The innate immune
response
Innate and Adaptive Immunity
Characteristics
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Vertebrates and invertebrates
First line of defense
Rapid
Non-specific recognition of molecular
patterns
• Induces the adaptive response
Infection
Inflammation
Immunity
Innate immune
system
Functions of the (innate) immune
system
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Barriers:
Recognition:
Remove and destroy:
Distinguish self and non-self:
Memory?
Functions of the innate immune
system
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Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells
Barriers to microbial invasion
Figure 2-4
Microbiota
Respiratory tract
Skin
Mucociliary escalator
Infection can occur when
mechanical barriers fail
• Skin wound
• Pneumonia
– Cystic fibrosis
– Primary ciliary dyskinesia (immotile cilia)
– Snakes
• Urinary tract infection
– Obstruction
– Failure of peristalsis
Antimicrobial peptides
• Defensins and others
• Produced by epithelial cells
• Broad specificity:
Epithelial surfaces
– Bacteria
– Fungi
– Viruses
• Actions:
– Direct killing
– Modulation of microbiota
Microbiota
• The communities of microorganisms
on normal mucosal surfaces
• Bacteria, fungi, viruses, protozoa
• Mechanisms of protection:
– Competition
– Antibacterial products
– Stimulation of host defenses
Functions of the innate immune
system
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Barriers: Physical, chemical, microbial
Recognition: PAMPs, other receptors
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells
Toll: A drosophila gene
• Discovered in 1985: embryology of drosophila
• 1996: Required for innate immunity
Lemaitre, et al, Cell 86:973-983 (1996)
• 1997: Toll-like genes in mammals
Recognizing pathogens: PathogenAssociated Molecular Patterns (PAMPs)
• Characteristic molecules expressed by
classes of microorganisms:
– Bacteria: Cell wall and cell membrane
components, capsules
– Viruses: DNA, RNA, coat proteins
– Fungi, parasites: Surface molecules
– Microbe-associated (MAMPs)
• Pathogen response receptors (PRRs)
Toll-like receptors
Ligand
Recognition
domain
Signaling
domain
}
Receptor
Signal transduction
Gene expression
Other Pathogen Response Receptors
The inflammasome
IL-1
Endogenous pyrogen
Pathogen?
Helpful microbe?
Non-pathogen?
Damaged host cell?
Some of each?
Danger signals: DAMPs and
PAMPs
• Damage-associated molecular patterns
(DAMPs)
• Molecules released by damaged cells
– Extracellular/extranuclear DNA
– ATP
– Lysosomal contents
– Etc.
• Recognize damaged host cells
• Distinguish pathogens from nonpathogens
Classes of PAMP and DAMP receptors
receptors
• NOD = Nucleotide-binding oligomerization
domain: activation site
– NOD-like receptors, NLR
– Intracellular/intracytoplasmic PRRs
• RIG-like receptors (retinoid acid-inducible gene):
– RLR
– Cytosolic DNA and dsRNA
– PAMP, DAMP receptor
• RAGE:
– Receptor for Advanced Glycosylation End-Produces
– DAMP receptor
Tang D, et al Immunological Reviews. 2012;249(1):158-175.
Functions of the innate immune
system
•
•
•
•
Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy: Phagocytes
Distinguish self and non-self: NK cells
Phagocyte functions
• Phagocytes: Neutrophils, Macrophages,
Dendritic cells
– Recognition, removal and killing of
pathogens
– Release of necrotizing enzymes
– Cytokine and chemokine secretion
• Induction of an adaptive response
Consequences of pattern recognition
by phagocytes
• Binding, internalization and degradation
(killing)
• Release of toxic products/tissue destruction
• Cytokine production
• Inflammation
• Activation of adaptive immunity
Lysosomal degradation
• Kill microbes
• “Collateral damage”
Collateral damage: Frustrated phagocytosis
Frustrated
Normal
Reactive Oxygen
Species (ROS)
• Enzymes:
– Phagocyte oxidase
– Nitric oxide synthetase (iNOS)
– Myeloperoxidase
• Products:
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Superoxide
Hydrogen peroxide
Nitric oxide
Halides
• Respiratory burst
Myeloperoxidase
Gross photo alert!
Phagocyte toxic products: Microbe
killing and tissue destruction
Functions of the innate immune
system
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Barriers: Physical, chemical, microbial
Recognition: PAMPs
Remove and destroy:Phagocytes
Distinguish self and non-self: NK cells
Natural killer (NK) cells: selfrecognition
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“Innate lymphoid cells”
Kill cells on contact
Pre-programmed
Recognize self by the presence of the Major
Histocompatability Complex (MHC)
– Self MHC present: no activation
– Self MHC absent or abnormal: activation and
killing
Natural Killer Cells: recognition of self
Foreign cell
Virus infected cell
Major Histocompatibility Molecules
• Principal determinants of self-recognition
• Surface-expressed
• Functions:
– Compatibility of transplanted tissues:
Histocompatibility
– Recognition by Natural Killer cells
– Antigen presentation to T cells
• Two classes:
– MHCI: present on all nucleated cells:
recognition of self
– MHCII: Present on antigen presenting cells
When is self-MHC absent or
abnormal?
• Non-self MHC (example?)
• Abnormal self-MHC (examples?)
Killing by NK cells
• Kill by contact: “Kiss of death”
• Pore formation
• Induce apoptosis
– Toxic granules secreted directly into target cells
– Cytokine production
IFNg
TNFa
Complement
• 20+ plasma proteins and cleavage
products
• Proteolytic cascade(s)
• Designated by C#
• Innate and adaptive immunity
Complement: History
• 1890-1900
• Bactericidal serum factors
– Heat-labile: Non-specific, bactericidal
– Heat-stable: micro-organism specific
• Heat-labile factor is necessary for
(“complements”) activity of the heat stable
factor
• Heat-stable = antibodies
• Heat-labile = complement
What is complement?
• Multiple proteins
• An enzyme cascade
• Many functions:
– Entire cascade: Direct killing
– Components:
• Activation of phagocytes
• Chemotaxis
• Different components have different
functions
The complement cascade
Adaptive
C3 lysis
Innate
Actions of complement
Innate
Adaptive
Opsonization = the process of coating particles to make them recognizable by
phagocytes
Membrane attack complex
Overview of innate immunity
• Physical and chemical barriers
• Phagocytosis:
– Bacterial killing
• Lysosomal enzymes
• Toxic oxygen radicals
– Cytokine and chemokine secretion
– Antigen presentation
Adaptive immunity
• Complement activation:
– Chemotaxis
– Membrane attack complex
– Opsonization
Adaptive immunity