Barrier Immunity and Innate Recognition

Question 1

What are the 3 ways in which we prevent infection?

Answer 1

Barriers/intrinsic immune system
Innate immunity - recognises non-self non-specifically
Adaptive immunity - recognises non-self specificially

Question 2

Give examples of mechanical, chemical and microbiological barriers to infection

Answer 2

Mechanical
- epithelial cells joined by tight jucntions
- longitudinal flow of air or fluid
- movement of mucus by cilia
- tears, nasal cilia
Chemical
- fatty acids on skin
- antibacterial peptides on skin, gut, lungs
- low pH of gut
- lysozymes in tears
Microbiological
- normal flora of skin and gut

Question 3

Give examples of ways in which the skin can be compromised.

Answer 3

skin disease e.g. infantile eczema
Iv cannula
catheterising bladders
sun exposure
heat burn

Question 4

Mucosal vs systemic immunity

Answer 4

can interact but can be autonomously regulated
The mucosal surface is a major portal of entry for pathogens
The mucosal system contains the most lymphocytes

Question 5

1. The immune system has a ………….. function to prevent trouble developing
2. And a ……….. function to sort any problems out
3. What is meant by friendly fire?
4. To work you need the right cell …… in the right ………
5. Cells must …….. to the site of infection
6. and express the …… …….. to kill/restrict the pathogen
7. These functions require a combination of ………..-dependent mechanism and ……… factors

Answer 5

1. prophylactic
2. therapeutic
3. dealing with disease comes at a cost, can be devastating
4. type, number
5. travel
6. appropriate molecules
7. contact, soluble

Question 6

Give two examples of immune deficiency syndromes and their associated diseases

Answer 6

1. leukocyte adhesion deficiency = widespread pyogenic bacterial infections
2. chronic granulomatous disease = intracellular and extracellular infection, granulomas

Question 7

Name the 6 innate immune cells and describe their function/s

Answer 7

1. macrophages - phagocytosis and activation of bactericidal mechanisms, antigen presentation
2. neutrophils - phagocytosis and activation of bactericidal mechanisms
3. basophil - unknown
4. mast cell - release of granules containing histamine and active agents
5. eosinophils - killing of antibody-coated parasites
6. dendritic cell - antigen uptake in peripheral sites, antigen presentation

Question 8

The innate system recognises molecules that are non-self and reacts to these in a ‘noneducated’ manner.
How?

Answer 8

Macrophages express receptors for many microbial constituents:

• mannose receptors, LPS receptor (CD14), TLR-4. scavenger receptor, glucan receptor, TLR-2
• toll like receptors

Question 9

Toll like receptors can have extracellular o intracellular expression and mostly signed through……. and …….

Answer 9

MyD88 and NFkappaB

Question 10

What is PAMP and PRR? What do they do?

Answer 10

Some microbial molecules are recognised by innate immune cells.
PAMP = Pathogen Associated Molecule Pattern
PRR = Pattern Recognition Receptor
PRR located on immune cells, PAMP located on microbe
Attachment by PRR
Pseudopodia forming a phagosome
Granule fusion and killing
Release on micro products

Question 11

Activation of immune cells results in the secretion of cytokines which can have local and systemic effects

Answer 11

Il1beta, TNFalpha, IL-6, CXCL8, IL12
Activates vascular endothelium
Activates lymphocytes
Fever
Mobilisation

Question 12

Cytokines have systemic effects that act to mobilise the host and co-ordinate an effective response. What are the effects in the:

1. liver
2. bone marrow endothelium
3. hypothalamus
4. fat, muscle
5. dendritic cells

Answer 12

1. acute phase proteins –> activation of complement opsonization
2. neutrophil mobilisation –> phagocytosis
3. increased body temperature –> decreased viral and bacterial replication, increased antigen processing, increased specific immune response
4. protein and energy mobilisation to allow increased body temperature –> decreased viral and bacterial replication, increased antigen processing, increased specific immune response
5. TNFalpha stimulates migration to lymph nodes and maturation –> initiation of adaptive immune response

Question 13

An important role of for the immune system responses is to control infection by preventing bacterial spread through the body. What happens when this goes wrong

Answer 13

Sepsis –> systemic infection

Question 14

This is achieved by having an immune system that response quickly with “forts” of cells to prevent spread:
Give some examples

Answer 14

blood monocytes
liver Kupffer cells
kidney mesangial phagocytes
alveolar macrophages 
connective tissue histiocytes
splenic macrophages
lymph node resident and recirculating macrophages 
brain microglial cells

Question 15

How does exposure to an antigen induce inflammation?

