Module 1: innate immunity
Innate and adaptive immune system
The immune system can be split into two functional arms
The innate immune system
o Limited specificity
o Action within hours of antigen appearance
o Fights potential pathogens without the requirement for a specific directed response
The adaptive immune system
o Requires time
o Specific and directed response against pathogen
o Epitope specific naïve B or T lymphocytes have to be activated and start proliferating
The innate and adaptive immune response should not be considered completely separate
First barrier:
Physical barrier: skin, mucus, cilia in respiratory and gastrointestinal tracts
Chemical barrier: gastric acid and lysozyme on skin
Biological barrier: commensal bacteria compete for nutrients, space and secrete growth
inhibiting compounds
Second line of defence:
Cellular and humoral components:
o Activation depends on the recognition of conserved pathogenic structures called
pathogen associated molecular patterns (PAMPs)
Recognition of PAMPs is mediated by receptors on immune cells called
pattern recognition receptors (PRRs)
Including:
o Toll-like receptors (TLRs)
o C-type lectin receptors (CLRs)
Cells of the innate system
Monocytes: antigen presenting cells that take up pathogens by a process called phagocytosis
and produce cytokines when foreign compounds are encountered
o Macrophages
o Dendritic cells
Polymorphonuclear granulocytes
o Neutrophils
Most abundant
Function by phagocytosis and intracellular killing of microbes or by the
release of antimicrobial factors and Neutrophil Extracellular Traps (NETs)
NETs consist of DNA strands that capture extracellular bacteria and
prevent them from spreading
o Eosinophils
function in phagocytosis but are primarily involved in extracellular killing of
large microbes such as worm parasites (helminths) and fungi, usually in
collaboration with IgE antibodies
o Basophils
promote inflammation through the release of histamine that acts as a
vasodilator and causes the chemotaxis of effector cells
Mast cells are similar but reside in tissue
Third category is related to lymphocytes
1
, o innate lymphoid cells (ILCs)
plays an important role in protective immunity and regulation of immune
homeostasis
o natural killer (NK) cells
function by recognizing infected or stressed cells (like tumours). In stressed
cells certain molecules are upregulated and can bind to activating receptors
on the NK cells and will be killed by release of cytotoxic granules
In tumour cells the MHC-I complex is downregulated. MHC-I normally bind to
an inhibitory receptor (Ly49) on NK cell. Failure of binding to the inhibitory
receptor leads to killing of the infected cell
Deficiencies:
o classical NK cell deficiency (CNKD)
quantitative
low NK cell numbers
o functional NK cell deficiency (FNKD)
qualitative
numbers of NK cells are normal
their activity is impaired
o both ILCs and NK cells are defined by the lack of an antigen-specific B or T cell
receptor
humoral components
the humoral or soluble components of the innate system also function in the early defence against
pathogens upon PAMP recognition. Includes:
acute phase proteins (C-reative protein (CRP) and mannose binding lectin (MBL))
complement
cytokines
Acute phase proteins and complement function by opsonizing (i.e. binding to) invading microbes. The
opsonin (i.e. the humoral component bound to the microbe) is recognized by specific receptors on
the surface of phagocytic cells.
With the activation of complements factors are generated that promote recruitment of phagocytic
cells
CRP and MBL are induced by pro-inflammatory cytokines such as TNF-α, IL-1 and IL-6
CRP is produced by the liver and is observed in systemic circulation after infection or damage
to tissues.
Important cytokines
type I interferons
IFNα and -β, which are produced by infected cells.
o IFNs inhibit viral protein synthesis, degrade viral mRNA thus inhibiting viral gene
expression and assembly.
