Lecture 8 - Innate immunity - the cells

Question 1

What is commensal symbiosis?

Answer 1

microbes benefit and host is unaffected

Question 2

What is parasitic symbiosis?

Answer 2

microbes benefit at the expense of the host

Question 3

What is mutualist symbiosis?

Answer 3

microbe and host benefit

Question 4

What is the innate response?

Answer 4

Innate (immediate/early) immune response:
Starts when a cell/organism encounters a microbe
Not (highly) specific
Fast – almost immediate
Resolves without creating a “memory” reservoir
Aiming to clear the pathogen/infected cells and to alert the adaptive arm of the immune response
millions of animal species rely solely on innate immunity to fight infections

Question 5

What does a cell do upon encountering a microbe?

Answer 5

Clear the microbe or inhibit its replication
(phagocytosis, the interferon system)

Process the microbe and present it to cells of the adaptive immune system
(antigen processing and presentation)

Alert and attract other cells that will help clear the infection
(up-regulation of surface receptors, cytokines, and chemokines)

Kill itself (apoptosis)

All cells have the potential to perform these activities
Some cells are specifically made and programmed and exceptionally good at doing the first three actions
These are called cells of the innate immune system

Question 6

What is inflammation?

Answer 6

A process occurring as a result of infection of damage (wounding) of a tissue aiming to clear the infection and/or repair tissue damage

Inflammation is a prerequisite for a successful immune response

The characteristics of inflammation - heat, redness, swelling, pain

Question 7

What are the three roles of inflammation in combating infection?

Answer 7

Delivery of effector cells and molecules to the site of infection to enhance microbe clearance

Blood clotting to form a physical barrier and prevent spreading of the infection to the blood stream

Enhancement of the tissue repair process

Question 8

What are the three changes in blood vessels during inflammation?

Answer 8

Increased vessel diameter to enhance the number of cells and molecules reaching the site of infection

Increased adhesion molecules that bind leukocytes

Increased vascular permeability, that allows exit of fluid and proteins into tissue leading to edema (swelling)

Question 9

What is extravasation?

Answer 9

The process of attachment of leukocytes to the endothelium followed by their migration through the blood vessels to the infected tissue

Question 10

What are neutrophils?

Answer 10

first at the scene
Form the polymorphonuclear cell family together with basophils and eosinophils

The most abundant (40% to 75%) type of white blood cells

Recruited to the site of infection or injury within minutes

They are the predominant cells in pus

Short lived, quick acting, motile

They kill pathogens through phagocytosis, degranulation, or neutrophil extracellular traps

Question 11

What is phagocytosis?

Answer 11

Occurring in phagocytes such as neutrophils, macrophages, etc

Targets are usually coated in opsonins (protein tags such as the antibody FcR that enhance phagocytosis)

Requires substantial membrane rearrangement

Phagocytosis: it takes five steps

1. Attachment/ adhesion and engulfment
2. Phagosome formation
3. Recruitment of lysosomes
4. Phagosome-lysosome fusion = phagolysosome
5. Microbe killing due to the high concentration of reactive oxygen species (superoxide, NO), defensins (antimicrobial peptides) and hydrolytic enzymes and low pH in the phagolysosome

Question 12

What is degranulation?

Answer 12

Release of azurophilic (primary) or specific (secondary) granules containing proteases, defensins, reactive oxygen species

Question 13

What are neutrophil extracellular traps?

Answer 13

Networks of extracellular fibers primarily composed of DNA and antimicrobial proteins such as histones and neutrophil elastase

They act by trapping bacteria and killing them through localised and high concentrations of antimicrobial proteins

Question 14

What are macrophages?

Answer 14

Belong to the myeloid lineage. A mature form of monocytes.

Macrophages reside in tissues (monocytes are in circulation)
Microglia: brain
Kuppfer Cells: liver
Osteoclasts: bone

Upon infection tissue-resident macrophages phagocytose microbes while circulating, monocytes are also recruited to the infected tissue and mature into macrophages

Question 15

How are macrophages activated?