Answer 15

sentinel cells like mast cells help regulate inflammation through PRR’s, binding of IgE and more.
Degranulation
Histmaine - increases blood flow and vascular permeability
products of arachidonic acid metabolism
prostaglandins and leukotrienes

Question 16

Describe how the liver plats an important role in generating acute phase proteins that have diagnostic potential .

Answer 16

1. bacteria induce macrophages to produce IL-6, which acts on hepatocytes to induce synthesis of acute-phase proteins
2. C-reactive protein binds phosphocholione on bacterial surfaces, acting as an opsonin, and also activating complement
3. Mannose-bidning lectin bins mannose residues on bacterial surfaces, acting as an opsonin, and also activating complement

Question 17

An exaggerated response can have dramatic consequences.

Describe anaphylaxis

Answer 17

• Local and moderate mast cell activation reduces the chance of foreign material entering the body by promoting inflammation
• Local excessive mast cell activation leads to symptoms e.g. IgE mediated allergic disease
• Systemic excessive mast cell activation leads to widespread blood vessel dilation, smooth muscle contraction in bronchi, vascular permeability, catastrophic drop in blood pressure.
  This is anaphylaxis and histamine mediated. Treat with adrenaline

Question 18

What are additional mechanisms help protect against viral infections

Answer 18

Virus infected host cell
IFNalpha, IFNbeta
Induce resistance to viral replication in all cells
Increase MHS class 1 expression and antigen presentation in all cells
Activate dendritic cels and macrophages
Active NK cells to kill virus-infected cells

Question 19

Describe acute vs chronic inflammation

Answer 19

Acute
- often protective by to remove the stimulus must be removed
- resolution involves the clearance of the threat, dead host cells, tissue regeneration and/or scarring
- part of the healing process
Chronic
- characterised by infiltrate of lymphocytes, monocytes, and plasma cells
- can evolve from acute inflammation but often arises de novo
- harmful and typified by rheumatoid arthritis and asthma
- often requires treatment - NSAIDs, anti-histamines, antiTNFalpha inhibitors - etanercept and infliximab

Question 20

Describe the importance of the complement cascade?

Answer 20

The complement system is a collection of soluble proteins in the blood
The components are generally made in the liver
They are prone to activation and so a network of inhibitor proteins exist to stop this
There are three ways to activate the system
They converge to share effector function
They play significant roles in protecting against bacterial infections
They also are important for ‘housekeeping’.

Question 21

The complement system is a cascade of proteins in the blood that help destroy extracellular bacteria. What three things does the cascade do?

Answer 21

recruitment of inflammatory cells - tells the cells where to go
opsonisation of pathogens - tell the cells who to eat
killing of pathogens - can kill the cells directly

Question 22

What is central to the function of the complement pathway?

Answer 22

• the generation of C3 convertase
• compartment activation can be regulated at different stages through soluble and host cell surface inhibitors
  loss of C3 results in increased risk of serious infection

Question 23

Cleavage of C3 and C5 to C3a and C5a attracts inflammatory cells

Answer 23

small complement cleavage products act on blood vessels to increase vascular permeability an cell-adhesion molecules
Increased permeablitliy allows increased fluid leakage from blood vessels and extravasation of immunoglobulin and complement molecules.
Migration of macrophages, polymorphonuclear leukocytes, and lymphocytes is increased. Microbicidal activity of macrophages and PMNs is also increased

Question 24

Labelling a bacterium with C3b plants a flag to identify the cell as one to be phagocytksed (needs other components of complement too)

Answer 24

Bacterium is coated with complement by the alternative and MBL pathways
When only C3b binds to CR1, bacteria are not phagocytosed
C5a can activate macrophages to phagocytose via CR1

Question 25

In addition to attracting more cells complement can form membrane attach complexes and lyse bacteria directly

Answer 25

membrane attack complex pore

death by osmotic lysis and ion loss

Question 26

pathogens have evolved multiple strategies to evade complement

Answer 26

Staphylococcal proteins that interfere with complement are shown in green