PHYSIOLOGY 344
IMMUNOLOGY READINGS + SELF-STUDY
,READING 1: CME INNATE IMMUNITY
Innate immune mechanisms confer essential first-line host defence against the unrelenting
threat posed by environmental microbial and viral pathogens.
Mechanical barriers presented by the skin and mucus membranes, together with anti-
infective chemicals and enzymes on their surfaces, inhibit potential pathogens from
accessing the epithelium and underlying tissues. If these are undermined, invasive
pathogens will be recognized by various receptors on epithelial cells and cells of the
innate immune system such as macrophages. This results in a localized inflammatory
response, characterized by an early influx of neutrophils.
The two divisions of the immune system do not function in isolation, but rather cooperate
to provide optimum host defence. Epithelial cells, endothelial cells, and to a lesser extent
structural cells such as fibroblasts and smooth-muscle cells, are involved in promoting both
innate and adaptive immune responses.
Epithelial cells produce pro-inflammatory chemokines and cytokines, while endothelial
cells orchestrate leukocyte trans endothelial migration at sites of infection.
Epithelial recognition receptors are involved in triggering protective inflammatory
responses. The epithelium functions as both a barrier and hostile environment.
The Epithelium as a Barrier
The physical barriers presented by epithelial surfaces (skin, upper and lower respiratory
tract, gastrointestinal tract, conjunctiva) represent a resilient first-line barrier to most
infectious agents, which is complemented by several additional mechanisms including:
• The expulsive effects of the mucociliary escalator in the airways
• The flushing effects of saliva, tears and urine on epithelial surfaces
• Peristalsis in the GIT, as well as the low pH of gastric fluid, antagonism by normal gut
flora, and the antimicrobial actions of bile acids.
Anti-Infective Mechanisms of the Epithelial Lining Fluid
Epithelial lining fluids contain high concentrations of the anti-infective proteins and anti-
infective peptides.
Lysozyme is a ubiquitous enzyme present in tears, saliva, mucus, gastric juice and human
milk. It is produced by various types of cell including granulocyte precursors in the bone
marrow, monocytes/macrophages, various exocrine glands, cartilage, and Paneth cells
of the GIT. It selectively targets the cell wall of gram-positive bacteria, hydrolysing the 1,4-
beta linkage between N-acetylmuramic acid and N-acetyl-D-glucosamine.
Secretory phospholipase A2 is also present in tears and saliva and preferentially targets
gram-positive bacteria.
SP-A and SP-D are present in pulmonary epithelial lining fluid; they are produced by type II
pneumocytes and Clara cells and belong to the pattern recognition receptor family of C-
, type lectins, which bind to surface carbohydrates on microbial pathogens and promote
their phagocytosis by alveolar macrophages.
The Physical Barriers Presented by Epithelial Surfaces (skin, upper and lower respiratory
tract, gastrointestinal tract, conjunctiva) Represent a Resilient First-Line Barrier to Most
Infectious Agents
Epithelial surfaces also contain high concentrations of broad-spectrum, cationic,
antimicrobial, and antiviral peptides which belong to the histatin, cathelicidin, and
defensin families. In the case of antimicrobial activity, these anti-infective
peptides/proteins appear to share a common mechanism of action, targeting the outer
membrane, resulting in membrane disruption and dysfunction.
Histatins 1, 3 and 5 are present in the saliva of humans, being secreted by the parotid and
sub-mandibular salivary glands. They are preferentially active against fungi, with more
limited antibacterial activity.
Cathelicidins target bacteria, fungi, yeasts, and viruses. The human cathelicidin, LL-37, is
produced constitutively by the epithelia of the respiratory, gastrointestinal, and
reproductive tracts, as well as by immature neutrophils, monocytes, mast cells,
lymphocytes, eccrine and salivary glands.
‘Defensin’ is the collective term for a large family of anti-infective peptides which possess
broad-spectrum anti-infective properties encompassing gram-positive and gram-
negative bacteria, fungi and yeasts, as well as many enveloped and non-enveloped
viruses. The defensins consist of two major sub-families known as the alpha-defensins and
beta-defensins.
These differ according to structure, amino acid composition and cellular origin, while the
individual members of each sub-family vary with respect to size (18 - 45 amino acids) and
target pathogens.
Pattern Recognition Receptors (PRRs)
These receptors are found on/in the cells of the innate and adaptive immune systems and
are also expressed by epithelial and endothelial cells. They recognise and bind to
molecular structures which are common to pathogenic microorganisms and viruses, but
which are not found on human cells. Other well characterised families of PRRs in humans
are the Toll-like receptors (TLRs), the nucleotide oligomerisation domain-like receptors
(NLRs), and the abundant cytosolic microbial and viral DNA sensors.
The pro-inflammatory cytokines/chemokines and histamine and the vasoactive peptide,
bradykinin, initiate a local inflammatory response characterised by the early influx of
neutrophils
Toll-like Receptors (TLRs)
TLRs are located on the plasma membrane of cells of the innate immune system and
epithelial cells and recognise a range of pathogen-associated molecular patterns found
on the cell-wall of bacteria. Some TLRs are located in endosomes in the cytoplasm, where
they interact with viral dsRNA, ssRNA and viral and bacterial DNA. The interaction of TLRs
IMMUNOLOGY READINGS + SELF-STUDY
,READING 1: CME INNATE IMMUNITY
Innate immune mechanisms confer essential first-line host defence against the unrelenting
threat posed by environmental microbial and viral pathogens.
