Innate Immune System

Question 1

How can the immune system be divided?

Answer 1

Into innate immune system and adaptive/acquired immune system

Question 2

What happens when we are exposed to a pathogen?

Answer 2

An infectious agent first encounter the elements of the innate immune system. These may be sufficient to prevent disease but if not, disease may result. The adaptive immune system is then activated to produce recovery and a specific immunologic memory. Following re-infection with the same agent, no disease results and the individual has acquired immunity to the infectious agent

Question 3

What are the soluble factors of the innate immune system?

Answer 3

Lysozyme, complement, acute phase proteins, e.g., C-reactive protein

Question 4

What are the soluble factors of the adaptive immune system?

Answer 4

Antibodies

Question 5

What are the cells involved in innate immunity?

Answer 5

Phagocytes and NK cells

Question 6

What are the cells involved in acquired immunity?

Answer 6

T lymphocytes

Question 7

What are the major differences between the innate immune system and the adaptive immune system with regards to response to microbial infections?

Answer 7

The innate immune system is non-specific, has no memory, and resistance is not improved by repeated contact.
The adaptive immune system is specific, has memory and resistance is improved by repeated contact

Question 8

What are chemical and physical defences of the innate immune system?

Answer 8

Mucous (prevents the attachment of pathogens)
Cilia lining the trachea (brush-like structures that prevent attachment of pathogens)
Acid in the stomach (highly acidic environment kills pretty much every microbe that goes into our stomach; exception are spores
Skin (acts as a barrier)

Question 9

What are biochemical defences of the innate immune system?

Answer 9

Lysozyme in most tears, nasal secretions and saliva (breaks down the cell walls of bacterial pathogens)
Sebaceous gland secretions (they secrete fatty acids that have an anti-microbial activity)
Commensal organisms in the gut and vagina
Spermine in the semen

Question 10

What are the two main mechanisms of the innate immune system?

Answer 10

Limitation of entry

Limitation of growth

Question 11

How does the innate immune system limit entry?

Answer 11

Skin
Membranes
Normal flora

Question 12

How does skin limit entry?

Answer 12

It is normally impermeable to the majority of infectious agents
It’s a hostile environment to the majority of infectious agents (lactic acid and fatty acids in sweat and sebaceous secretions; lower pH)
The loss of skin (e.g., burns) can lead to serious infections

Question 13

How do membranes limit entry?

Answer 13

The line the inner surfaces of the body and secret mucous
The inhibit bacterial adherence and inhibit entry
Ciliary action removes microbes and other foreign particles
Flushing action of tears, saliva, urine protect epithelial surfaces and there is also the presence of antimicrobial compounds (gastric juice, spermine and zinc in the semen, lactoperoxidase in the milk, lysozyme in the nasal secretions, tears and saliva)

Question 14

How does normal flora limit entry?

Answer 14

Bacteria and fungi which are permanent residents of the body surfaces (skin and mucosal membranes) suppress the growth of pathogenic microbes (protective layer, competition for nutrients, production of inhibitory compounds such as acids and colicins)

Question 15

How does the innate immune system limit growth?

Answer 15

Phagocytosis

Soluble chemical factors (bactericidal enzymes)

Question 16

What are phagocytes?

Answer 16

Macrophages
Polymorphonuclear granulocytes (neutrophils, polymorphs)

Question 17

Describe the production of macrophages

Answer 17

Promonocytes (found in the bone marrow) become circulating blood monocytes, which then become mature macrophages in the tissues

Question 18

Where are macrophages found?

Answer 18

They are concentrated in the lymph, liver, lining of the lymph nodes
They are well placed to filter off foreign material

Question 19

What are polymorphs?

Answer 19

Dominant white cell in the bloodstream
They share common hemopoietic precursor
They have no mitochondria (they have glycogen reserves for energy)
They are non-dividing, short lived, segmented nucleus
They have a granular cytoplasm

Question 20

What are the steps of phagocytosis?

Answer 20

Attachment of pattern recognition receptors (PAMPs and PRPs)
Pseudopodia forming a phagosome
Granule fusion and killing (oxygen dependent and independent)
Release of microbial products

Question 21

What are PAMPs?

Answer 21

Pathogen-associated molecular patterns
They are found on microbes
Examples: LPS, proteins

Question 22

What are PRPs?

Answer 22

Pathogen-recognition receptors

They are found on phagocytes

Question 23

What are oxygen independent antimicrobial mechanisms?