These cytokines also increase MHC-I expression enabling cell lysis by cytotoxic T cells
Complement function
Complement system: consists out of a large number of specialized plasma proteins that react with
each other so that pathogen are opsonized and inflammatory responses are induced to recruit
immune cells and molecules to the site of infection
Functions:
o Direct lysis of microbes
2
Innate and adaptive immune system
The immune system can be split into two functional arms
The innate immune system
o Limited specificity
o Action within hours of antigen appearance
o Fights potential pathogens without the requirement for a specific directed response
The adaptive immune system
o Requires time
o Specific and directed response against pathogen
o Epitope specific naïve B or T lymphocytes have to be activated and start proliferating
The innate and adaptive immune response should not be considered completely separate
First barrier:
Physical barrier: skin, mucus, cilia in respiratory and gastrointestinal tracts
Chemical barrier: gastric acid and lysozyme on skin
Biological barrier: commensal bacteria compete for nutrients, space and secrete growth
inhibiting compounds
Second line of defence:
Cellular and humoral components:
o Activation depends on the recognition of conserved pathogenic structures called
pathogen associated molecular patterns (PAMPs)
Recognition of PAMPs is mediated by receptors on immune cells called
pattern recognition receptors (PRRs)
Including:
o Toll-like receptors (TLRs)
o C-type lectin receptors (CLRs)
Cells of the innate system
Monocytes: antigen presenting cells that take up pathogens by a process called phagocytosis
and produce cytokines when foreign compounds are encountered
o Macrophages
o Dendritic cells
Polymorphonuclear granulocytes
o Neutrophils
Most abundant
Function by phagocytosis and intracellular killing of microbes or by the
release of antimicrobial factors and Neutrophil Extracellular Traps (NETs)
NETs consist of DNA strands that capture extracellular bacteria and
prevent them from spreading
o Eosinophils
function in phagocytosis but are primarily involved in extracellular killing of
large microbes such as worm parasites (helminths) and fungi, usually in
collaboration with IgE antibodies
o Basophils
promote inflammation through the release of histamine that acts as a
vasodilator and causes the chemotaxis of effector cells
Mast cells are similar but reside in tissue
Third category is related to lymphocytes
1
, o innate lymphoid cells (ILCs)
plays an important role in protective immunity and regulation of immune
homeostasis
o natural killer (NK) cells
function by recognizing infected or stressed cells (like tumours). In stressed
cells certain molecules are upregulated and can bind to activating receptors
on the NK cells and will be killed by release of cytotoxic granules
In tumour cells the MHC-I complex is downregulated. MHC-I normally bind to
an inhibitory receptor (Ly49) on NK cell. Failure of binding to the inhibitory
receptor leads to killing of the infected cell
Deficiencies:
o classical NK cell deficiency (CNKD)
quantitative
low NK cell numbers
o functional NK cell deficiency (FNKD)
qualitative
numbers of NK cells are normal
their activity is impaired
o both ILCs and NK cells are defined by the lack of an antigen-specific B or T cell
receptor
humoral components
the humoral or soluble components of the innate system also function in the early defence against
pathogens upon PAMP recognition. Includes:
acute phase proteins (C-reative protein (CRP) and mannose binding lectin (MBL))
complement
cytokines
Acute phase proteins and complement function by opsonizing (i.e. binding to) invading microbes. The
opsonin (i.e. the humoral component bound to the microbe) is recognized by specific receptors on
the surface of phagocytic cells.
With the activation of complements factors are generated that promote recruitment of phagocytic
cells
CRP and MBL are induced by pro-inflammatory cytokines such as TNF-α, IL-1 and IL-6
CRP is produced by the liver and is observed in systemic circulation after infection or damage
to tissues.
Important cytokines
type I interferons
IFNα and -β, which are produced by infected cells.
o IFNs inhibit viral protein synthesis, degrade viral mRNA thus inhibiting viral gene
expression and assembly.
These cytokines also increase MHC-I expression enabling cell lysis by cytotoxic T cells
Complement function
Complement system: consists out of a large number of specialized plasma proteins that react with
each other so that pathogen are opsonized and inflammatory responses are induced to recruit
immune cells and molecules to the site of infection
Functions:
o Direct lysis of microbes
2
