Chapter 2
Innate Immunity: The First
Lines of Defense
Copyright © 2022 W. W. Norton & Company, Inc.
Infectious phases
2
Variety of pathogens can cause disease
Immune compromised
3
Pathogens in different parts of the body
4
Damage of tissues by pathogens
5
Damage of tissues by pathogens
vasculitis
Rheumatoid arthritis
glomerulonephritis
6
Infectious stages
7
The adhesion of pathogens to host cells
8
Preformed barriers
9
Skin
• Protects from micro-organisms entering the body
• Open cuts/ sores provide entrance
• Cells die and are shed
10
Mucous Saliva and tears
• Moist linings around all
entrances to body
• Covered with mucous
• Mucous = sticky substance
• Mucous traps pathogens
• Mucous is released from body
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Secretion
12
Cilia
• Tiny hair-like structures
• Trap pathogens
• Help remove mucous
13
Digestive Tract
• Moves pathogens out of body
• Acids/ chemicals in digestive tract
• Stomach/ intestines/ bladder
• Chemicals kill pathogens
• Epithelial cells secrete antimicrobial
peptides (for example defensins)
14
Microbiota
15
Antimicrobial proteins
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Defensins
18-45 amino acids in length
Found in plants and animals
Function by binding to the microbial
Cell membrane forming pore like
Membrane defects
17
Antimicrobial proteins are activated by proteolysis
Primarily in neutrophils, NK cells, certain T-lymphocyte
and DEFA5 and DEFA6 are expressed in Paneth cells.
(primary granules – phagosomes or secreted (paneth cells))
Widely distributed, secreted
by leukocytes and epithelial cells of many kinds
(tongue, skin, cornea, salivary glands, kidneys,
esophagus, and respiratory tract) (secreted)
Found in neutrophils and many other cells
including epithelial cells and macrophages after
activation by bacteria, viruses, fungi. (secondary
granules – phagosomes or secreted)
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Epithelia produce antimicrobial proteins
Keratinocytes produce defensins and cathelicidins
Pneumocytes produce defensins
Paneth cells produce many kinds of antimicrobial defensins
20 lumen
Not very effective at normal pH but becomes active at lower pH in sweet, tears and intestinal
21
The Complement System
The most well described innate immune systems humorale components
22
The Complement Components
- More than 30 soluble and cell-bound proteins
- Participate in both innate and adaptive immunity
- Produced by hepatocytes (mainly), monocytes and
epithelial cells of the gastrointestinal and genitourinary
tracts
- Constitute 5% (by weight) of the serum globulin
fraction
- Many components are proenzymes (zymogens), which
are functionally inactive until proteolytic cleavage,
which removes an inhibitory fragment and exposes the
active site.
- Reaction starts with an enzyme cascade.
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The Functions of Complement
1. Lysis of cells, bacteria, and viruses – the major effector
of the humoral branch of the immune system
2. Opsonization, which promotes phagocytosis of
particulate Ags
3. Binding to specific complement receptors on cells of
the immune system, triggering specific cell functions,
inflammation, and secretion of immunoregulatory
molecules
4. Immune clearance, which removes immune complexes
from the circulation and deposits them in the spleen
and liver
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Complement Activation
1. Classical Pathway – begins with the formation of Ag-Ab
complex
2. Alternative Pathway – is initiated by cell-surface
constituents that are foreign to
the host
– Ab-independent
3. Lectin Pathway – is activated by the binding of mannose-
binding lectin (MBL) to mannose
residues on glycoproteins or
carbohydrates on the surface of
microorganisms
– Ab-independent
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28
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Classical pathway
Cr cleaves Cs, active protease
Bacteria
C-reactive protein (binds pneumococcal C polysac)
Main: Binds Fc regions (IgM natural antibodies)
30
The alternative pathway is an amplification loop for C3b formation
that is accelerated by properdin in the presence of pathogens
Opsonization by Ab and complement
34
Protection of host cells
CR1 and DAF inhibits C3 convertase formation
(competes with Factor Bb)
Factor H binds on vertebrate cells (sialic acid)
Factor I cleave C3b to iC3b
35
C5 Convertase
36
Formation of C5b6789,
Membrane-attack Complex
C5b attaches to C6, then to C7, and the
C5b67 complex inserts into the membrane.
↓
binding of C8 to membrane-bound C5b67
induces a 10 Å pore.
↓
binding and polymerization of C9, a perforin-
like molecule, to C5b678
↓
The completed membrane-attack complex
(MAC) has a tubular form and functional pore
size of 70 – 100 Å
37
Neisseria escape MAC formation
Recruits factor H
38
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40
41
Formation of Membrane-attack Complexes
(MAC) on the cell surface
Poly-C9 complex Complement-induced lesions
formed in vitro on the membrane of a RBC
42
43
Lysis of an E. coli by Complement
44
45
Some complement deficiencies
Properdin deficiency
- X-linked
- common
- meningococcal disease
- High fatality rate (75% versus 3%)
C3 deficiency
- opsonization dysfunction
- deficient leukocyte chemotaxis
- decreased bactericidal killing
- decreased formation of MAC
- clinically, patients with overwhelming infections
from encapsulated bacteria.
- inadequate clearance of circulating immune
complexes,
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