Mechanical barriers presented by the skin and mucus membranes, together with anti-
infective chemicals and enzymes on their surfaces, inhibit potential pathogens from
accessing the epithelium and underlying tissues. If these are undermined, invasive
pathogens will be recognized by various receptors on epithelial cells and cells of the
innate immune system such as macrophages. This results in a localized inflammatory
response, characterized by an early influx of neutrophils.
The two divisions of the immune system do not function in isolation, but rather cooperate
to provide optimum host defence. Epithelial cells, endothelial cells, and to a lesser extent
structural cells such as fibroblasts and smooth-muscle cells, are involved in promoting both
innate and adaptive immune responses.
Epithelial cells produce pro-inflammatory chemokines and cytokines, while endothelial
cells orchestrate leukocyte trans endothelial migration at sites of infection.
Epithelial recognition receptors are involved in triggering protective inflammatory
responses. The epithelium functions as both a barrier and hostile environment.
The Epithelium as a Barrier
The physical barriers presented by epithelial surfaces (skin, upper and lower respiratory
tract, gastrointestinal tract, conjunctiva) represent a resilient first-line barrier to most
infectious agents, which is complemented by several additional mechanisms including:
• The expulsive effects of the mucociliary escalator in the airways
• The flushing effects of saliva, tears and urine on epithelial surfaces
• Peristalsis in the GIT, as well as the low pH of gastric fluid, antagonism by normal gut
flora, and the antimicrobial actions of bile acids.
Anti-Infective Mechanisms of the Epithelial Lining Fluid
Epithelial lining fluids contain high concentrations of the anti-infective proteins and anti-
infective peptides.
Lysozyme is a ubiquitous enzyme present in tears, saliva, mucus, gastric juice and human
milk. It is produced by various types of cell including granulocyte precursors in the bone
marrow, monocytes/macrophages, various exocrine glands, cartilage, and Paneth cells
of the GIT. It selectively targets the cell wall of gram-positive bacteria, hydrolysing the 1,4-
beta linkage between N-acetylmuramic acid and N-acetyl-D-glucosamine.
Secretory phospholipase A2 is also present in tears and saliva and preferentially targets
gram-positive bacteria.
SP-A and SP-D are present in pulmonary epithelial lining fluid; they are produced by type II
pneumocytes and Clara cells and belong to the pattern recognition receptor family of C-
, type lectins, which bind to surface carbohydrates on microbial pathogens and promote
their phagocytosis by alveolar macrophages.
The Physical Barriers Presented by Epithelial Surfaces (skin, upper and lower respiratory
tract, gastrointestinal tract, conjunctiva) Represent a Resilient First-Line Barrier to Most
Infectious Agents
Epithelial surfaces also contain high concentrations of broad-spectrum, cationic,
antimicrobial, and antiviral peptides which belong to the histatin, cathelicidin, and
defensin families. In the case of antimicrobial activity, these anti-infective
peptides/proteins appear to share a common mechanism of action, targeting the outer
membrane, resulting in membrane disruption and dysfunction.
Histatins 1, 3 and 5 are present in the saliva of humans, being secreted by the parotid and
sub-mandibular salivary glands. They are preferentially active against fungi, with more
limited antibacterial activity.
Cathelicidins target bacteria, fungi, yeasts, and viruses. The human cathelicidin, LL-37, is
produced constitutively by the epithelia of the respiratory, gastrointestinal, and
reproductive tracts, as well as by immature neutrophils, monocytes, mast cells,
lymphocytes, eccrine and salivary glands.
‘Defensin’ is the collective term for a large family of anti-infective peptides which possess
broad-spectrum anti-infective properties encompassing gram-positive and gram-
negative bacteria, fungi and yeasts, as well as many enveloped and non-enveloped
viruses. The defensins consist of two major sub-families known as the alpha-defensins and
beta-defensins.
These differ according to structure, amino acid composition and cellular origin, while the
individual members of each sub-family vary with respect to size (18 - 45 amino acids) and
target pathogens.
Pattern Recognition Receptors (PRRs)
These receptors are found on/in the cells of the innate and adaptive immune systems and
are also expressed by epithelial and endothelial cells. They recognise and bind to
molecular structures which are common to pathogenic microorganisms and viruses, but
which are not found on human cells. Other well characterised families of PRRs in humans
are the Toll-like receptors (TLRs), the nucleotide oligomerisation domain-like receptors
(NLRs), and the abundant cytosolic microbial and viral DNA sensors.
The pro-inflammatory cytokines/chemokines and histamine and the vasoactive peptide,
bradykinin, initiate a local inflammatory response characterised by the early influx of
neutrophils
Toll-like Receptors (TLRs)
TLRs are located on the plasma membrane of cells of the innate immune system and
epithelial cells and recognise a range of pathogen-associated molecular patterns found
on the cell-wall of bacteria. Some TLRs are located in endosomes in the cytoplasm, where
they interact with viral dsRNA, ssRNA and viral and bacterial DNA. The interaction of TLRs