Answer 23

Damaging the microbial membranes
Complexing with iron by lactoferrin
Splitting proteoglycan by lysozyme
Degradation of dead microbes by acid hydrolases

Question 24

What proteins are responsible for damaging microbial membranes in oxygen independent killing?

Answer 24

Cathepsin G and elastase
Low molecular weight defensins
High molecular weight cationic proteins
Bactericidal permeability-increasing protein

Question 25

What are the two oxygen-dependent antimicrobial mechanisms?

Answer 25

Reaction sequence generated by NADPH Oxidase (involves hexose monophosphate shunt, NADPH oxidase, spontaneous dismutation, myeloperoxidase, superoxide dismutase, catalase)
Nitric Oxide Reaction Sequence (involves NO synthase)

Question 26

What is the main cause of chemotaxis?

Answer 26

Formyl methyl peptides, which attract leucocytes. This is generally a weak signal because of the low concentration. The complement system helps by producing soluble proteins that coat pathogens. They are secreted in higher concentration so that our immune system can sense them better

Question 27

How does the complement system work?

Answer 27

In a cascade; the product of one reaction acts as an enzyme for the next reaction (important for precise control)

Question 28

How are complement proteins designated? Which one is the most abundant?

Answer 28

Complement proteins are designated by a “C” followed by a number. C3 is the most abundant and most central component of the complement system (a lack of C3 causes makes someone immunocompromised)

Question 29

What happens in normal plasma with regards to the complement system?

Answer 29

C3 undergoes spontaneous activation at a very slow rate to generate C3a and C3b. C3b complexes with factor B -> C3bB. Factor D acts on C3bB to create the C3-splitting enzyme C3bBb (aka C3 convertase). C3bBb splits more C3 into C3a and C3b.

Question 30

What happens in the presence of CHO or other bacterial surface molecules with regards to the complement system?

Answer 30

In the presence of CHO and other bacterial surface molecules, C3 convertase can become attached and stablized against breakdown. This leads to active generation of new C3 convertase molecules and what is known as the ‘alternative complement pathway’ can swing into full tempo

Question 31

What happens after the activation of the alternative complement pathway?

Answer 31

C3b covalently binds to microbial surface and acts as an opsonin (a marking system; it coats the bacterial cells and makes them more susceptible to engulfment by phagocytic cells)
C3b + C3 converts act on the next component, C5
C5 is split into C5a and C5b
C5a and C3a have a direct effect on mast cells to cause their degranulation.
C5b becomes membrane bound, joined by C6, C7, and C8, which, together, induce a conformation change in C9.
The unfolded C9 becomes inserted into the lipid layer of the membrane and form membrane attack complex (MAC), which causes cell lysis (transmembrane channel)

Question 32

What do C5a and C3a do?

Answer 32

C5a and C3a cause mast cell degranulation. This causes the release of chemicals that mediate:

1. Increased vascular/capillary permeability, which allows the flow of fluid and plasma components to the site of infection (acute inflammatory response)
2. Chemotactic attraction of polymorphs through blood vessel walls to C3b-coated bacteria

Question 33

What are other soluble factors of the innate immune system?

Answer 33

Acute phase proteins
Antimicrobial factors
Interferons
Natural Killer Cells (NK cells)
Eosinophils

Question 34

What do acute phase proteins do?

Answer 34

They are present in low concentration normally but increase in concentration in response to early ‘alarm’ mediators (IL-1, IL-6, TNF) released as a result of tissue injury
Includes: C-reactive protein, mannose binding protein (MBL).
They use PRPs to bind to PAMPs

Question 35

What do antimicrobial factors do?

Answer 35

They act within phagocytic cells but also in the body fluids.
E.g., lysozyme works in the tears and saliva
E.g., lactoferrin works in the blood

Question 36

What do interferons do?

Answer 36

They are secreted in response to viral infection by infected cells. They bind to specific receptors on nearby uninfected cells. IFN causes cells to produce two types of enzymes that interfere with virus replication

Question 37

What do NK cells do?

Answer 37

NK cells bind to receptors on virus-infected cells causing NK activation and release of granules (e.g., perforin inserts into host membranes forming pores)
They allow the entry of a second molecules, granzyme B, which leads to apoptosis

Question 38

What do eosinophils do?

Answer 38

They combat large parasites (e.g., helminths, which are too large to be engulfed by phagocytes)
They bind to C3b (via C3b surface receptors) which cause activation
Several toxic compounds are released that damage the membrane via hole formation