Answer 15

Upon infection tissue-resident macrophages phagocytose microbes while circulating monocytes are also recruited to the infected tissue and mature into macrophages

They become activated through direct interaction with pathogens or through factors secreted by T helper lymphocytes (e.g. IFNg, IL4)

Question 16

How do macrophages function?

Answer 16

Highly phagocytic: they engulf and destroy pathogens

They secrete cytokines that orchestrate the inflammatory response

They can present antigens to T lymphocytes

They can contribute to tissue repair and formation of new blood vessels

Question 17

What are dendritic cells?

Answer 17

Myeloid and plasmacytoid (lymphoid) dendritic cells

They have long finger-like processes

Myeloid Immature dendritic cells migrate from the bloodstream to tissues or are tissue-resident

They are phagocytic (but in general not as much as macrophages)

Upon encountering antigens, dendritic cells become activated (mature)

Question 18

How do dendritic cells mature?

Answer 18

1. Become less phagocytic and endocytic
2. Proliferate
3. Process microbial proteins to small peptides that can be recognised by T lymphocytes (antigen presentation)
4. Up-regulate expression of surface proteins and cytokines that are required for optimal antigen presentation to T lymphocytes
5. Secrete type I interferons that inhibit pathogen replication, induce apoptosis of nearby infected cells, and enhance antigen presentation
6. Migrate to the nearest lymph node through the lymphatic system

Question 19

What are Plasmacytoid DCs (pDCs)?

Answer 19

A subset of DCs derived from the CLP that look like plasma cells*

Rare, less than 0.5% of PBMCs

Antigen sensing/recognition similar to myeloid DCs

Main function is not antigen presentation, but production of type I interferons (IFNa and IFNb)

Very important in antiviral responses

Question 20

What are Innate Lymphoid Cells (ILCs)?

Answer 20

A newly discovered family of lymphoid cells that translate signal cytokines into effector cytokines without expressing an antigen specific receptor

ILCs mirror the phenotypes and functions of T cells*

NK cells -> cytotoxic CD8+ T cells
ILC1 -> CD4+ T helper 1 (TH1) cells
ILC2 -> CD4+ T helper 2 (TH2) cells
ILC3 -> CD4+ T helper 17 (TH17) cells

No antigen receptors and no clonal selection upon stimulation

They do not respond directly to antigen

ILCs respond to signals from infected or injured tissues and produce cytokines

Question 21

What are natural killer cells?

Answer 21

Terminally differentiated cell of the lymphoid lineage

Larger than B and T lymphocytes, they are characterised by cytoplasmic granules containing cytotoxic proteins (granzyme and perforin). These can be secreted to kill infected cells
They also secrete IFNg and kill infected cells before cytotoxic T-lymphocytes

Question 22

How are natural killer cells activated?

Answer 22

They become activated in response to type I interferons (IFNa and IFNb) secreted by other innate cells (e.g. macrophages, dendritic cells) or other cytokines produced in an infected tissue (e.g. IL15)

Their cytotoxic activity is controlled through inhibitory and activating receptors on their cell membrane.

Clearance of “missing self” cells and Antibody-Dependent Cellular Cytotoxicity are the main functions of NK cells

Almost every cell in the body expresses MHC-I on its surface. This is how the immune system recognises our own cells (“self”)

Many pathogens down-regulate MHC-I expression in the infected cells (“non-self”) to avoid clearance by cytotoxic T lymphocytes

MHC-I down-regulation is also common in cancer cells

NK cells are programmed to kill any cell with no/low MHC-I expression (“missing or altered self”)

Question 23

Explain Natural killer cells and Antibody-Dependent Cellular Cytotoxicity

Answer 23

NK cells also carry receptors for the Fc region of antibodies.

Microbes or cells coated with antibodies can trigger NK cells to release their cytotoxic granules. This is called Antibody-Dependent Cellular Cytotoxicity (ADCC)