The Immune System – Peter Parham
Chapter 2: Innate Immunity: The Immediate Response to Infection
2.1 - Physical barriers colonized by commensal microorganisms protect against infection by
pathogens
The first barrier against infection by pathogens are the epithelial tissues of the skin and those inside
the body. Further protection is provided by the commensal microorganisms that colonize the skin
and the mucosal surfaces of healthy individuals. This population of commensal microorganisms will
start to grow after birth.
2.2 - Intracellular and extracellular pathogens require different types of immune response
The type of immune response depends on the type of infection that has taken place. Two types of
infections exist that pathogens can produce. Firstly extracellular infections are those where
pathogens live and replicate in the spaces between human cells, and secondly there are intracellular
infections where pathogens replicate inside human cells. Extracellular infections are accessible to the
soluble, secreted molecules of the immune system, where intracellular infections are not. In the case
of an intracellular infection the infected cells are killed.
2.3 - Complement is a system of plasma proteins that mark pathogens for destruction
When a pathogen a detected, the defence mechanisms of the innate immune system are activated.
One of the first weapons to fire is the complement system or just complement, which is a system of
soluble proteins found in the blood, lymph and extracellular fluids. Many complement components
are proteolytic enzymes, which circulate in an inactive form known as zymogens. Infection triggers
complement activation, which proceeds by a cascade in which each protease cleaves and activates
the next protease. In the complement system, complement component 3 (C3) is by far the most
important. This C3 is cleaved into a small C3a and a large C3b fragment when activation of the
complement system has taken place. The C3b fragment binds to the pathogen in a process called
complement fixation. This tags the pathogen for destruction by phagocytes and also organizes the
formation of protein complexes that damages the pathogen’s membrane. The C3a fragment acts to
recruit effector cells such as phagocytes to the site of infection. The unusual feature that underlies
the unique function of C3 is the thioester bond within the protein. When C3 is cleaved this thioester
bond is exposed and is now subject to nucleophilic attack by molecules on the surface of pathogens.
Three pathways of complement activation are defined. All three lead to C3 activation. The pathway
that works at the start of infection is the alternative pathway of complement activation. The second
pathway is the lectin pathway of complement activation, which is also part of innate immunity.
Thirdly there is the classical pathway of complement activation, which is part of innate and adaptive
immunity and requires the binding of either antibody or C-reactive protein to the pathogen’s surface.
2.4 - At the start of an infection, complement activation proceeds by the alternative pathway
The protein C3 is made in the liver and subsequently secreted into the blood. At a slow rate, without
being cleaved, the C3 protein spontaneously changes it’s conformation and exposes the thioester
bond. The thioester then binds a water molecule, as these are plentiful. This gives a form of C3 called
iC3 or C3(H2O). The environment near the surface of certain pathogens, particularly bacteria,
Chapter 2: Innate Immunity: The Immediate Response to Infection
2.1 - Physical barriers colonized by commensal microorganisms protect against infection by
pathogens
The first barrier against infection by pathogens are the epithelial tissues of the skin and those inside
the body. Further protection is provided by the commensal microorganisms that colonize the skin
and the mucosal surfaces of healthy individuals. This population of commensal microorganisms will
start to grow after birth.
2.2 - Intracellular and extracellular pathogens require different types of immune response
The type of immune response depends on the type of infection that has taken place. Two types of
infections exist that pathogens can produce. Firstly extracellular infections are those where
pathogens live and replicate in the spaces between human cells, and secondly there are intracellular
infections where pathogens replicate inside human cells. Extracellular infections are accessible to the
soluble, secreted molecules of the immune system, where intracellular infections are not. In the case
of an intracellular infection the infected cells are killed.
2.3 - Complement is a system of plasma proteins that mark pathogens for destruction
When a pathogen a detected, the defence mechanisms of the innate immune system are activated.
One of the first weapons to fire is the complement system or just complement, which is a system of
soluble proteins found in the blood, lymph and extracellular fluids. Many complement components
are proteolytic enzymes, which circulate in an inactive form known as zymogens. Infection triggers
complement activation, which proceeds by a cascade in which each protease cleaves and activates
the next protease. In the complement system, complement component 3 (C3) is by far the most
important. This C3 is cleaved into a small C3a and a large C3b fragment when activation of the
complement system has taken place. The C3b fragment binds to the pathogen in a process called
complement fixation. This tags the pathogen for destruction by phagocytes and also organizes the
formation of protein complexes that damages the pathogen’s membrane. The C3a fragment acts to
recruit effector cells such as phagocytes to the site of infection. The unusual feature that underlies
the unique function of C3 is the thioester bond within the protein. When C3 is cleaved this thioester
bond is exposed and is now subject to nucleophilic attack by molecules on the surface of pathogens.
Three pathways of complement activation are defined. All three lead to C3 activation. The pathway
that works at the start of infection is the alternative pathway of complement activation. The second
pathway is the lectin pathway of complement activation, which is also part of innate immunity.
Thirdly there is the classical pathway of complement activation, which is part of innate and adaptive
immunity and requires the binding of either antibody or C-reactive protein to the pathogen’s surface.
2.4 - At the start of an infection, complement activation proceeds by the alternative pathway
The protein C3 is made in the liver and subsequently secreted into the blood. At a slow rate, without
being cleaved, the C3 protein spontaneously changes it’s conformation and exposes the thioester
bond. The thioester then binds a water molecule, as these are plentiful. This gives a form of C3 called
iC3 or C3(H2O). The environment near the surface of certain pathogens, particularly bacteria,
