mediated step is chemotaxis, the directional migration of cells along a gradient of chemokines. Rolling, integrin activation, arrest,migration

Question 31

What is opsonisation

Answer 31

coating of micro-organisms with proteins to facilitate phagocytosis opsonins are molecules that bind to antigen, and also can be bound by phagocytes antibody and complement function as opsonins

Question 32

List the killing mechanisms of neutrophils

Answer 32

``` oxygen-independent enzymes lysozyme hydrolytic enzymes antimicrobial peptides (defensins) oxygen-dependent respiratory burst: superoxide anion hydrogen peroxide singlet oxygen hydroxyl radical reactive nitrogen intermediates nitric oxide ```

Question 33

Describe the NETs

Answer 33

neutrophils die when they NET- contains DNA and proteins. Traps microorganisms, prevents them from spreading, signal of infection, recruit other cells to fight infection. Activated neutrophils release granule proteins and chromatin to form extracellular fibres

Question 34

What are the characteristics of mast cells

Answer 34

secrete histamine and other inflammatory mediators, including cytokines can recognise, phagocytose and kill bacteria can be activated by complement products (anaphylatoxins) leads to vasodilation and increased vascular permeability Can reside in tissues

Question 35

What causes mast cells to be produced

Answer 35

Produced in bone marrow under the influence of T helper cells, IL-3 and IL-4.

Question 36

What happens when mast cells are activated

Answer 36

Results in degranulation, release of pre-formed substances, and activation of arachidonic acid metabolism to produce a range of freshly made mediators.

Question 37

What may the granules contain, and what functions doe they perform

Answer 37

Mast cell enzymes (proteolytic enzymes, tryptase and chymotrypsin)- activates components of the complement and kinin pathways- promoting inflammation Histamine- promotes smooth muscle contraction in the gut, lungs and blood vessels- increasing vascular permeability. Cytokines. TNF- activates endothelium to enhance diapedesis IL-4- activates Th-2 IL-3,-5 Stimulates eosinophil production and activation. Arachidonic acid metabolites cyclooxygenase pathway- produces prostaglandins and thromboxane- vasodilation, vascular permeability and constriction of smooth muscle in the gut and bronchi. Lipoxygenase pathway produces leukotrienes (vasodilation, increased vascular permeability, bronchial smooth muscle contraction) and platelet activating factors (chemotactic and activating for eosinophils and neutrophils)

Question 38

Describe NK cells

Answer 38

large granulated lymphocytes: cytotoxic, lyse target cells and secrete the cytokine interferon- 5-10% peripheral blood lymphocytes no antigen-specific receptor, but express both activating and inhibitory receptors: balance of signals have receptors which bind to antibody-coated cells (Antibody Dependent Cell-mediated Cytotoxicity) important in defence against tumour cells and viral infections (esp. herpes)

Question 39

What are the roles of NK cells

Answer 39

Kill virally infected cells | Like macrophages, they can also stimulate the adaptive immune system.

Question 40

What does natural mean in the context of natural killer cells

Answer 40

It means that the cells are capable of recognising and interacting with a target without any priming or previous sensitization.

Question 41

Where do NK cells develop and acquire their receptors

Answer 41

Bone marrow.

Question 42

Describe NK target cell recognition

Answer 42

``` Ligation of inhibitory NK receptors (KIRs) with MHC class 1 inhibits target cell killing- target cell left alone. However in missing cell- under expression of MHC class 1 (seen in some cancer cells)- loss of inhibitory signal- lysis of target cell. Stress induces change in MHC class 1 molecules- recognised by activating receptors (a special Fc receptor) on NK cells, more activation- triggers killing of infected cell. The balance between the stimulatory and inhibitory signals determines the outcomes of NK cell activation; preferentially they kill cells with absent MHC 1 expression. ```